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.