Dear Editor,

A recent editorial by Hajjar[1] concisely highlighted the key challenges of cancer immunotherapy in immunocompromised patients. We wish to expand on those emerging issues and their relevance to clinical practice.

Since the advent and inclusion of cancer immunotherapies in the treatment of solid cancers and hematologic malignancies, their impact on immunosuppressed patients was prominently questioned. Cancer immunotherapy not only offers novel mechanisms of action but also offers lack of cross-resistance with other treatment modalities. Although the concept of cancer immunosurveillance is certainly not new, it was not until recently that immune evasion was considered a hallmark of cancer[2] and that any disequilibrium of the immune function has the potential to drive or promote carcinogenesis. The mechanisms of immune evasion leading to cancer are complex and not completely elucidated yet, but the higher incidence of certain malignancies in immunosuppressed patient is well established.[3,4] The degree of this association is highly variable and depends on the specific aspects of immune deficiency and other factors, such as the duration of immunosuppression, the immunomodulatory agents used, and the different patient populations. However, a more intriguing and perhaps even less understood aspect is the bidirectional relationship between immunosuppression and malignancy and their interplay with agents manipulating and directing the immune system toward antitumor responses.

Limited data exist, to date, on the efficacy of immunotherapy in this unique population of immunosuppressed patients. These patients were excluded from early immunotherapy trials; however, retrospective studies reported safe use of immune checkpoint inhibitors (ICI) in patients with underlying immunosuppression due to HIV infection or autoimmune disorders.[5,6] Clinical trials are underway to answer the question of safety and efficacy of ICI in these patients. On the other hand, literature on the safety and efficacy of ICI is rather conflicting in transplant recipients, where there is a real risk of potentially fatal organ rejections.[7] Interestingly, no association between the particular ICI used and rejection was observed, and most patient deaths were ultimately attributed to disease progression rather than graft rejection sequelae. Nevertheless, with graft rejection rates of close to 40%, physicians should be wary using immunotherapies in this context, where clinical trials are lacking due to rarity of these patients.

Finally, one has to also consider immunosuppressed patients those receiving steroids at low dose for a variety of reasons. Many patients receive steroids for dyspnea, fatigue, or cerebral edema. There is evidence stemming from retrospective studies on patients with lung cancer, supporting that early or baseline use of corticosteroids impacts adversely ICI response rates and outcomes.[8,9] In those cases, it is reasonable switching to alternative medications or decreasing corticosteroid dose (<10 mg), if feasible, recognizing that patients who are receiving steroids have typically more aggressive and extensive disease, which represents a possible confounding effect when interpreting these data. In contrast, late use of steroids in the treatment course may confer improved outcomes, perhaps reflecting the evidence linking immune-related adverse events and efficacy of ICI.[9,10]

Immunocompromised patients with cancer pose a real challenge for clinicians. and the incidence is only about to increase as supportive care is optimized further. In parallel, as the knowledge of the immune system expands, more mechanisms between the interaction of immunosuppressive states, malignancy, and immunotherapies will hopefully be unveiled. In the meantime, clinicians do have some evidence to apply in patient care, with caution and clinical judgment always having paramount importance.

References

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Conflicts of interest

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