4. Immune Checkpoint Inhibitors Role in COVID-19 Infection:
One of the most important clinical challenges during the COVID-19 pandemic is the management of patients who need to receive anti-cancer therapy due to significant immunosuppressive effects of conventional chemotherapy agents. Immune checkpoint inhibitors like anti-PD-1/PD-L1 or anti-CTLA-4 have been introduced in past decades as novel anti-cancer agents for specific carcinomas like non-small cell lung cancer and melanoma, colorectal cancer, and others. This class’s immunomodulatory property is a considerable advantage over conventional chemotherapy agents as they are not associated with significant immunodeficiency during treatment (27). For example, one of the concerns with conventional chemotherapy agents is the reactivation of past viral infections or contributions to the spread of current concomitant viral infections like HIV and HCV due to their immunosuppressive side effects. However, a large number of clinical trials proved that immune checkpoint inhibitors are not associated with this risk, So they can be safe and effective in treating virally related or unrelated cancer patients with active COVID-19 infection (28).
Another hypothesis is that these agents might be useful in treating active COVID-19 infection, even in non-cancerous patients, due to their profound immunomodulatory effects and especially T cells activation (29).
Recent research showed that PD-1 expression is upregulated in the early phase of COVID-19 infection, which can be a T cell exhaustion marker. This evidence suggests that certain immune checkpoint inhibitors with anti-PD-1/PD-L1 activity (e.g., nivolumab, pembrolizumab, avelumab) might reinvigorate exhausted T cells and improve virus clearance (30). There is a question here, how T cell exhaustion is implicated in disease progression?
Studies on chronic viral infections’ pathophysiology revealed the association between functionally exhausted T cells and viral infection persistence. T cell exhaustion is a deterrent factor in preventing cellular damage by extra inflammatory cytokines in immune responses. However, on the other hand, it can be an excellent opportunity for the pathogen to invade cells in the absence of sufficient immune system activity and developing a persistent infection. Viral pathogens induced early T cell exhaustion by targeting the cellular and molecular pathways that determine T cell differentiation and produce effector and memory cells(31).
As mentioned before, analytical studies on infected cells in COVID-19 patients showed higher levels of PD-1 in CD4+ & CD8+ T cells, especially in more severe forms of the disease that led to the patient’s ICU admission. Another important finding in serum analysis of these patients is extra high levels of Interleukin-10 (IL-10), an inhibitory cytokine implicated in T cell exhaustion by inducing inhibitory effects on T cell proliferation. According to this evidence, the application of potential T cells reinvigorating agents such as immune checkpoint inhibitors in the early phase of the disease might limit the COVID-19 progression(32).
So, can these agents be the preferable anti-cancer choice in this situation or even be an independent therapeutic option for COVID-19 treatment?
Recent studies showed that although immune checkpoint inhibitors do not expose patients to immunodeficiency, which is a considerable criterion in this pandemic and might be useful for treating active COVID-19 infection, they might be associated with greater concerns that even overweight their immunomodulatory benefits.
The first concern related to these agents is the promotion of extra inflammatory events in response to different immune-activating mechanisms associated with increased cytokine-mediated toxicity (33). The incidence of immune-related adverse events (IrAEs) with these agents depends on the dose and mechanism of action. For example, ipilimumab, an anti-CTLA4 antibody, is associated with about 60% IrAEs that 10-30% of these are considered serious and life-threatening, such as hepatitis, hypophysitis, and autoimmune thrombocytopenia. Generally, anti-PD-1 antibodies (such as nivolumab or pembrolizumab) are associated with less frequent and milder immune-mediated side effects. Approximately only 10% of patients receiving these agents experience serious IrAEs such as hepatitis and pneumonitis(34). The major concern here is the possible overlap between the possible pneumatological toxicity from anti-PD-1/PD-L1 agents and the coronavirus-related interstitial pneumonia. Although interstitial pneumonia is a rare adverse reaction of immune checkpoint inhibitors, it is one of the fatal forms of reactions associated with an estimated 35% mortality and cannot be ignored(35).
In the end, what is the best recommendation? Regarding the lack of enough clinical studies on both advantages and disadvantages of these agents in the COVID-19 pandemic, the use of immune checkpoint inhibitors cannot be strongly suggested as a COVID-19 treatment protocol or definite prior choice in cancer treatment. However, the probable overlap of adverse drug reactions should not encourage oncologists to deprive patients of these agents if they are an effective treatment choice for them.