Jyoti Bajpai1, Ram Abhinav Kannan1, Hemant Malhotra2, Vivek Radhakrishnan3, Rakesh Jalali4, Gaurav Narula1, Amit Awasthi5, Girdhari Lal6, Rahul Purvar7, Kumar Prabhash1, Senthil Rajappa8, Atul Sharma9, Moni Kuriakose10, Vikram Matthews11, Reena Nair3, Smruti Koppikar12, Shubhda V Chiplunkar13, Shripad Banavali1
1Department of Medical Oncology, Tata Memorial Centre (TMC), Homi Bhabha National Institute Mumbai, Maharashtra, India. 2Department of Medical Oncology, Sri Ram Cancer Center, Mahatma Gandhi Hospital, Mahatma Gandhi University of Medical Sciences & Technology, Sitapura, Jaipur, India. 3Department of Haematology, Tata Medical Center, Kolkata, West Bengal, India. 4Apollo Proton Centre, Chennai, India. 5Associate Professor, Translation Health Science and Technology Institute, Faridabad-Gurgaon, India. 6National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India. 7Department of Biosciences & Bioengineering, Indian Institute of Technology (IIT) Bombay, Mumbai, Maharashtra, India. 8Department of Medical Oncology, Basavatharakam Indo American cancer Hospital, Hyderabad, India. 9Department of Medical Oncology, IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India. 10Cochin Cancer Research Centre (CCRC) , Government Medical College Campus, Kalamassery, Ernakulam, Kerala, India. 11Department of Haematology, Christian Medical College (CMC), Vellore, India. 12Department of Medical Oncology, Lilavati/Bombay Hospital, Mumbai, Maharashtra, India. 13Advanced Centre for Treatment Research & Education in Cancer(ACTREC), Homi Bhabha National Institute, Mumbai, Maharashtra, India.
Immunotherapeutic agents have led to a transformative development of treatment of cancer in the last decade. There is a recent explosion in the use of immunotherapeutic agents in clinical practice, considering the significant gains achieved by it in both solid and hematological malignancies. In spite of its considerable usage, there has been a lacuna of knowledge in the management of its side effects and useage indications in certain subtypes of cancer. In a developing country like India, it is of utmost importance to be clear about when and where to use these drugs and their complications, considering the significant costs associated with the use of immunotherapy drugs.
The Immuno-Oncology Society of India (I-OSI) was launched on February 24, 2018, and registered on November 2, 2018, to become the first legal entity in this regard in the country,with a view to promote and advance the scientific knowledge and research in immune-oncology. The Society serves as a platform to share, learn, and further advance understanding of immuno-oncology to help the ultimate beneficiary- the patients.
The executive members of I-OSI are eminent faculties who include:
President: Dr. Shubhada Chiplunkar (Advanced Centre for Treatment Research &Education in Cancer [ACTREC], Tata Memorial Centre [TMC],Mumbai)
General Secretary: Dr. Jyoti Bajpai (Professor, Medical Oncology, TMC, Mumbai)
Vice President: Dr. Hemant Malhotra (Professor, Medical Oncology, Sri Ram Cancer Center, Jaipur)
Joint Secretary: Dr. Vivek Radhakrishnan (Senior Consultant, Hematology/Oncology, TMC, Kolkata)
Treasurer: Dr. Gaurav Narula (Professor, Medical Oncology, TMC, Mumbai)
Other executive members include Drs. SD Banavali (Professor, Medical Oncology, TMC, Mumbai), BK Smruti (Senior Medical Oncologist, Lilavati/Bombay Hospital), Vikram Matthews (Professor, CMC Vellore), Reena Nair (Senior Consultant, Tata Medical Center, Kolkata),Atul Sharma (Professor, AIIMS, New Delhi), Rakesh Jalali (Medical Director, Apollo Proton Centre, Chennai), Kumar Prabhash (Professor, TMC, Mumbai), Senthil Rajappa (Medical Oncologist, Basavatharakam Indo American Cancer Hospital, Hyderabad), Moni Abraham Kuriakose, CCRC, Ernakulum), Amit Awasthi (Associate Professor, Translation Health Science and Technology Institute, Faridabad-Gurgaon), Girdhari Lal (PhD, Scientist, Pune), and Rahul Purvar(Assistant Professor, IIT, Bombay).
The first I-OSI Congress (I-OSICON 2019) was one of the efforts to address the issues. The Congress was introduced to provide an international platform for discussion of present and future challenges in immuno-oncology. National and international faculties presented cutting edge and practical techniques based on evidence and ongoing research. The conference was held in Mumbai, India, March 15–17, 2019.
There were discussions on all disciplines of oncology, immunology research, industry regulations, and expert opinions from subject matter experts. It included plenary lectures, keynote speeches, poster and oral presentations, workshops, and exhibitions. Experts discussed emerging immunotherapies, engineered and non-engineered cellular therapies, evidence-based immunotherapy, potential immunotherapy targets, immune checkpoint inhibitors, immune responses and adverse events, response evaluation in immunotherapy, precision genomics and precision medicine for immune-oncology, technological developments of immune-oncology, Chimeric antigen receptor (CAR) T cell production, and regulatory challenges in immunotherapies.
The highlights of the conference were a collation of real-world practice data from using immunotherapy drugs in patients with cancer across physicians in India, which will provide the practice pattern of care and efficiency and safety data with regards to immunotherapeutics across India shortly. There were many student-focused sessions with exclusive awards, including best abstract presentation and a quiz competition.
The esteemed international speakers included Drs. Sanjiv Agarwal from St. Luke University Health Network, USA, Aung Naing, MD Anderson Cancer Center, USA, Herbert Loong, Prince of Wales Hospital, Hong Kong, Uri Tabori, Hospital for Sick Children, Canada, Naval Daver, Leukemia Research Alliance Program, MD Anderson Cancer Center, USA, Jair Bar, Institute of Oncology, Chaim Sheba Medical Center, Israel, Nirali Shah, National Cancer Institute, among other international and national faculties. The key points of their presentation were as follows.
Dr. Sanjiv Agarwal presented “Philosophy of apparently infinite yet possibly finite game!” He discussed:
State of the art review of immunotherapy for melanoma and head and neck cancers
Basic aspects of the immunotherapy revolution as it applies to these cancers
Insights into future directions
Practical issues for patient management
Dr. Aung Naing gave detailed presentations about:
Responses to immunotherapy
Side-effects of immunotherapy
Need for biomarkers
Dr. Herbert Loong presented “A science of uncertainty and an art of probability,” and explained:
The role of immunotherapy in sarcomas and rare tumors
Successes and failures of developing immunotherapeutics in sarcomas
Future directions in immunotherapy for sarcomas
Dr. Uri Tabori's presentations explained:
Role of replication repair deficiency and hypermutation in response to immune checkpoint inhibition in childhood cancer
Combination of targeted and immune checkpoint inhibitors
Dr. Naval Daver presented “Immuno-therapeutics in acute myeloid leukemia (AML): Way forward into future!” His talk included:
Role of immunotherapy in AML
Toxicities of immunotherapy in AML
Ongoing trials in AML
Dr. Jair Bar discussed the role of immunotherapy in small-cell lung cancer (SCLC) including:
Indications for immunotherapy in SCLC
Role of immunotherapy in different lines in SCLC
Safety and future directions
Dr. Nirali Shah presented “Curiosity keeps leading us down new paths!” She explained:
Role of Immunotherapy in acute lymphoid leukemia (ALL)
Toxicities of immunotherapy in ALL
Ongoing trials in ALL
There were state-of-the-art talks by eminent national speakers like Drs. SD Banavali, who explained immuno-modulating the tumor microenvironment, Giridhari Lal, Rahul Purwar, and Sanjiv Agarwala, with regards to the basics of immunotherapy. This was followed by an excellent talk on drug repositioning by Dr Amit Awasti.
Dr. Atul Sharma explained the role immunotherapy in hepatocellular cancers in a superlative manner. Panel discussion on colorectal cancer moderated by Dr. Amish Vora was quite engaging. Dr. Vivek Radhakrishnan in his talk on CART cell therapy in non-Hodgkin's lymphoma introduced us to a new world of directions. There was an intense debate between Dr. Hari Menon and Dr. Reetu Jain on the role of Autologous Stem Cell Transplant (ASCT) in the era of immunotherapy, which kept the audience on edge of the seats. The panel discussion by Dr. Vikram Matthews made it clear where to place immunotherapy in the management of lymphoma and myeloma. Immunotherapy in breast and gynecological cancer was discussed by Dr. Shona Nag with her panel members in an accomplished manner. Dr. Rakesh Jalali delivered an exceptional presentation on the role of radiation along with immunotherapy. Dr. Ashish Bakshi's talk took us to a new world of possibilities of immunotherapy with systemic and ancillary therapies. Dr. Hemanth Malhotra “dared to dream big” in his panel discussion of management algorithms for leukemias with immunotherapies. There was an exciting session of discussion regarding the role of biomarkers in immunotherapy by Drs. Nilesh Lokeshwar, Anita Ramesh, Abhishek Mahajan, and Amit Verma. Dr. Sewanti Limaye's panel made us aware of the present utility of biomarkers in solid tumors. The audience was awestruck by the speech from Mrs. Ragini Salgia, a cancer survivor, and a documentary film by another survivor, Mrs Shubhada Varadkar. The challenges faced by Non-governmental organizations(NGO)'s in providing support for immunotherapy were highlighted in the session by Dr. Prakash Chitalkar and Ganapathy KV.
There was a “Meet the Professor” session on the morning of 16 March 2019. There was an interactive discussion between experts and students. Dr. Tarini Prasad and Dr Senthil Rajappa described the role of immunotherapy in non-small-cell lung cancer (NSCLC)_like never before. This was followed by brilliant panel discussions led by Drs. Kumar Prabhash and Amit Rauthan, as you would normally expect from them. Dr. Purvish Parikh brought out important discussion points on “How to counsel a patient before starting immunotherapy,” which provoked many questions.
Dr. Gouri Shankar Bhattacharyya discussed the difficulties in making biosimilars in immuno-oncology.There was an interesting and thought-provoking panel discussion entitled “Unique challenges to use immunotherapy in India: “Story of CINDERELLA,” by Dr. Jyoti Bajpai. In this unique panel, apart from the lead immuno-oncologists, representatives from the regulatory agencies, media, and industry, as well as visionary community leaders participated, and unique challenges specific to India were addressed.
The role of immunotherapy in head and neck cancers was ironed out by Dr. Ankur Bahl. The clinical application of immunotherapy in melanoma, sarcoma, and head and neck cancers was discussed in an exemplary manner by Dr. Sameer Bakshi.
The interactive panel on genitourinary cancer was moderated by Dr. Senthil Rajappa. Dr. Amit Rauthan gave a magnificent speech on second-line therapy in renal cell carcinoma (RCC) and second line therapies in metastatic NSCLC. The session on “Indian Data on Immunotherapy,” which discussed the India-specific challenges, feasibility of immunotherapy, outcomes, and available data was a hugely interactive session.
In addition, there was a fabulous Presidential oration delivered by Prof Shubdha Chiplunkar on “Opportunities and Challenges with Unconventional T cells.” The inauguaration was done by Mr. Jayant Banthia, guest of honor, followed by Dr. Badwe, the Chief guest, delivered a motivational talk on the future of immuno-oncology in India, including challenges and opportunities and the role of I-OSI in taking this momentum forward in the country. A special keynote lecture on “Artificial Intelligence” by Dr. Ajay Bhakshi enlightened the audience about practical applications of artificial intelligence in medicine and oncology.
To conclude the conference was the most exciting session on toxicity management in immuno-oncology, which was one of the most interactive sessions moderated by Drs. Naval Daver and Smruti Koppikar. Eminent faculties from various specialties were among the panelists, and there was a belief that a consensus was made with regards to management of immune-related toxicities.
A total of 34 abstracts were received. The importance of these cannot be understated because ongoing studies and trials are few in India, and these abstracts present a valuable evidence of effectiveness and toxicities in an India specific scenario.
We thank I-OSI coordinator, Ms. Suvarna B Damanapally for her valuable support.
Abstract No 1: FACILITY MANAGEMENT OF cGMP LABORATORY FOR CELL BASED MEDICINAL PRODUCTS (CBMPS)/ CAR T CELLs - TATA MEMORIAL CENTRE EXPEREINCE.
Nisar A, Poojary M, Pandit D, Tailor H, Ghadi P, Bangale S, Dhamne C, Jain H, Chiplunkar S, Narula G, Banavali SD
Tata Memorial Hospital, Mumbai, India.
Cell-based therapies have emerged as the most promising form of curative treatment for cancer patients today and are being tested in clinical trials world over. At Tata Memorial Centre too, we are in the process of setting up of cGMP facility, a CART-T Cell Centre (CTCC), in order to support the manufacture of CAR-T cells for conducting clinical trials in relapsed/refractory B-ALL and B-cell Lymphoma patients. The facility is expected to be completed by March 2019 and is being developed in accordance with Current Good Manufacturing Practice for Phase 1 Investigational Drugs; US FDA guidelines for cells and tissue products. CTCC is an 87 square foot, Biosafety level 2 contained area with two hepa filtered rooms, located on the 3rd floor of the Paymaster Shodika Building at ACTREC, Kharghar, Mumbai. One positive pressure room, ISO 7 is designed exclusively for manufacture of CART-cells. It is supported by ISO Class 8 room and entry/exit areas. Adjacent to the exit areas, is a storage room termed Post-Quarantine Room and a cleaners' sluice. The entry is through a dedicated Grade D change room designated for changing street cloth to Grade C attire upon entry to clean room area. The overall operational plan for the facility includes controlled access, facility cleaning, air pressure and equipment, scheduled routine preventive maintenance and environmental monitoring programme. The quality system for the facility will include the appropriate management of out-of-specification (OOS) lab results and investigations, non-conforming materials and products, equipment and process deviations, change control, corrective and preventive actions (CAPA), product review/release, and internal audits. The design, consultation, and development of CTCC hastaken us more than 3 years before our first clinical trial can be initiated. The next milestone to be achieved will be operation & maintenance of the facility for manufacture of CAR-T cells and similar cell based products.
Abstract No 2: Cancer immunotherapy: What are we missing?
Rizwan A, Srivastava A
Department of Surgical Discipline, AIIMS , New Delhi, India.
The war between cancer cells and immune cells are interesting area of researches. Various obstacles increasing day by day to control the disease. Thus, by keeping all complexity in mind, an innovative therapy must be developed to hoist the flag of survival over cancer. However, this is challenging question, so we need to develop a therapeutic weapon to defeat the tumor cells and boost the immunity. Cancer cells develop from our own body cells, hence, they do not have strong antigenicity. However, Tumour infiltrating lymphocytes (TILs) are an important prognostic factor in cancer and their presence is associated with improved survival as well as treatment response. Various studies are in progress to develop tumor vaccine based on increasing CD8 T cells, but no research has been undertaken to abrogate the T regulatory cells (Tregs) function. Treg cells are found in human cancers, and studies in animal models suggest their role in cancer progression. What are we missing? The way forward for cancer immunotherapy is challenging. Some pertinent issues are 1) Turning cold TIL to hot. Most cancers are immunologically “cold” as they exhibit relatively low T cell infiltration; and 2) Suppressing Treg cells function. To suppress Treg cells as well as boost up effector T cells. An important aspect of future studies will be to clearly describe the therapeutic window of deleting Treg cells as a major gatekeeper of self-antigen recognition. A number of questions remain unanswered and should motivate further studies. Q1-The mechanisms underlying the increased infiltration of Treg cells in aggressive cancers such as TNBC and their function?Q2-Can they be specifically targeted? Q3-Does immune therapy like HSP based vaccine affect the Treg cells dynamics?
Abstract No 3: Radiological evaluation of immune related adverse events of immunotherapy
Patwardhan S, Deshpand S, Janu A
Tata Memorial Centre, Mumbai, India
Background: There is a significant interest in immunotherapy for the treatment of lung cancer. As treatment options for lung cancer grow, so do the adverse events related to them. Consequently, different patterns of radiological response can also be seen. Immunotherapy has an important emerging role in head & neck & bladder cancers as well. Thus, it is of paramount importance to evaluate the radiological findings after immunotherapy and distinguish immune-related adverse events, pseudoprogression & frank progression. Methods: We have retrospectively analysed 50 cases treated with immunotherapy at our institute & the various radiological features of adverse events and pseudoprogression using the iRECIST criteria. The scans have been performed on SIEMENS 16 slice Computed Tomography machine.The cases included predominantly lung cancer cases as also head & neck & urinary bladder cancers.The analysis was done by senior consultant radiologist & resident radiologists. Results: Of the total number of patients analysed, about 50% of patients had varying degrees of colitis.30% showed pulmonary adverse effects. Autoimmune pancreatitis, myositis, arthritis, sarcoid-like reaction, vasculitis and fasciitis were some other complications which were diagnosed.10% of the adverse events turned out to be disease progression.Frank progression was seen in less than 20%.Conclusions :Imaging plays an integral role in the care of cancer patients. It is crucial that radiologists be aware of the major advancements in the treatment of cancer. Radiologists must recognize potential immune-related adverse events & the novel treatment response patterns for appropriate clinical management.It is important to recognize particular unique adverse events associated with specific immunotherapy to guide appropriate treatment and avoid potential fallacies that could be labelled as the progression of the disease.Considering the rapid growth & use of immunotherapy in cancer patients, the radiologist must advance his knowledge & skill of immunotherapy & its imaging features to ensure the disease management group provides the best possible treatment to the cancer patient.
Abstract No 4: Cancer Immunotherapy-Tertiary care centre experience from western India
Naseer M, Tahiliani N, Patel A, Anand A
Department of Medical Oncology, Gujarat Cancer & Research Institute, Ahmedabad, India.
Background: There has been a great momentum in the field of immuno-oncology after Nobel laureates James P Allison and Dr. Tasuku Honjo published pioneering work on anti-tumour immunity. The spectrum of immunotherapeutic options have increased beyond Melanoma/Renal cell carcinoma. There is paucity of data in Indian experience. We at our institute evaluated efficacy of Immune Checkpoint Inhibitors(ICIs) in advanced solid cancers. Methods: All patients with advanced solid cancers who received ICIs after failure of chemotherapy at our centre were retrospectively assessed. Patient characteristics Clinical Benefit Rate (CBR), Progression free survival (PFS) calculated. Results: Median age of patient was 57 years with Male : Female ratio of 3:1. Majority of patients were in ECOG PS 1. Head & Neck cancer (38.4%) was the most common underlying malignancy followed by Lung carcinoma (27%). Other malignancies included were Ca Esophagus, HCC, RCC, Ca Bladder, Mesothelioma, colon, penis & IHCC. Majority received ICI as 2nd line therapy (46%). Nivolumab, Pembrolizumab and Atezolizumab were used in 22, 2 and 2 patients respectively. Of the 26 patients, 19 were eligible for evaluation. CBR was seen is 35%. Pseudoprogression was seen in two patients. Two patients have had maximum CBR. CBR was 50% & 35% in Lung and Head & Neck cancers respectively. Grade 3 adverse events (IRAE) were seen in 3 patients (11.5%) who responded to prednisolone. With a maximum follow up of a period of 9.6 months the PFS is 4.5 months. Conclusion: A comparable CBR (35%) was seen in our study with two patients having a durable response. As ICI are not immune to adverse events and there is a need to detect them with high index of suspicion and pretherapy work up. Major drawback of ICI in our country is the high cost which makes its usage in clinical setting a practical challenge.
Abstract No 5: Expression of immunomodulatory molecule PDL-1 (programmed death ligand -1) in triple negative invasive breast cancer in the Indian population
Gorijavolu NB, Augustine P, Lakshmi S, Jayasree K, Mathew A, Antony GR
Regional Cancer Centre, Trivandrum, India
Background: Triple negative breast cancer(TNBC) account for about 30% of invasive breast cancers. TNBC is inherently aggressive cancer with limited treatment options. Hence alternative lines of treatment are the urgent need of the day.Immune checkpoint inhibitors are a new class of drugs used in the treatment of various cancers, the advantage being long lasting response, reduced toxicity.PDL-1 is a ligand which is a part of this immunomodulating pathway. Methods: Paraffin blocks of TNBC patients are tested for the expression of PDL-1 expression. Clinico-Pathological features associated with PDL-1 expressing cancers were (collected from the case files and pathology reports) compared with PDL-1 negative cancers. Disease-free survival (DFS) was also compared between PDL-1 positive and negative TNBC patients. Results: 201 blocks of TNBC patients were evaluated for expression of PDL-1 receptor with immunohistochemistry.48.2% of patients were PDL-1 positive,51.7% were PDL-1 negative. The probability of 5 year DFS of PDL-1 positive patients was 82% .The probability of 5 year DFS in PDL-1 negative patients was 87.2%.There was no statistically significant difference in DFS between PDL-1 positive and negative patients. There is no statistically significant association between PDL- 1positivity and clinico-pathological factors like age, pathological tumor stage, pathological nodal status, grade and lymphovascular invasion. Conclusions: Expression of PDL-1 was approximately 50% in triple negative invasive breast cancers in the Indian population. Disease free survival and overall survival is comparable between PDL-1 positive patients and negative patients. Factors like age, histological type, pathological tumor stage, pathological nodal status or lymphovascular invasion were not significantly different PDL-1 negative and positive patients.PDL-1 expression may serve as a predictive factor for response to treatment with immune check point inhibitors in the future. PDL-1 testing needs further standardization.PDL-1 expression may predict better response to chemotherapy.
Abstract No 6: MANAGEMENT OF TOXICITES ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS: A SINGLE-CENTRE EXPERIENCE
Murthy NY1, Rauthan A1, Patil P1, Somashekar SP2, Zaveri S2, Lahkar K1, Nigade G1, Kulkarni S1, Sood T1
1. Department of Medical Oncology, Manipal Comprehensive Cancer Centre, Bangalore, India
2. Department of Surgical Oncology, Manipal Comprehensive Cancer Centre, Bangalore, India
Introduction: Immune check point inhibitors (ICI) are being increasingly used in treatment of various cancers. Despite important clinical benefits, they are associated with a unique spectrum of side effects called immune related adverse effects(irAE) which represent a special emerging challenge. Methods: A retrospective review was carried out of patients who received checkpoint inhibitors between 2016–2018 at our centre. Results: There was a total of 106 cases who received immunotherapy between 2016–2018. The commonly used ICI was Nivolumab(n=90,84.9%), Pembrolizumab (n=13, 12.3%).Ipilimumab was added to Nivolumab in 2 patients. The commonest indications for use were in lung cancer (n=30, 28.3%), RCC (n=28, 26.4%), GIT + Hepatobiliary malignancies (n=14,13.2%).Most common side effects were fatigue (n=40 ,37.77%), thyroid dysfunction ( n= 25,23.5%), skin toxicity ( n=15,13.20%). 19 had hypothyroidism and out of 6 with hyperthyroidism, subsequently 4 became hypothyroid ,2 euthyroid. Hypothyroidism was managed with thyroid supplements, Grade 1–2 skin toxicity with emollients and topical steroids. 6 patients developed pneumonitis (5.6%): 4 had Grade 3 pneumonitis,1 patient required addition of mycophenolate to steroids. Grade 2 Arthritis was seen in 1 patient after 8 cycles, required temporary interruption and showed good resolution after treatment with oral steroids. Grade 2 Encephalitis was seen in 1 patient after 10 cycles of Nivolumab, which resolved with oral steroids and recurred on restarting ICI leading to permanent discontinuation. Immune mediated retinopathy was seen in 1 patient after 16 cycles of Nivolumab which reduced with oral steroids. There was no added toxicity when Ipilimumab was added to Nivolumab.
Conclusions: Treatment with check point inhibitors was well tolerated. There was no treatment related death. Only 4.7% had grade 3 toxicities requiring permanent discontinuation of ICI. Vigilance and awareness of side effects will ensure early detection, appropriate management and timely initiation of steroids.
Abstract No 7: SPECTRUM OF USE OF CHECKPOINT INHIBITORS IN VARIOUS CLINICAL SCENARIOS: A SINGLE-CENTRE EXPERIENCE OF 106 CASES
Murthy NY1, Rauthan A1, Patil P1, Somashekar SP2, Zaveri S2, Lahkar K1, Nigade G1, Kulkarni S1, Sood T1
1. Department of Medical Oncology, Manipal Comprehensive Cancer Centre, Bangalore, India
2. Department of Surgical Oncology, Manipal Comprehensive Cancer Centre, Bangalore, India
Introduction: Immune checkpoint inhibitors (ICIs) have substantially improved the prognosis for patients with advanced malignancy. Based upon landmark phase II and phase III studies, antibodies inhibiting PD-1 and CTLA-4 (ipilimumab) have been approved for a number of clinical indications. There is lack of data in the Indian setting on the various uses of checkpoint inhibitors. Methods: A retrospective review of all patients who received checkpoint inhibitors for various malignancies between 2016–2018 in our centre. Results: There was a total of 106 cases who received immunotherapy between 2016–2018. Nivolumab was the most commonly used ICI in 90 patients (84.9%), followed by Pembolizumab in 13 patients (12.3%),Atezolizumab in 2 patients, and Durvalumab in 1 patient. Ipilimumab was used in 2 patients along with Nivolumab. A total of 594 cycles of immunotherapy was administered during the study period (median=4),with maximum number of cycles received by a patient being 22. The commonest indication for use was in 30 patients of Lung cancer (28.3%) followed by 28 patients of Renal Cell carcinoma (26.4%). 8 patients of NSCLC received Immunotherapy as first line with PDL1 being positive in 4 of them. In patients with GI malignancy who received ICI (n=14), there were 4 cases of carcinoma stomach (2 were MMR deficient, 2 were PDL1 positive),2 cases of MMR deficient colon cancer, 2 cases of Pancreatic cancer (1 with intermediate TMB and 1 was PDL1 positive), 1 case of PDL1-positive esophageal cancer and 5 cases of Hepato-biliary malignancies. Conclusion: Checkpoint inhibition has become a widely used treatment modality for patients who have failed prior treatment in many types of cancers .Its use is alsobecoming prevalent in a first line setting in recent times.
Abstract No 8: Dual Immunotherapy in Malignant Melanoma: A Feasibility Study from a Tertiary Cancer Center of India
Abraham G, Bajpai J
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
Background: The advent of immunotherapy has revolutionized the outcomes of malignant melanoma both in metastatic and adjuvant settings. The combination blockade of CTLA -4 and PD-1 inhibition had shown superior survival (3 year OS of 58% vs 43.7% with nivolumab monotherapy and 19% with ipilimumab monotherapy). Dual therapy is of additional benefit with high tumour burden, fastly growing disease and in metastatic brain disease however with added toxicity and cost . We are reporting the first series of Ipilimumab as monotherapy or in combination from India in malignant melanoma. Our aim is to evaluate the safety and efficacy of CTLA -4 inhibitor Ipilimumab given as dual ( with nivolumab or monotherapy in malignant melanoma in Indian setting. Methods: All consecutive patients who received Ipilimumab for malignant melanoma from August 2015 till February 2019 were included in this prospective database. Standard staging investigations, PDL1 staining (SP263 clone), and BRAF mutation status was carried out. Results: There was a total of 4 patients who received Ipilimumab of which 3 had received dual immunotherapy in combination with nivolumab. 2 patients received ipilimumab 200 mg and nivolumab 70 mg when combined with ipilimumab in metastatic setting. One patient received nivolumab240 mg and ipilimumab 200 mg in recurrent but adjuvant settings along with concurrent radiotherapy. The median age of the patients was 55 (34–60) years. There was 50% response (SD, PR) and, 2 (50%) had progressive disease. The dose administered was 200 mg for 4 cycles give every 3 weeks. The toxicities included nausea and vomiting grade 1 and fatigue grade 2 in 2 (50%) patients ; grade 2 skin rash in 1 (25%) and grade 1anorexia in 1(25%). The median follow up duration was 13 months (range 2–25). The median progression free survival was 4 months (0.5–23) while median overall survival was not reached. The progression free survival in evaluable ½ patients was and overall survival post Ipilimumab was 23 and 25 months respectively at our centre. Conclusions: With the limitation of small numbers, thisIpilimumab alone or in addition to nivolumab has better outcomes in metastatic/ recurrent malignant melanoma and our limited experience prove its feasibility and safety with limited toxicities in Indian scenario. However, cost is still the major barrier preventing the access of ipilimumab to patients with metastatic malignant melanoma.
Abstract No 9: Correlation of Tumor-infiltrating lymphocytes (TILs) with NACT response in breast cancer in India
Vai1, Khatpe A1, Shah R2, Reddy R3, Puntambekar A4, Kelkar D1, Koppiker C3, Kulkarni M1
1. Centre for Translational Cancer Research: Indian Institute of Science, Education and Research, Pune and Prashanti Cancer Care Mission (PCCM), Pune, India.
2. Ahmadabad University, Ahmedabad, India.
3. Prashanti Cancer Care Mission, Pune, India.
4. Pathology Department, Ruby Hall Clinic-Pune, Pune, India.
Background: Despite the available therapies for breast cancer, increasing number of patients show no response or recur within few years, and therefore it has become important to understand underlying causes. Recent studies have shown that the extent of immune response to tumor in terms of tumor infiltrating lymphocytes (TILs), can serve as a prognostic marker. Many other studies have validated the prognostic and predictive value of TILs in several randomized clinical trials. Several reports demonstrate the association between response to NACT and TILs. TNBC, the most aggressive form of breast cancer shows significant association between TILs % and treatment response. In our study we aim to evaluate TILs in primary ER/PR positive, HER2+ve and TNBC patient tissue and analyze any underlying association with NACT response with pCR as an end point to the study. Here I will present our data on TILs evaluation in primary tumor tissue of breast cancer. Methods: For TILs evaluation, we are analyzing primary biopsy tissue samples, collected with appropriate ethical approvals from patients at PCCM, Pune. FFPE blocks of primary tissue of invasive breast carcinoma are selected and stained with H&E following standard protocol. To assess, TILs from stromal areas are scored by certified pathologist as low medium and high as per theImmuno-Oncology Working group guidelinesfor TILs evaluation. With this cohort, we plan to compare the scores to pTN status, pCR for at least 50 samples of each subtypes. Results: Since June 2018, we have processed 89 samples, out of which about 50% are ER+, followed by TNBC andHER2+ve. I will be presenting the distribution of TILs scores in these 3 subtypes and our preliminary correlation with post-NACT pCR. Conclusion: Out of the total samples processed, we observed low levels of TILs in majority of ER/PR+ samples, whileHER2+ and TNBC subset show even distribution of low, medium, and high scores.
Abstract No 10: Cancer Immunotherapy and Endocrinopathies: A critical review
Tata Memorial Centre, Mumbai, India
Background: Clinical development and approval of immune-checkpoint inhibitors have transformed the natural history of certain malignancies. However, treatment is frequently limited by immune related adverse effects. Toxicities are reversible in most patients using established treatment algorithms, with the exception of those that affect the endocrine system. Endocrinopathies if not recognized early, can prove to be fatal. Therefore, early recognition and appropriate management of these endocrinopathies is essential. Methods: PubMed indexed full-text papers and case reports using keywords “cancer”, “immunotherapy”, “endocrinopathies” were included. The types, characteristics, and management of immune-related endocrine events that may occur with administration of immune checkpoint inhibitors were reviewed. Results: Immune-related endocrine events were found to frequently affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. The diagnosis and management of endocrinopathies was often complicated by simultaneous multi-organ immune adverse effects. Immune related endocrine events were unique because these manifestations were often irreversible and were typically grade 1/2 in severity, presenting with non-specific symptoms further making them difficult to diagnose. Management includes appropriate laboratory testing for endocrine function, replacement of hormones, close patient monitoring, consultation with an endocrinologist when appropriate. Conclusions: Given the advances in immunotherapy, clinicians should be aware of the unique set of immune-related adverse effects. In most cases, endocrine side-effects can be adequately managed and do not contraindicate the continued use of immunotherapy. It is essential to know the clinical behavior and therapeutic management of these endocrine related immune events and involve a multidisciplinary team in conjunction with the oncologist.
Abstract No 11: Gemcitabine, Bevacizumab and Atezolizumab palliative chemotherapy for first line treatment of advanced platinum resistant NSCLC
Gandhi SS, Kulkarni P, Nilegaokar S, Basu S, Misery R
Tata Memorial Centre, Kolkata, India
Introduction: Advances in oncology have improved the management and prognosis of patients with advanced NSCLC. Recently, immunotherapy has revolutionized the treatment of NSCLC. Case Presentation: A 38-year-old nonsmoker gentleman presented in Sept 2017 with dry cough. Chest x-ray, computerized tomography (CT) and PET-CT scan revealed lesion of 36X40X38 mm in right lower lobe, encasing superior segment bronchus with mediastinal nodes. CT guided biopsy of the lung mass showed lepidic adenocarcinoma lung. The biopsy was negative for EGFR mutation, ALK1 and ROS1 gene rearrangements. Subsequently he received three cycles of Pemetrexed and Cisplatin followed by wedge resection. The histopathology report suggested ypT0N1Mx with positive subcarinal node. He then received chemoradiation with Paclitaxel and Carboplatin, followed by three cycles of Pemetrexed and Cisplatin. PETCT after completion of treatment showed complete disease control. He presented again in Sept 2018 with headache and transient ischemic attack. MRI of brain showed multiple nodular lesions in the supra and infraorbital brain parenchyma and leptomeningeal carcinomatosis. PETCT and MRI spine was negative for extracranial disease. He was treated with whole brain radiation for brain metastasis. PDL1 could not be done due insufficient sample. PET CT and MRI in Nov 2018 showed hilar lymphadenopathy, new lytic bone lesions and leptomeningeal carcinomatosis in brain and spine. In view of a short DFS of 3 months after Paclitaxel and Platinum based therapy, he was offered treatment with Gemcitabine, Bevacizumab and Atezolizumab. He also needed palliative radiation to lumbar spine. PET CT done in Feb 2019 after four cycles of chemotherapy demonstrated regression in hilar nodes and spinal lesions with persistent brain lesions. This is also accompanied by good improvement in his performance status. Conclusion: Gemcitabine, Bevacizumab and Atezolizumab combination chemotherapy is effective and feasible first line palliative chemotherapy in advanced NSCLC resistant to paclitaxel and platinum based chemotherapy.
Abstract No 12: Nivolumab in the treatment of advanced squamous non-small cell lung cancer
Deshmukh C, Gandhi SS, Nilegaokar S, Puntambekar D, Sathe S
Tata Memorial Centre, Kolkata, India.
Background: Advanced squamous cell lung carcinoma in elderly patients has a limited chance of cure with chemotherapy and radiotherapy. The development in immunotherapy is changing the scenario. Nivolumab, an anti-programmed death-1 monoclonal antibody, has not only proven to be of benefit in refractory squamous non-small cell lung cancer (NSCLC), but also provides a durable response for first-line advanced NSCLC. As we found in this case report of an elderly, refractory advanced lung cancer patient who achieved complete remission after this immunotherapy. Case Presentation: A 66-year-old male patient, K/C/O ischemic heart disease, hypertension, diabetes mellitus, with history of repeated admission for heart failure, presented with c/o breathlessness, hoarseness of voice, in Jan 2018 .Computed tomography (CT) and PET CT revealed large mediastinal mass, encasing arch of aorta, left main bronchus, part of SVC, main and left pulmonary artery with moderate pericardial effusion. The Echocardiogram suggested pericardial effusion with EF 40%, therefore subsequently he underwent pericardiocentesis. A pericardial fluid cytology turned out to be negative for malignancy. CT guided biopsy of the lung mass showed invasive poorly differentiated squamous carcinoma and PDL 1 was found to be > 55 to 60%. He subsequently received two cycles of Gemcitabine/Carboplatin chemotherapy. Then patient admitted with complain of breathlessness, found to have moderate pericardial effusion, with four performance status(PS). Due to poor PS he started on Nivolumab based immunotherapy after completion of six cycles, PET CT in Sep 2018 demonstrated near complete regression, with improved performance status. Therefore, he continues on Nivolumab, recent PET CT in Dec 2018 suggested stable disease. Conclusion: In patients with advanced NSCLC who does not respond to first line chemotherapy, complete remission can be achieved with an immunotherapy. In our case, Nivolumab was tolerated well despite of the patient's other co-morbidities and poor PS. And he could achieve complete remission.
Abstract No 13: Post-progression survival after cessation of treatment with nivolumab for advanced non-small cell lung cancer – Case report
Gandhi SS, Deshmukh C
Tata Memorial Centre, Kolkata, India.
Background: Lung cancer is one of the leading causes of mortality worldwide. In recent years, the immune checkpoint inhibitors have received great attention. Nivolumab is the first PD-1 inhibitor approved. Patients with NSCLC showed a survival benefit of treatment with Nivolumab. Case Presentation: A 41 year old nonsmoker female presented with complaint of dry cough since 2 months in March 2015, computed tomography(CT) of chest and PET CT demonstrated metastatic carcinoma of lung. She underwent CT guided biopsy, histopathology suggested adenocarcinoma of lung and negative EGFR mutation. She received four cycles of pemetrexed/ carboplatin. Follow-up scans showed stable disease. Then she received second-line chemotherapy with Gemcitabine/ Cisplatin. Unfortunately, repeat scans in Nov 2015 suggested progressive disease. She was subsequently started with Third-line chemotherapy with Docetaxel. Follow-up scans in June 2016 showed disease progression. Then she received six cycles of fourth-line chemotherapy Vinorelbine/Cisplatin. A repeat scan in Dec 2016 showed a progressive disease. Later, she received Vinorelbine for six more cycles, scans in July 2017 showed stable disease. But she again presented in 2 months with complaint for right supraclavicular lymphadenopathy, biopsy suggested metastatic adenocarcinoma. As she had a good performance status, she started on nivolumab based regimen, after completion of 16 cycles of Nivolumab, scans in April 2018 suggested regression of disease. And she opted for observation. After 6 months she presented with recurrent right supraclavicular lymphadenopathy. A scan also showed progression of disease, but she refused for further chemotherapy and opted for observation despite of progression. She continues with observation. And so post-progression survival after cessation of treatment is 5 months. Conclusion: In our case regardless of cessation nivolumab based chemotherapy and limited progression free survival, patient is still under observation with good performance status
Abstract No 14: Standardization of Flowcytometry Tissue Immunophenotyping using automated tissue dissociator
Karmakar T1,Bag S2, Arora N1,3,4, Arun P4, Brahma S1, Banerjee S1, Shewale S1, Mukherjee G2, Mishra DK1,3, Radhakrishnan V1
1Department of Laboratory Haematology, TATA Medical Center, Kolkata, India.
2Department of Histopathology, TATA Medical Center, Kolkata, India,
3Department of Laboratory Haematology and Molecular Genetics, TATA Medical Center, Kolkata, India.
4Head and Neck Surgery Oncology,TATA Medical Center, Kolkata, India.
Background: Diagnosis of tumor samples are routinely done using biopsies with the conventional histology and immunohistochemistry (IHC) methods. However, these methods involve multiple steps for its preparation including frozen and fixed tissues. With the advancement of tissue dissociation and panel designing, most of the developed countries have initiated performing Flowcytometricimmunophenotyping (FCI) using tissues samples for the diagnostic purpose also. We have used this standardized method in our ongoing preliminary assay on subset analysis of tumor infiltrating immune cells (TILs)/blood from Oral cancer patients. Methods: Additional/Excessive randomised diagnostic FNAC and biopsy samples (cervical Lymph nodes, mediastinal mass, testicular biopsies and abdominal mass) and tissues from surgically resected Oral cancer were processed by fully automated tissue dissociator (gentle MACSOctodissociator with heaters) and subsequently evaluated by both the routine IHC and blood FCI. In addition, we attempted phenotyping immune cells in the TME and blood of oral squamous cell carcinoma – gingivobuccal. Results: The FCI data was consistent with the histological and IHC diagnosis in almost all the diagnostic cases (n=9/9). The Leukemia/Lymphoma cases of Pre-BALL (n=5), T-ALL (n=1), AML (n=1), Burkitts Lymphoma (n=1) and non-malignant (n=1) showed concordance with the IHC. Flowcytometric subset analysis of oral samples showed similar trends in the expression of common markers (HLADR, CD56, CD4, perforin, granzyme, CD103 etc.) also used for IHC profiling. The tissue and peripheral / bone marrow blood FCI were comparable. Conclusions: The highly sensitive and specific tissue FCI has been considered to be comparable to the gold standard method of IHC. The automated tissue dissociation using mechanical and enzymatic steps produces homogenized, reproducible, good quantity and quality viable single cell suspensions with conserved epitopes within 1 hr. Comparison with corresponding blood samples will enhance the diagnosis and prognosis of cancer leading to therapeutic interventions.
Abstract No 15: Retrospective analysis of response and toxicity profile with immunotherapy at Apollo Cancer Institute
Raj T, Ramya A, Yabesh A, Bang M
Apollo Cancer Institute, Chennai, India.
Introduction: The standard treatment options in malignancies have always been surgery, radiotherapy, targeted therapy and cytotoxic chemotherapy. Immunotherapy is a recent and valuable addition for the treatment of advanced diseases. While the initial options are directed against malignant cells, immunotherapy is an option that indirectly targets the malignancy by activating the host immune systems. It also has a synergistic effect when given along with chemotherapy.Indian data for immunotherapy is still in the infant stage. This abstract will throw light on our institutional experience with immunotherapy.
Methods: We did a retrospective analysis of 52 patients who received immunotherapy either in the first or subsequent lines of treatment in our institution. The objective was to analyse the best response achieved and the toxicity profile. Results: The 52 patients were as follows – 20 lung cancers, 13 RCC, 8 melanoma, 3 HCC, 4 metastatic colorectal malignancy, and 4 Head and neck malignancies. 30% had partial response, 40% had stable disease and 30% had disease progression. The age ranged from 25 years to 98 years. Grade 1 Fatigue was the most common adverse effect, seen in 12(23%) of the patients. Hypothyroidism was seen in 3 (5.7%) patients. Skin rash (grade 1) with pruritis was noticed in 2 (3.8%) patients. None had serious adverse infusion reactions. Grade 2 diarrhea was seen in 2 (1.04%) patients. Grade 1 elevation in liver enzymes was noticed in 2 (3.8%) patients. 1 patient had grade 2 pneumonitis which was managed with temporary suspension of treatment and steroid support. Hematological toxicity noticed in these patients was grade 1 anemia, seen in 19 patients (10%). Conclusion: Immunotherapy is well tolerated across all the age groups. Majority of the patients achieved either a stable disease or partial response making it a good option for treatment of metastatic diseases.
Abstract No 16: Immunotherapy in Recurrent Metastatic Triple Negative Breast Cancer (TNBC) with suspected autoimmune disease
Kumar A, Bajpai J
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
Introduction: Check point inhibitors (CPI) has shown promise in various difficult to treat tumours including the poor prognostic TNBC. In CPI trials, patient with autoimmune diseases (ADs) are excluded and sparse data is available in this regard.We report a case of recurrent metastatic TNBC who is challenged with CPI despite high level of antinuclear antibody (ANA) at baseline. Case Summary: A 35 year old lady, without any family history, presented with left breast lump.Core biopsy showed triple negative,grade III, infiltrating duct carcinoma. PET CT revealed liver metastasis. She was negative for BRCA mutation. She progressed on multiple lines of chemotherapy including anthracycline, cyclophosphamide, taxanes, platinum, capecitabine, eribulin, vinorelbine and metronomic therapy with first relapse at an interval of 5.5 months and subsequent at even shorter duration but had good performance status.She was subsequently planned for CPI.Howeverdetected to have high ANA level without any features suggestive of AD.Rheumatologist suggested that high ANA is likely due to tumour itself. She received 5 cycles of nab paclitaxel and pembrolizumabwithout any significant toxicity. There was both clinical and radiological response present. CPI was further withheld due to financial issues. She further received gemcitabine and carboplatin but progressed and developed bone metastases; presently on Lipodox. Conclusion: A positive ANA level alone does not indicate an AD. It should be interpreted in the context of other laboratory studies and clinical history. Even if she had a pre-existing AD, retrospective data suggest that selected patientswith close monitoring in a multidisciplinary setting may be safely treated with CPI monotherapy with similar outcome. Though flares of AD are common but manageable and rarely result in treatment cessation. Background immunosuppression should be tapered to the lowest possible dose.
Abstract 17: Expression pattern of PDL-1 in cases of Malignant Melanoma: Tata Memorial Hospital Experience
Vidya R1, Rekhi B1, Ramadwar M1, Bajpai J2
1. Department of Pathology, Tata Memorial Hospital, Mumbai, India.
2. Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
Background: Primary melanomas when treated with surgical excision yield high survival rates, however in a metastatic setting, the 5-year survival is dismal, when treated with surgery alone. Newer targeted therapeutic agents including immunotherapy-Anti-PDL1 and anti-PD1 agents have demonstrated sustained and better response rates than dacarbazine in metastatic melanoma cases. Methods: Testing for PDL-1 expression by immunohistochemistry was performed on melanoma cases (diagnosed from June 2016, till date), either on clinical request or in cases which demonstrated significant inflammatory tumor response. Clinical details were retrieved from the electronic medical records and histological characteristics including morphological variant, Breslow's thickness, Clark's level, presence of tumor infiltrating lymphocytes were reviewed. Immunohistochemistry was performed using Ventana PDL-1 (SP263) rabbit monoclonal antibody. Any membranous linear (complete or incomplete) staining was interpreted as positive. Staining was assessed in both, tumor cell population and inflammatory component, separately. Results: PDL-1 expression in tumor cells and infiltrating inflammatory cells was evaluated in 13 cases. Age ranged from 17–69 years with M:F ratio of 6:7.Cutaneous melanoma with primary in the extremities was the most common presentation. Metastasis was noted in nearly 50% (Nodal and distant metastasis – 4/6; Nodal metastasis only – 2/6). Nodular melanoma as a morphological variant was noted in 2 cases. Breslow's thickness varied from 2mm to 1cm with Clark's level II to V. Inflammatory response was seen in 8/13 cases(61.5%), most of which showed PDL15/8. PDL1 immunoexpression in tumor cells was noted in 7 cases (53.8%) with 1 of them also showing immunostaining in the tumor infiltrating lymphocytes. A single case showed negative staining in tumor cells, but focal positivity in the inflammatory cells. Percentage expression varied from 2 to 30% positivity. Conclusions: This forms a proof of concept study regarding PDL1 immunostaining across various cases of melanoma. It would be worthwhile drawing evidence from a greater number of melanoma cases regarding PDL-1 immunoexpression.
Abstract 18: Combination Immunotherapy in Metastatic Malignant Melanoma Gives Durable Disease Control: First Case Report from India
Kapoor A1, Kumar SM1, Rekhi B2, Jyoti Bajpai1
1. Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
2. Department of Pathology, Tata Memorial Hospital, Mumbai, India.
Introduction: Immunotherapy has caused a paradigm shift in the management of metastatic melanoma. Here, we present a patient of metastatic malignant melanoma treated with combination immunotherapy at our centre.
Case Summary: 57 yrs old gentleman, CEO in a company at Dubai with hypertension, hyperlipidemia and diabetes mellitus type 2 developed ulcer with black edges on right sole lat aspect in Aug 2015. Biopsy was malignant melanoma for which wide excision with skin graft was done on Sep 2015. Histopathology showed melanoma infiltrates papillary dermis, max depth -0.1cm. Regrafting in Nov 2015 was done due to healing issues. PET-CT done in March 2016 showed FDG avid ill-defined soft tissue in right common iliac region and right level II LN s/o metastatic melanoma. He was started on initially on 2 weekly cycles of Nivolumab (1mg/kg) and then combination immunotherapy (Nivolumab 1mg/kg and Ipilimumab 3mg/kg) 4 cycles.Main toxicities were Grade 2 Anorexia, G2 Fatigue, G3 hyponatremia and G3 diarrhea. He showed CR in all other sites except at common iliac node hence underwent Robotic RPLND on 13-8-16. Maintenance Nivolumab (3mg/kg) was given for four cycles till October 2016.He was then kept on observation and resumed his office work. PET-CT in December 2017 showed an increase in necrosis of the right common iliac node (decrease in SUV from 6 to 4) s/o sustained response. However, the patient developed progressive disease in liver and bones in March 2018. He received three cycles of pembrolizumab but he developed further progression in the form of new intramedullary disease with paraparesis. He was given palliative radiotherapy and was planned for best supportive care alone. Conclusion: In our knowledge, this is the first case report on use of combination immunotherapy (Ipilimumab and Nivolumab) followed by short course maintenance Nivolumab in metastatic melanoma from Indian subcontinent.It is interesting to note that his diabetes also got controlled/cured pointing towards immunological basis of type II DM.
Abstract 19: Immunotherapy in Malignant Melanoma: A Feasibility Study from a Tertiary Cancer Center of India
Kapoor A1, Kumar SM1, Mantri A1, Kumar R2, Rekhi B2, Ghosh J1, Bajpai J1
1. Department ofMedical Oncology, Tata Memorial Hospital, Mumbai, India.
2. Department ofPathology, Tata Memorial Hospital, Mumbai, India.
Background: Immunotherapy has been established as the standard of care in metastatic melanoma. However, there is limited experience and no published data in India owing to the rarity of the diagnosis and unavailability of the drugs. Pharmacogenomic differences can augment the responses and toxicity in varied population and hence, we conducted a feasibility study in real world Indian setting. Methods: All consecutive patients who received immunotherapeutic drugs for metastatic malignant melanoma from August 2015 till December 2018 were included in this prospective data base. Standard staging investigations, PDL1 staining (SP263 clone), and BRAF mutation status was carried out. Results: There was a total of 19 patients who received immunotherapy; two received in adjuvant, rest in metastatic settings. Thirteen (68%) patients received nivolumab alone, 2 (10%) patients received pembrolizumab, 4 (21%) patients received ipilimumab and nivolumab combination. The median age of the patients was 61 (43–78) years. On response assessment in metastatic patients, 2 (12%) patients had complete metabolic response (CMR) as best response, 4 (21%) patients had partial response, 4 (21%) had stable disease, 5 (24%) had progressive disease while 1 (6%) patient had psuedo-progression. In 1 (5%) patient, response assessment was not performed. The toxicities included myalgia in 12 (63%) patients, hypothyroidism in 5 (26%) patients, fatigue in 10 (53%) patients; dermatitis in 3 (16%), vitiligo in 3 (16%) and pneumonitis with hepatitis occurred in 1 (5%) patient. However, in a background of rapidly progressive disease with liver and lung involvement, the immune toxicity versus disease was a diagnostic challenge. The median follow up duration was 11 months (range 2–25). The median progression free survival was 8 months (95% CI: 0–19) while median overall survival was not reached. Conclusions: Immunotherapy has changed the landscape of metastatic malignant melanoma and our limited experience prove its feasibility in Indian scenario in both monotherapy as well as dual immunotherapy. However cost, different metric for response assessment and management of toxicities are challenging.
Abstract 20: Rare spectrum of Schwanomma-Melanocytic Schwanomma–Malignent Melanoma treated with Immunotherapy and radiation: First Case Report
Kapoor A1, Sridhar E2, Jalali3, Bajpai J1
1. Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
2. Department of Pathology, Tata Memorial Hospital, Mumbai, India.
3. Department of Radiotherapy, Tata Memorial Hospital, Mumbai, India.
Introduction: Melanocytic schwanomma has an unpredictable prognosis and is essentially data free zone with very limited options. We report an extremely rare case of recurrent melanocytic schwanomma/melanoma treated with immunotherapy and radiotherapy. Case Summary: A 34 years lady presented with backache from 4 months in April 2016. On contrast MRI, she was found to have dumbbell shaped mass 2 in left L3/4 intervertebral foramen suggestive of schwanomma. She was kept on observation initially, however, on progression in next 6 months with increasing radicular pain, she underwent gross total excision of L3 lesion; histopathology was consistent with melanocytic schwanomma. She developed recurrence in June 2017 with MRI showing multiple nodules in paraspinal muscles. She underwent second surgery (R0 resection)with L3-L4 laminectomy;HPR revealed high grade melanocytic tumour consistent with melanoma(histological progression). However, review from MSKCC still corresponded with aggressive melanocytic schwannoma. She was started on Nivolumab with concurrent adjuvant external beam radiotherapy to spine. She developed grade 2 skin rash and grade 1 diarrhea which was managed with prednisolone in tapering dose and immunotherapy was held. She completed her planned radiotherapy 50 Gy in 25 fractions and Nivolumab was restarted. She tolerated well, however, noted to have4 mm lung nodules, which were FDG avid. Immunotherapy was continued under close monitoring. After 31 doses of Nivolumab (15 months of immunotherapy), these lung nodules increased in size (largest 1 cm) with locoregional recurrence of nodules(largest 1.6 cm). Since patient was clinically well with minimal progression, Ipilimumab was added to Nivolumab for 4 cycles which she tolerated well. The patient is planned for response assessment. Conclusion: Concurrent radioimmunotherapy is a feasible option in patients with aggressive melanocytic schwannoma with possibility of good clinical benefit and potential for long term survival in patients with this kind of rare and difficult to treat tumours with acceptable toxicity.
Abstract 21: Toxicity profile of AntiPD1/PDL1 monotherapy in melanoma: Is real world experience different than trial population?
Panda G, Kapoor A, Simha V, Turkar S, Bajpai J
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
Background: Immunotherapeutic drugs Nivolumab and pembrolizumab bind to the PD-1 receptor and block its interaction with PD-L1 and PD-L2. High cost and rarity of diagnosis adds to scarcity of published data from India. Methods: We reviewed the records of patients with melanoma who were treated with nivolumab and pembroliuzumab in our hospital Results: Dermatologic toxicity manifesting as rash, vitiligo occurred in 4 (27%) patients. Diarrhea was observed in 2 (13%) patients. Hepatotoxicity in the form of transaminitis and hyperbilirubinemia was noticed in 3 (20%) and 2 (13%), respectively. One patient (7%) developed pneumonitis. Endocrinopathies were also recognized: hypothyroidism in 4 (27%), hyperthyroidism in 1 (7%), raised ACTH in 2 (13%) and hyperglycemia in 4 (27%) patients. Fatigue with a frequency of 53% (8 patients) was one of the common side effects. Amongst hematologic adverse events, anemia was commoner (60%) than thrombocytopenia (33%) and neutropenia(20%). Arthromyalgia was experienced by 11 (73%) and it was mild in all cases.Hypokalemia in 2 (13%) and hyponatremia in 7 (47%) patients were noted. A total of Eleven grade 3/4 adverse events occurring in 4 patients are as follows: hyponatremia (27%), anemia (20%), fatigue (13%), pneumonitis (7%), hyperbiliribuinemia (7%). Three (20%) patients required oral prednisolone(1mg/kg) for a median duration of 4 weeks. None required other immunosuppressive agents or permanent interruption of immunotherapy. Conclusion: The monotherapy with anti PD1/PDL1 is well tolerated and showing similar trend as literature with majority being mild to moderate and well managed. Frequencies of some toxicities appear different than the literature, which might be due to pharmacogenomic variations and/or small sample artifact and need reproducibility in larger cohorts.
Abstract 22: Immunotherapy with Nivolumab in metastatic Renal Cell Carcinoma: A significant change in clinical practice
Rauthan A, Patil P, Murthy NY, Kulkarni S, Sood T, Nigade G, Somashekhar SP, Zaveri
Comprehensive Cancer Center, Manipal Hospital, Bangalore, India.
Background: Metastatic renal cell cancer (mRCC) patients usually receive first line sunitinib or pazopanib, and at progression, are treated with everolimus. In the Checkmate025 trial, nivolumab in the second line setting, showed a median overall survival(OS) of 26 months, 2year OS rate of 52% and overall response rate(ORR) of 26%; which was better than everolimus. There is limited data about use of nivolumab in Indian patients. Methods: This is a single centre, retrospective study, which included mRCC patients who received nivolumab. The endpoints were ORR, OS and adverse events(AEs). Results: 28 patients of mRCC received nivolumab. Median age was 58 years (22–82 years). 24 patients had received first line therapy earlier - 13 sunitinib, 10 pazopanib, and 1 sorafinib. 4 patients received nivolumab as 1st line therapy. 3 patients(11%) achieved complete response(CR), 7(25%) achieved partial response, 7(25%) had stable disease and 11(39%) had progressive disease. 3 patients with CR, received 18 doses, after which their treatment was stopped; and continue to be in CR at follow up. 8 patients havecompleted more than 12 cycles. OS at 1 year is 60% and median OS has not been reached. The common AEs were fatigue in 8(28.5%), hypothyroidism in 5(17.8%), skin rash in 4(14%) and pneumonitis in 3(10.7%). Immune retinopathy, myocarditis and colitis was each seen in 1 patient. Grade 3 AE were seen in 3 patients and treatment was discontinued in them. Conclusions: Nivolumab is a very effective second line regimen in mRCC, which has now replaced everolimus in practice. Achieving an ORR of 36% and an OS of 1 year of 60% is the best we have seen in this setting. Long-lasting responses, even after discontinuing treatment, has been seen in our responding patients. It is very well tolerated; but a careful lookout should be kept for immune related AEs.
Abstract 23: Immunotherapy with nivolumab in metastatic non-small cell lung carcinoma-a change in approach to treatment
Rauthan A, Patil P, Murthy NY, Sood T, Kulkarni S, Nigade G, Somashekhar SP, Zaveri S
Manipal Comprehensive Cancer Center, Manipal Hospital, Bangalore, India.
Background: Chemotherapy has been the mainstay of first and second line treatment in non-driver dependent non-small-cell lung cancer (NSCLC). Immunotherapy with nivolumab, pembrolizumab and atezolizumab is now approved in squamous cell and adeno-carcinoma lung in the second line setting with significant improvement in overall survival(OS). There is limited data about use of immunotherapy in Indian patients. Methods: This is a single centre, retrospective study, which included metastatic NSCLC patients without driver mutations, who received nivolumab as second line therapy. The endpoints were overall response rate(ORR), progression free survival(PFS), OS, 1 year survival and adverse events(AEs). Results: 26 patients with metastatic NSCLC, who had progressed on first line chemotherapy received nivolumab. Median age of patients was 67 years (range 36–87 years). There were 23 males and 3 females. 21 patients had adenocarcinoma and 5 had squamous cell cancer. Overall response rate (ORR) was 38.5%. 1 patient (3.8%) achieved complete response, 9 patients (34.6%) achieved partial response, 6 had stable disease(23%) and 10 patients(38.5%) had progressive disease. Duration of treatment ranged from 1 month to 17 months. The median progression free survival (PFS) was 5 months. The median OS was 13 months. The 1 year survival rate was 55%. The common AEs were hypothyroidism in 34%, skin toxicity in 30.7%, fatigue in 27%, pneumonitis in 7.6%. 1 patient with stable disease discontinued treatment due to pneumonitis. Conclusions: With an ORR of 38.5%, median OS of 13 months and a 1 year survival rate of 55%, which is better than any chemotherapy, nivolumab has become our standard second line treatment option in metastatic NSCLC. It is well tolerated, and has also enabled us to treat many older patients, who would have otherwise got palliative care. Immune related AEs are known, but can be effectively managed with awareness, and early steroid usage.
Abstract 24: An Exceptional Response to Nivolumab In Relapsed and refractory malignant mesothelioma
Talreja VT, Noronha V, Joshi A, Patil V, Mahajan A, Prabhash K
Tata Memorial Centre, Mumbai, India.
Malignant pleural mesothelioma (MPM) is a rare, highly lethal form of cancer. Presently, there are no FDA-approved second-line therapies for MPM in palliative settings. Vinorelbine with gemcitabine is typically used as salvage therapy after failure of cisplatin-pemetrexed based therapy, but response rates are low (~10%) and have a treatment limiting side effect profile for many patients. Our patient is a 41 year lady with no habits no comorbidities and family history of cancer. She presented with pain in the upper back for which she was evaluated to have malignant pleural mesothelioma with metastasis to bone ( Right Iliac Bone , Sacro-Iliac Joint and ischial bone).She was administered four lines of chemotherapy with 2cycles of Carboplatin and Paclitaxel, 3 cycles of Pemetrexed – Carboplatin and Bevacizumab, 3 cycles of Single Agent Topotecan, and 3 cycles of Vinorelbine, none of them showing promising activity with disease progressing with each subsequent treatment. Post fourth line of chemotherapy there was pleural based lesion of 7.2 cm, new brain metastasis, appearance of new mediastinal node and pleural effusion. Her disease progressed rapidly, and she became significantly debilitated requiring continuous supplemental oxygen.Patient and relatives were very keen on exploring checkpoint inhibitors in view of emerging data available.Shewas started on Nivolumab 240 mg (3 mg/ kg) every 14 days in our tumor board on compassionate grounds based on limited clinical data.Her performance status improved to ECOG performance status 1 and her requirements of supplemental oxygen therapy drastically reduced with subsequent cycles and by the end of 3rd cycle she didn't require supplemental oxygen. CT Scan done at 12 weeks showed partial response with pleural mass reduced to 3.5 cm(Figure). She has completed 24 cycles of Nivolumab with sustained response. She tolerated regimen well with Grade 2 hypothyroidism (CTCAE Ver 4.03) requiring 50 mcg levothyroxine supplementation as well as a low-grade elevation of his serum lipase, but no evidence of hepatitis or pancreatitis could be found and required no intervention. At the time of this writing, she remains active and disease controlled more than 24 months after malignant disease was diagnosed. Further studies may provide insight into the role of this treatment in management of MPM.
Abstract 25: An integrated genomics and immune cell-based platform to profile cancer vaccine candidates
Sudheendra H V1, Ramesh A1, Majumder S1, Shi S2, Kode V2, Shah P1, Gupta R1, Coral K1, Chaudhuri A2, Chakraborty P2
1. MedGenome Labs Ltd, Narayana Health City, Hosur Road, Bangalore, India.
2. MedGenome Labs Inc, Foster City, CA, USA
Background: Therapeutic cancer vaccines represent a viable cancer immunotherapy modality that aims to treat late stage diseases by mobilizing patient's own immune system. Cancer vaccines can be utilized to inhibit growth of advanced cancer that are refractory to conventional therapies. Tumors express T cell-specific mutant antigens resulting from somatic mutations. Mutated antigens undergo proteasomal processing and generate mutated peptides that bind to human leukocyte antigen (HLA) to induce antigen-specific CD8 cytotoxic T cell (CTL) response and aids tumor clearance. Methods: MedGenome has built a proprietary cancer vaccine prediction platform called “OncoPept VAC” based on a combination of T cell receptor (TCR) binding, HLA binding, gene expression and proteasomal processing. In silicoepitope prediction tool serves as an excellent first line resource to prioritize a small number of immunogenic peptide candidates from hundreds of somatic mutations in tumors. In a second validation step, we used a high-throughput immune cell-based assay using peripheral blood mononuclear cells (PBMCs) from healthy donors to examine candidate peptide specific CTL activation. 95 mutant peptides from high frequency somatic mutation was screened in 22 different HLA-matched donors. Results: We validated our pipeline with the prioritized peptides from different cancers and about 75% of the predicted peptides elicited a T-cell response and 54% were found to be T-cell activating in ex vivo assays. Conclusions: We identified 28 high frequency somatic mutations across various cancers such as pancreatic, stomach and colon adenocarcinoma, adrenocortical carcinoma, bladder urothelial carcinoma and cholangiocarcinoma that can serve as a shared cancer vaccine candidate.
Abstract 26: Role of WNT and TLR signaling pathways in the prostate cancer cell death induced by recombinant fragment of Human Surfactant protein D (rfhSP-D)
Mukherjee N, Ganguly K, Gupta TM
ICMR-National Institute for Research on Reproductive Health, Parel, Mumbai, India.
Background: Human Surfactant Protein-D, a collagenous C-type lectin and integral component of innate immune response, is associated with severity of prostate cancer. Our previous studies showed that recombinant fragment of Human Surfactant Protein-D (rfhSP-D) induced apoptosis in prostate cancer cells. Wnt/β-catenin signaling pathway is up regulated in prostate cancer and is suggested to play an important role in regulating cancer stem cell functions which affects prostate cancer recurrence and resistance to androgen deprivation therapy (ADT). Combing β-catenin inhibitors with chemotherapy drugs showed an enhanced therapeutic efficacy. In the present study we aim to understand the role of WNT and TLR signalling in in the prostate cancer cell death induced by rfhSP-D. Methods: The androgen sensitive prostate cancer cell line (LNCaP) and androgen independent prostate cancer cell line (PC3) were treated with the effective concentration of recombinant Surfactant protein D. The expression of Wnt associated genes and TLR genes were examined in the rfhSPD treated cells by qRT-PCR. Results: A down regulation in CTNNB1 (β-catenin), WNT6 and WNT5A were seen in both LNCaP and PC3 cells on rfhSPD treatment. Interestingly an increase in TLR mRNA expression, in particular TLR 2/4/9 were seen in rfhSPD treated LNCaP cells but not in PC3 cells. Treatment with β-Catenin/Tcf Inhibitor II, PKF-118310 for 48 hours inhibited the proliferation of LNCaP and PC3 cells with LNCaP being more sensitive to PKF-118310 mediated inhibition. Conclusion: Surfactant Protein-D may have role in down regulating Wnt/β-catenin signaling via TLR-mediated up regulation of transcription factors such as NFkβ in prostate cancer. Further studies are needed to validate the inference.
Abstract 27: Smart nanoengineered green materials for cancer immunotherapy
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
Introduction: Though surgery, radiation and chemotherapy have improved cancer treatments advanced tumors are highly immunosuppressive. They are unresponsive to common anticancer chemotherapeutic agents well-known for inefficiency of drug penetration, non-selectivity, poor water solubility, poor pharmacokinetics, short half-life, adverse drug effects like systemic-neurotoxicity and multidrug / radiation-resistance which limits the therapeutic window, an impediment in patient-care treatment. Cancer is a complex immunological impediment which requires smart immunotherapeutics. Our own immune system to target, fight and eliminate cancer cells without affecting healthy cells represents an attractive treatment strategy. Cancer immunotherapy has become a powerful tool for the clinicians to treat cancer patients. To optimize the effectiveness of immunotherapy targeting antitumor immune response at multiple levels is needed. Another aspect is sky-rocketing cost of immunotherapeutics and multiple dose administrations unaffordable for patients. Nanoengineered formulations for biomedical applications and immunocancer therapy are the current trend. Main advantages of nanoparticulate carriers are improved solubility, bioavailability of the variety of cargos, durable long-term circulation and cost-effectiveness. Designing green nanoparticulate carriers for delivery of tumor immunotherapy for desired immune responses is demanding. Synergistic combinations such as combining immune checkpoint inhibitors or epigenetic immune-modulators or monoclonal antibodies, or chemotherapy combined with targeted delivery nanocarriers encapsulated inhibitors of immunosuppressive tumor microenvironment. Methods: We are working on the synthesis, physico-chemical characterization of immuno-targeted inorganic metallic nanoparticles using green chemistry, and intracellular analysis of this delivery system in specific targeted cancer cells such as squamous cell carcinomas and solid tumors. Results: The present study will lead to synthesis of potent nano-immuno-cancer therapeutics using green nanomaterials. Conclusions: The present strategy would serve for improved designing and promoting of these smart green nanomaterials as safe and more effective immuno-cancer therapeutics. Its mechanistic role leveraged to potentiate the immunotherapeutic effects against squamous cell carcinomas and solid tumors will also be understood.
Abstract No 28: Challenges to Immunotherapy and perception amongst Indian oncologists: A survey
SGCCRI, Thakurpukur, India.
Background: Though immunotherapy in oncology is extensively practiced amongst western population, there is still restricted use in Indian population due to various factors. The objective of this study is to understand the perception regarding immunotherapy and challenges towards usage amongst practicing oncologists of Eastern India. Methods: 90 practising oncologists (Medical, Radiation, Surgical and Hematology) were interviewed using a region specific questionnaire. Their identity was kept anonymous. Results: 98% oncologists believe that immunotherapy is expensive, and 97% oncologists are aware about the mechanism of action. Main advantage cited - less side effects (33%)> good response (33%)> target specific approach (22%). Main disadvantage cited – cost (64%)> adverse effects(18%)> autoimmunity (7%)> lack of response (5%). 82% believe that immunotherapy is more toxic than chemotherapy, 13% believe the other way round and 5% are unsure. 58% of oncologists believe immunotherapy should not be limited to advanced malignancies. 62% oncologists believe conducting trials on immunotherapy in India is a challenge and main barriers identified are unpredictable toxicity, lack of knowledge amongst professionals and public, unsuitable patients, administrative issues, late introduction to treatment. Certain other barriers outside the scope of clinical trials identified are - lack of experience, gap in communication, lack of established biomarkers and lack of response in a good number of patients.69% clinicians are aware of the phenomenon called pseudoprogression. Ways suggested to differentiate with true progression - imaging (46%), clinical assessment (19%), biopsy (6%), continue treatment and close follow up (16%). 13% answered don't know. Conclusion: The above survey identifies gaps and barriers in the usage of immunotherapy in India and can serve as a platform for more scientific and enhanced usage in cancer treatment.
Abstract No 29: Armored Glypican-3-specific CAR T cells for the Immunotherapy of Hepatocellular Carcinoma (HCC).
Batra SA, Rathi P, Guo L, Courtney AN, Nguyen, Fleurence, Metelitsa LS, Heczey A
Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Background: HCC is the third most common cause of cancer related mortality worldwide and to date there are no curative therapies for unresectable HCC. Immunotherapy targeting glypican-3 (GPC3) offers a promising approach to treat HCC. Previously, we developed GPC3-specific Chimeric-Antigen-Receptor (CAR) T cells for HCC. However, treatment of solid tumors using traditional CAR T cells has yielded only modest clinical benefit. Absence of homeostatic cytokine IL-15 in solid tumors is associated with defective lymphocyte activation and decreased patient survival. We hypothesized that transgenic expression of IL-15 in GPC3-CAR T cells will enhance their antitumor effect. We also hypothesize that co-expression of both IL-15 and IL-21 will further improve their antitumor effect. Methods: We systematically examined the antitumor properties of T cells co-expressing an optimized GPC3-CAR (GBBz) along with IL-15, IL-21 or both (15.GBBz, 21.GBBz and 21.15.GBBz, respectively) in preclinical models of liver cancer. Results: Armored GPC3-CAR T cells co-expressing cytokines IL-15 and/or IL-21 efficiently killed tumor cells in an antigen dependent manner. Constitutive IL-15 and IL-21 co-expression induced the enrichment of lesser differentiated T cells after initial expansion and also protected cells from apoptosis during tumor cell killing (p<0.05). Consequently, CAR T cells co-expressing both IL-21 and IL-15 (21.15.GBBz) had enhanced expansion compared to GBBz, 15.GBBz or 21.GBBz both in vitro and in vivo (p<0.001). Further analysis revealed that the combined expression of IL-15 and IL-21 best maintained TCF-1 (p<0.05), a transcription factor crucial for T cell development and survival. Lastly, IL-21 and IL-15 co-expressing GPC3-CAR T cells (21.15.GBBz) had robust antitumor activity superior to all the other constructs tested leading to improved survival of HCC-xenograft bearing mice (p<0.01). Conclusion: These studies indicate that co-expression of both IL-15 and IL-21 improves the antitumor properties of GPC3-CAR T cells and provides rationale for clinical testing in patients with HCC.
Abstract No 30: CT assessment of imaging response patterns of lung carcinoma to active immunotherapy.
Deshpande S, atwardhan S, Janu A
Tata Memorial Centre, Mumbai, India.
Background: Active immunotherapy is an emerging therapy that harnesses the adaptive response of the immune system to kill cancer cells that attempt to evade the immune system. This new immunomodulatory approach to cancer treatment shows new patterns of treatment response and treatment-related toxic effects that were not seen with traditional cytotoxic chemotherapy. Immunomodulatory therapy may show delay in response to treatment, such as slow decrease in tumor size and the appearance of new or enlarging lesions immediately afterinitiation of treatment that resolve or decrease in size over time, even without further therapy. Apart from various new patterns of response on imaging in lung carcinoma, the autoimmune toxicity provoked by these drugs may mimic progression of metastatic disease on serial CT scans. Methods: We have retrospectively analyzed CT scans of about 50 patients of lung carcinoma receiving immunotherapy in our institute. The serial scans were done at intervals of 12–16 weeks on a 16-slice multidetector Siemens CT machine, following administration of non-ionic iodinated intravenous contrast. The accompanying changes in the patient's clinical condition have also been taken into account. Bidimensionalassessment of the lesions was made. The i-RECIST criteria served as guidelines for characterizing the various imaging patterns. Results: About 35 patients showed the classical features of iUPD [unconfirmed disease progression] on the initial response assessment scans out of which 24 eventually fell in the iCPD category. 7 showed iPD on the initial response assessment scans, while 5 showed features favoring immune toxicity. The remaining 4 cases showed atypical imaging findings which could not be precisely characterized. Conclusions: The salient features of the immune response criteria are as follows. Due to a potentially delayed response to immunotherapy treatment, assessment for treatment response after completion of a cycle of therapy should be made with two consecutive follow-up CT scans performedat least 8 weeks apart. Unlike the RECIST criteria, new or enlarging lesions are not always consistent with progression of disease immediately after completion of treatment. These findings shall have significant impact on patient management, including management of immunotoxicity and most importantly, reporting of false-positive disease progression in lung carcinomas by amateur radiology.
Abstract No 31: Immunotherapy in Metastatic Thymoma: A rollercoaster ride
Medical Oncology, Max Hospitals, Delhi, India.
Background: Immunotherapy has ushered in a new era of cancer therapeutics. As it is increasingly becoming a crucial sword in our armamentarium against cancer, its judicious use and management of the adverse effects still remains a challenge. Case Report: 49 year old male, performance status 1 was diagnosed as a case of Metastatic Thymoma Type B1 with anterior mediastinal mass and pleural based nodular lesions in the right lung. He received 6 cycles of neoadjuvant chemotherapy with Cyclophosphamide, Cisplatin and Adriamycin followed by total pleurectomy and wedge resection of the underlying lung along with visceral pleurectomy (T4NxM0). Patient received 4 cycles of adjuvant chemotherapy with Gemcitabine + Docetaxel followed by a disease free interval of 22 months.He then had a recurrence in form of superior mediastinal mass with multiple nodules in right lung and supraclavicular node. Biopsy from supraclavicular node showed Thymoma Type B1, strongly positive for CD20. Patient was started on RICE protocol. PET-CT scan post 3 cycles showed complete response. He finished 6 cycles of RICE and was put on everolimus maintenance. After 3 months, patient developed interstitial lung disease and everolimus had to be stopped. In March 2010, patient had a recurrence and underwent a right redo thoracotomy with macroscopic resection of pleural tumor, pleurectomy, wedge resection and hyperthermic intrathoracic chemotherapy with Cisplatin. Histopathology showed thymoma right lower lobe-Type B1, Stage IVa, pT4N0Mx. Post surgery patient received External Beam Radiotherapy by Image Guided Radiation therapy to thorax to a dose of 50.4 Gy in 24 fractions followed by Stereotactic body radiation therapy boost to a dose of 6 Gy in single fraction. Immunohistochemistry showed a positive PDL1 score of 10%. Pembrolizumab was initiated at standard doses of 200mg q3 weekly. Post 9 weeks of therapy, after 3 cycles of immunotherapy patient presented with fatigue, right hypochondrium pain and breathlessness. Blood tests showed deranged thyroid profile and grade 3 hepatotoxicity as per Common terminology criteria, version 5.0. Thyroxin supplementation and steroids were initiated.Over a period of 2 days patient became severely dyspnoeic and oxygen dependent with development of Type 2 Respiratory failure. Chest X ray showed raised right diaphragm. Creatine phosphokinase was found to be significantly raised. Drug induced rhabdomyolysis of diaphragm was suspected. Respiratory failure worsened. With strong suspicion of pulmonary embolism patient was given 1 dose of Low molecular weight heparin while awaiting CTPA. Patient had a sudden fall in hemoglobin from 10 to 5.6 g/dl and became hypotensive. CT pulmonary angiography showed no evidence of pulmonary embolism but revealed a retroperitoneal hematoma of 16X12 cm with contrast ooze and raised diaphragm. Also evident was thrombosis in bilateral brachiocephalic and jugular veins. Patient was taken for abdominal angiography with embolisation of bilateral retroperitoneal hematoma. Post procedure patient's blood pressure recovered. Patient was managed with Thyroxine replacement, Steroids, Antibiotics, Antifungal prophylaxis, PCP prophylaxis. Tracheotomy was done and patient was continued on mechanical ventilation. In post-operative period, patient had Cytomegalovirus infection that was managed with Gancyclovir. In ICU, thereafter patient developed critical illness neuropathy and received Intravenous Immunoglobulins for same. After a prolonged ICU stay of 90 days, with gradual weaning from ventilator, patient was discharged from hospital with tracheostomy in situ, off any oxygen support. Thereafter patient has been on constant follow up with us, in response. His last PET-CT done in January 2019 revealed no evidence of disease. Conclusion: In a case of metastatic thymoma, failing multiple lines of therapy, immunotherapy became a desperate answer. However, it came with multiple complications such as autoimmune hypothyroidism, hepatitis. It also led to life threatening complications in form of drug induced rhabdomyolysis of diaphragm, bleeding and thrombosis with possible contribution to neuropathy. Early use of steroids along with multi-speciality coordinated vigorous management of complications ultimately resulted in recovery of the patient. Many questions remain unanswered as to whether radiation contributed to drug induced myositis. Whether the persistent response to disease is due to the continued benefit of immunotherapy. As our experience with immunotherapy grows, we will hopefully have answers to these and many more questions.
Abstract No 32: Differential interaction of recipient peripheral blood lymphocyte counts (ALC) with different in vivo depletion strategies in predicting outcomes of allogeneic transplant: An international two centre experience.
Sheth V1*, Kennedy V2*, Mclornan D1, Lavallade1, Potter V1, Engelhardt BG3, Savani B3, Chinratanalab W3, Goodman S3, Greer J3, Kassim A3, York S3, Kenyon M1, Gandhi S1, Kulasekararaj A1, Marsh J1, Mufti G1, Pagliuca A1, Jagasia M**, Raj K1**
1. Department of Haematology and Stem Cell Transplantation, Kings College Hospital, London, UK.
2. Department of Haematology and Stem Cell Transplant, Stanford University, CA, USA.
3. Department of Haematology and Stem Cell Transplant, Vanderbilt university, TN, USA.
*These authors contributed equally to the manuscript.
**These senior authors contributed equally to the manuscript.
Background: Dosing regimens for antithymocyte globulin (ATG) and anti-CD52 antibody (alemtuzumab) for graft vs host disease prophylaxis (GVHD) are empiric or weight-based, and do not account for individual patient factors. Recently, it has been shown that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered to predict transplantation outcome. Similarly, we wanted to analyse if the recipient ALC interacts with alemtuzumab dosing to predict outcomes. Methods: We retrospectively compared 364 patients, 124 patients receiving ATG (anti-thymocyte globulin) for GVHD prophylaxis and undergoing unrelated first allogeneic transplant for myeloid and lymphoid malignancies (group 1) to 240 patients receiving alemtuzumab (group 2), in a similar time period. Results: 68 patients received alemtuzumab 60mg and 131 patients received 100mg, whereas in the ATG group 52 patients received 5mg/kg, 21 patients received 7.5 mg/kg and 13 patients received 10mg/kg doses respectively. Median follow-up was 35 months in alemtuzumab and 30 months in ATG group. More patients in the alemtuzumab group compared to the ATG group received 9/10 mismatched donor grafts (3 vs 22%, p=0.0001), had more intermediate disease risk index, (57 vs76%, p=0.004) and higher exposure to myeloablative regimen, (28 vs 40%, p=0.04). The 2-year overall survival (OS), progression free survival (PFS), relapses and 1-year NRM (non-relapse mortality) for alemtuzumab group was 48%, 42% 38% and 14%, respectively and was comparable to ATG group, being 45%, 40% and 44%, 15% respectively, except for early relapses before 2 years (44 vs 32%, p=0.05) being significantly lesser for alemtuzumab, after adjusting for baseline co-variate disparities. The incidence of severe (grade 3 and 4) acute and chronic GVHD were 12% and 11% vs 16% and 25% for alemtuzumab and ATG respectively. There was no statistical difference in mild/moderate acute and chronic GVHD between the groups, (p=0.06). Unlike ATG (where the pre-transplant recipient ALC interacted with ATG dose on day of its administration (day 1) to predict OS and DFS, (p=0.05, p=0.04), within alemtuzumab group, the recipient ALC on second day of alemtuzumab administration (day 2) and its interaction with alemtuzumab dose strongly predicted OS, DFS and relapse, (p=0.05, HR-1.81, 0.9–3.3; p=0.002, HR-2.41, CI, 1.3–4.2; and p=0.003, HR-2.78, CI, 1.4–5.2), respectively. ALC (day 2) of 0.08 × 109/lit or higher, had a specificity of 96% in predicting inferior DFS. Conclusions: In summary, like ATG, there is definite but differential interaction between the recipient peripheral blood ALC and alemtuzumab dose to predict OS, DFS, and relapses. Based on such an analysis, theoretically a norm gram of ALC and alemtuzumab dose could be developed prospectively, which could help in individualizing dose of alemtuzumab as per target recipient ALC, without compromising immune-reconstitution. Also, there is a need for further prospective PK/PD modeling studies for alemtuzumab/ATG and CD52 expression in host lymphocytes, in analysing differential days of interaction with recipient ALC.
Abstract No 33: A single centre experience of use of Check point inhibitors: Aiims New Delhi
All India Institute of Medical Sciences, New Delhi, India.
Background: Check point inhibitors are new kid in the block in the fight against cancer. Real world experience of use of these molecules in Indian context is limited. In this review we share the experience of use of check point inhibitors at AIIMS, New Delhi. Methods: A retrospective analysis of use of check point inhibitors from January 2016 to februrary-2019 was done. Data was retrieved through hospital medical records. The details of number of cycles and the responses and toxicities were recording according to RECIST and CTCAE criteria respectively. Results: A total of 45 patients received check point inhibitors during this period. Out of them, lung cancer was 18, melanoma 16, Hodgkin's lymphoma 5, esophageal carcinoma 2, urothelial malignancies 3, and hepatocellular carcinoma 1. The responses to therapy and toxicity profile will be presented in detail during the oral presentation. Conclusions: Immuno-oncology drugs are well-tolerated, and few patients have durable responses. Identification of predictive biomarkers and management of toxicities is the need of the hour.