Despite increased risk for lung cancer development in human immunodeficiency virus (HIV)-infected individuals,[13] this patient population has historically been excluded from lung cancer therapeutic clinical trials. One analysis performed in the preimmunotherapy era reviewed 462 lung cancer therapeutic clinical trial protocols and found that 26% explicitly excluded HIV-infected individuals while <1% of protocols explicitly included persons with HIV infection.[4] Over the last several years, immune checkpoint inhibitors (ICIs) blocking the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) axis have become an essential component of the treatment paradigm for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer based on data from large phase III clinical trials;[513] however, these studies did not allow inclusion of HIV-infected individuals, due to safety concerns and the hypothesis that severe HIV/AIDS with low CD4+ T-cell counts may compromise the efficacy of these agents. Many uncertainties still exist regarding the use of ICIs for lung cancer in the HIV-infected patient population.

Among the biomarkers that have been evaluated to help determine which lung cancer patients will derive the most therapeutic benefit from anti-PD-1/anti-PD-L1 immunotherapy, PD-L1 protein expression by immunohistochemistry (IHC) has been the most extensively studied. There are limited data regarding PD-L1 expression in individuals diagnosed with concomitant lung cancer and HIV. One French study evaluated tumor PD-L1 expression using two antibodies among 34 HIV-infected and 54 HIV-undetermined patients with NSCLC; no difference in PD-L1 expression frequency (>5% considered positive) was found between the HIV-infected and HIV-uninfected groups (18.7% vs. 9.3% using E1 L3N clone; 10.0% vs. 5.6% using 5H1 clone).[14] A case–control study evaluated PD-L1, PD-1, and B7-H3 expression among NSCLC patients with (n = 13) and without (n = 13) HIV infection (SP142 clone used for PD-L1 testing, staining >5% considered positive).[15] PD-L1 expression on tumor cells was positive in 23% of cases and 46% of controls, while PD-L1 expression on tumor-infiltrating immune (TII) cells was positive in 31% of cases and 69% of controls.[15] The study demonstrated no significant difference in PD-L1 percent expression on tumor cells (median 0% vs. 0%, P = 0.5) or PD-L1 percent expression on TII cells (median 0% vs. 10%, P = 0.2).[15] A Japanese study evaluated the expression of PD-1/PD-L1 and immune cell infiltration within tumors from 15 HIV-infected and 29 HIV-uninfected NSCLC patients (E1 L3N clone used for PD-L1 testing).[16] Tumor PD-L1 expression (IHC 2+ and 3+) was positive in 33.3% of HIV-infected and 27.6% of HIV-uninfected patients. In the HIV-infected cohort, high tumor tissue PD-L1 expression was associated with worse overall survival compared to those with low PD-L1 expression (p = 0.0003).[16] Using propensity-scored matching analysis which accounted for age, performance status, epidermal growth factor receptor mutation sites, cigarette smoking, recurrence, and advanced stage, high PD-L1 expression remained associated with shorter overall survival in the HIV-infected cohort (p = 0.001).[16] Collectively evaluating the results of these limited studies, PD-L1 expression does not appear to significantly differ between HIV-infected and HIV-uninfected individuals, and the data appear to support inclusion of HIV-infected lung cancer patients in immunotherapy clinical trials. Other potential biomarkers of interest, including tumor mutational burden, have not been evaluated in this patient population.

In chronic viral infections such as HIV, persistent viral replication leads to progressive loss of T-cell functions of proliferation and cytokine secretion.[1719] Known as “T-cell exhaustion,” this process results in ineffective immune response and inability to adequately clear the virus. PD-1 is upregulated on both HIV-specific CD4+ and CD8+ T-cells, and PD-1 expression correlates with HIV-specific cytotoxic T-cell dysfunction.[1719] Studies of simian immunodeficiency virus (SIV) in rhesus macaques, which is thought to closely model HIV disease in humans, have demonstrated that blockade of PD-1 and PD-L1 interaction in SIV results in reversal of functional exhaustion of T-cells [Figure 1].[18] Some investigators hypothesize that PD-1 or PD-L1 inhibition could theoretically improve outcomes from both HIV and malignancy standpoint.

Figure 1:

Interactions between PD-1/PD-L1 pathway and HIV. PD-1: Programmed death-1, PD-L1: Programmed death ligand-1, MHC-1: Major histocompatibility complex class 1, TCR: T-cell receptor, APC: Antigen-presenting cell, HIV: Human immunodeficiency virus, CD8+ T cells: Cytotoxic T-lymphocytes, or CTLs, Credit: Created with BioRender.

Figure 1:

Interactions between PD-1/PD-L1 pathway and HIV. PD-1: Programmed death-1, PD-L1: Programmed death ligand-1, MHC-1: Major histocompatibility complex class 1, TCR: T-cell receptor, APC: Antigen-presenting cell, HIV: Human immunodeficiency virus, CD8+ T cells: Cytotoxic T-lymphocytes, or CTLs, Credit: Created with BioRender.

Published data evaluating the use of immunotherapy agents in HIV-infected lung cancer patients have mainly been limited to case reports or small case series [Table 1].[2028] Collectively, HIV-infected NSCLC patients treated with ICIs targeting the PD-1/PD-L1 axis do not exhibit significant differences from HIV-uninfected patients in terms of both activity (overall response rate [ORR] 27.5% and disease control rate 55.2%) and safety (immune-related adverse events [irAEs] 35% and grade 3/4 irAEs 9.7%). No cases have been reported to date evaluating chemotherapy–immunotherapy combinations or dual-immune checkpoint blockade in the HIV-infected NSCLC population.

Table 1:

Activity and safety of PD-1/PD-L1 in patients with HIV and NSCLC

Activity and safety of PD-1/PD-L1 in patients with HIV and NSCLC
Activity and safety of PD-1/PD-L1 in patients with HIV and NSCLC

Data from a recent systematic review analyzing 73 HIV-infected patients with various advanced solid tumors (including 25 NSCLC patients) treated with ICIs either as single agent or in combination showed similar results, with no new safety signals noted in this population and relatively good efficacy (objective response rate of 30% for NSCLC).[29] Of the 34 included patients with known paired pre- and post-treatment HIV viral load (VL), HIV VL remained suppressed in 93% of the cases with pretreatment undetectable HIV VL. CD4+ T-cell counts was noted to increase in 14 of the 25 included patients with known paired pretreatment and posttreatment CD4+ T-cell counts; the mean (standard deviation) change in CD4+ T-cell count was 12.3 (28.5)/μL.[29] These results suggest that ICI treatment does not negatively impact HIV VL or CD4+ T-cell counts in HIV-infected cancer patients, including those with NSCLC. Similar results were reported in phase I Cancer Immunotherapy Trials Network 12 study evaluating pembrolizumab in HIV-infected patients with different advanced cancers, including one NSCLC patient.[28] All the participants were on antiretroviral therapy and none met the U.S. Department of Health and Human Services criteria for uncontrolled HIV. Pembrolizumab was well tolerated with most irAEs graded as mild/moderate (73.3%); 20% of the irAEs were grade 3. No statistically significant differences were noted in CD4 count in all participants (median increase of 19 cells/μL; P = 0.18) or in those with stable disease for ≥24 weeks (median increase 152 cells/μL; P = 0.13). HIV remained suppressed in all participants. One treatment-related death was reported in a Kaposi sarcoma (KS) patient from a diffuse KS herpesvirus (KSHV)-associated polyclonal B-cell lymphoproliferation. The patient had a previous history of elevated peripheral blood mononuclear cell-associated KSHV and KSHV-associated inflammatory cytokine syndrome.[28] Therefore, in these patients, treatment with ICIs should be evaluated with caution. ICIs are particularly active in KS patients (ORR 67% with 1 complete response in a recent retrospective study),[30] and upfront treatment with pembrolizumab is under evaluation in the phase II KAPKEY study.

In conclusion, as the number of indications for immune checkpoint blockade grows, the number of HIV-infected patients potentially treated with these agents is destined to rise. Current evidence, coming mostly from case reports and small case series, suggests that single-agent PD-1/PD-L1 inhibitors can be used safely in HIV-infected NSCLC patients with similar efficacy results observed in the overall population. Several ongoing clinical trials are evaluating ICIs in HIV-infected patients with different solid tumors (NCT03094286, NCT02408861) or NSCLC only (CHIVA-2/NCT03304093). The results of these studies are eagerly awaited and will provide further evidence on safety and efficacy of immunotherapy in this patient population.

References

References
1.
Engels
EA,
Brock
MV,
Chen
J,
et al.
Elevated incidence of lung cancer among HIV-infected individuals
.
J Clin Oncol
2006
;
24
:
1383
8
.
2.
Patel
P,
Hanson
DL,
Sullivan
PS,
et al.
Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003
.
Ann Intern Med
2008
;
148
:
728
36
.
3.
Sigel
K,
Makinson
A,
Thaler
J.
Lung cancer in persons with HIV
.
Curr Opin HIV AIDS
2017
;
12
:
31
8
.
4.
Persad
GC,
Little
RF,
Grady
C.
Including persons with HIV infection in cancer clinical trials
.
J Clin Oncol
2008
;
26
:
1027
32
.
5.
Brahmer
J,
Reckamp
KL,
Baas
P,
et al.
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer
.
N Engl J Med
2015
;
373
:
123
35
.
6.
Borghaei
H,
Paz-Ares
L,
Horn
L,
et al.
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
.
N Engl J Med
2015
;
373
:
1627
39
.
7.
Herbst
RS,
Baas
P,
Kim
DW,
et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial
.
Lancet
2016
;
387
:
1540
50
.
8.
Rittmeyer
A,
Barlesi
F,
Waterkamp
D,
et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial
.
Lancet
2017
;
389
:
255
65
.
9.
Reck
M,
Rodríguez-Abreu
D,
Robinson
AG,
et al.
Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
.
N Engl J Med
2016
;
375
:
1823
33
.
10.
Gandhi
L,
Rodríguez-Abreu
D,
Gadgeel
S,
et al.
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer
.
N Engl J Med
2018
;
378
:
2078
92
.
11.
Paz-Ares
L,
Luft
A,
Vicente
D,
et al.
Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer
.
N Engl J Med
2018
;
379
:
2040
51
.
12.
Antonia
SJ,
Villegas
A,
Daniel
D,
et al.
Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer
.
N Engl J Med
2017
;
377
:
1919
29
.
13.
Horn
L,
Mansfield
AS,
Szczęsna
A,
et al.
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
.
N Engl J Med
2018
;
379
:
2220
9
.
14.
Domblides
C,
Antoine
M,
Hamard
C,
et al.
Nonsmall cell lung cancer from HIV-infected patients expressed programmed cell death-ligand 1 with marked inflammatory infiltrates
.
AIDS
2018
;
32
:
461
8
.
15.
Scilla
KA,
Zandberg
DP,
Bentzen
SM,
et al.
Case-control study of PD-1, PD-L1 and B7-H3 expression in lung cancer patients with and without human immunodeficiency virus (HIV) infection
.
Lung Cancer
2018
;
123
:
87
90
.
16.
Okuma
Y,
Hishima
T,
Kashima
J,
et al.
Correction to: High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer
.
Cancer Immunol Immunother
2018
;
67
:
1477
9
.
17.
Trautmann
L,
Janbazian
L,
Chomont
N,
et al.
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
.
Nat Med
2006
;
12
:
1198
202
.
18.
Kaufmann
DE,
Walker
BD.
PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention
.
J Immunol
2009
;
182
:
5891
7
.
19.
Porichis
F,
Kaufmann
DE.
Role of PD-1 in HIV pathogenesis and as target for therapy
.
Curr HIV/AIDS Rep
2012
;
9
:
81
90
.
20.
Chang
E,
Sabichi
AL,
Kramer
JR,
et al.
Nivolumab treatment for cancers in the HIV-infected population
.
J Immunother
2018
;
41
:
379
83
.
21.
Guihot
A,
Marcelin
AG,
Massiani
MA,
et al.
Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer
.
Ann Oncol
2018
;
29
:
517
8
.
22.
Hentrich
M,
Schipek-Voigt
K,
Jäger
H,
et al.
Nivolumab in HIV-related non-small-cell lung cancer
.
Ann Oncol
2017
;
28
:
2890
.
23.
Lavolé
A,
Guihot
A,
Veyri
M,
et al.
PD-1 blockade in HIV-infected patients with lung cancer: A new challenge or already a strategy?
Ann Oncol
2018
;
29
:
1065
6
.
24.
Le Garff
G,
Samri
A,
Lambert-Niclot
S,
et al.
Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab
.
AIDS
2017
;
31
:
1048
51
.
25.
McCullar
B,
Alloway
T,
Martin
M.
Durable complete response to nivolumab in a patient with HIV and metastatic non-small cell lung cancer
.
J Thorac Oncol
2018
;
13
:
1037
42
.
26.
Ostios-Garcia
L,
Faig
J,
Leonardi
GC,
et al.
Safety and efficacy of PD-1 inhibitors among HIV-positive patients with non-small cell lung cancer
.
J Thorac Oncol
2018
;
13
:
1037
42
.
27.
Li
D,
He
C,
Xia
Y,
et al.
Pembrolizumab combined with stereotactic body radiotherapy in a patient with human immunodeficiency virus and advanced non-small cell lung cancer: A case report
.
J Med Case Rep
2018
;
12
:
104
.
28.
Uldrick
TS,
Gonçalves
PH,
Abdul-Hay
M,
et al.
Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer-A phase 1 study
.
JAMA Oncol
2019
.
doi: 10.1001/jamaoncol.2019.2244. [Epub ahead of print].
29.
Cook
MR,
Kim
C.,
Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: A systematic review
.
JAMA Oncol
2019
.
doi: 10.1001/jamaoncol.2018.6737. [Epub ahead of print].
30.
Galanina
N,
Goodman
AM,
Cohen
PR,
et al.
Successful treatment of HIV-associated kaposi sarcoma with immune checkpoint blockade
.
Cancer Immunol Res
2018
;
6
:
1129
35
.

Financial support and sponsorship

The authors disclosed no funding related to this article.

Conflicts of interest

The authors disclosed no conflicts of interest related to this article.