CANCER IMMUNOTHERAPY AND COVID-19

In an article published in the journal Immunotherapy, Melissa Bersanelli, MD, of the Medical Oncology Unit, University Hospital of Parma, Italy, discusses controversies regarding the use of immune checkpoint inhibitor therapy in patients with cancer during the COVID-19 pandemic, suggesting that such use is warranted for many patients under certain conditions.

While noting that recommendations regarding the postponement of active cancer treatments in stable patients and patients with advanced disease receiving chemotherapy are sound, she identifies a number of controversies regarding the use of immune checkpoint inhibitors. Some of the key points made in her discussion are reproduced or summarized below.

Potential Overlap of COVID-19–Related Interstitial Pneumonia and Checkpoint Inhibitor Pneumologic Toxicity  

• The overall incidence of immune checkpoint inhibitor–related pneumonitis is relatively low—eg, ranging from 2.5% to 5% with anti–programmed cell death protein 1(PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy, to 7% to 10% with anti–CTLA-4/anti–PD-1 combination therapy. However, associated mortality is marked (eg, accounting for 35% of immune checkpoint inhibitor immune-related toxicity deaths). Immune-related adverse events tend to occur within 6 months of starting immune checkpoint inhibitor treatment.
• The dominant radiologic pattern of lung immune-related adverse events associated with immune checkpoint inhibitors is organizing pneumonia, but immune checkpoint inhibitor–related pneumonitis could exhibit a variety of patterns that include nonspecific interstitial pneumonitis.
• Given that underlying lung disease—particularly including interstitial pneumopathy—is considered a risk factor for immune checkpoint inhibitor–related pneumonitis, it is reasonable to take into account the risk of treating patients with immune checkpoint inhibitors while they are in initial stages of COVID-19 infection.
• The hypothetical synergy between the two lung injuries cannot be ruled out. Nevertheless, such an ‘epidemiologic coincidence’ should not prevent oncologists from offering a potentially effective and often well-tolerated treatment even in the middle of the COVID-19 outbreak, since the duration of the pandemic is still currently unpredictable. Such an approach is reasonable, considering the potentially curative aim of immune checkpoint inhibitor treatment in the context of highly responsive diseases and may make sense in the adjuvant setting even more than in advanced disease.

Effect of Immune Checkpoint Inhibitors on COVID-19 Pathogenesis

• Immune hyperactivation represented by cytokine-release syndrome occurs in the setting of T cell–engaging immunotherapy, including anti–PD-1 therapy. Cytokine-release syndrome is characterized by elevated levels of cytokines that provoke consequences and symptoms related to immune activation, ranging from fever, malaise, and myalgias to severe organ toxicity, lung failure, and death.
• In COVID-19 infection, one of the most important mechanisms underlying patient deterioration is cytokine storm, which may lead to acute respiratory distress syndrome and multiple organ failure.
• Analyses of COVID-19 patients has shown hyperactivation of CD4 and CD8 T cells, increased concentrations of highly proinflammatory factors in CD4 T-cells, and high concentrations of cytotoxic granules in CD8 T-cells, with these findings suggesting that overactivation of T cells tends to contribute to the severe immune injury in the disease.
• Further, pathologic findings associated with acute respiratory distress syndrome in COVID-19 infection indicate an abundance of interstitial mononuclear inflammatory infiltrates in the lungs that is dominated by lymphocytes—again suggesting that immune hyperactivation mechanisms are at least partially responsible for COVID-19 infection severity.
• Given such considerations, the potential for synergy between immune checkpoint inhibitor mechanisms and COVID-19 pathogenesis in producing immune hyperactivation cannot be excluded. However, it needs to be noted that immune checkpoint inhibitor–induced cytokine-release syndrome is rare, and that cytokine storm is not an early event in COVID-19 pathogenesis, typically being observed in the late phase of the most severe cases of the virus. Thus, it is unlikely that patients with cancer would still be receiving immune checkpoint inhibitors during this phase of COVID-19 illness. However, careful consideration should be given to the prospect of delaying treatment for patients presenting with flu-like symptoms at the time of intended immune checkpoint inhibitor treatment.

Dr. Bersanelli concluded, “Clinical decisions about [patients with] cancer deserving immunotherapy in the current context of the COVID-19 pandemic should be characterized by separated reflections, avoiding generalizations and remembering their deeply different immunological status compared with that of … patients undergoing chemotherapy or targeted agents. In the end, …it is unfortunately likely that in this COVID-19 pandemic, the greatest risk for patients [with cancer] is the unavailability of the usually high-level medical services, since all our hospital resources, in terms of structures, tools, and health-care professionals, are currently strongly dedicated to outbreak management.”