Cutaneous Squamous Cell Carcinoma Lesion Regression After SARS-Cov-2 Infection and Discontinuation of Anti-PD-1 Therapy: Evidence For A Viral Abscopal Effect?

Emerging evidence indicates that immune checkpoint inhibitors (ICIs) may be safe and effective in cancer patients who become infected with the novel 2019 severe acute respiratory syndrome coronavirus (SARS-CoV-2), the etiological agent responsible for the ongoing COVID-19 pandemic. However, limited data exist on the interplay between checkpoint inhibition and anti-tumor immune responses in the context of SARS-CoV-2 infection. Persistent viral infection and cancer both cause T cell exhaustion via the PD-1/PD-L1 axis and severe COVID-19 is associated with dysfunctional T cell responses and upregulation of exhaustion markers coupled with a systemic inflammatory milieu sometimes characterized as a "cytokine storm." The potential for SARS-CoV-2 to affect anti-tumor immune responses has been described previously in isolated case reports. Here we describe a case of an older man with advanced cutaneous squamous cell carcinoma who became infected with SARS-CoV-2 while receiving anti-PD-1 checkpoint blockade. The patient not only recovered from COVID-19 with no long-term adverse effects despite the presence of comorbidities but also a pronounced reduction in tumor burden was seen 2 months after ICIs were stopped due to infection. The case provides evidence for a virally mediated abscopal effect in patients with COVID-19 and cancer.


Introduction
Furthermore, the patient's lesions continued to shrink after ICIs were halted, suggesting the possibility of a viral abscopal effect.

Abstract
Emerging evidence indicates that immune checkpoint inhibitors (ICIs) may be safe and effective in cancer patients who become infected with the novel 2019 severe acute respiratory syndrome coronavirus (SARS-CoV-2), the etiological agent responsible for the ongoing COVID-19 pandemic.However, limited data exist on the interplay between checkpoint inhibition and anti-tumor immune responses in the context of SARS-CoV-2 infection.Persistent viral infection and cancer both cause T cell exhaustion via the PD-1/PD-L1 axis and severe COVID-19 is associated with dysfunctional T cell responses and upregulation of exhaustion markers coupled with a systemic inflammatory milieu sometimes characterized as a "cytokine storm."The potential for SARS-CoV-2 to affect anti-tumor immune responses has been described previously in isolated case reports.Here we describe a case of an older man with advanced cutaneous squamous cell carcinoma who became infected with SARS-CoV-2 while receiving anti-PD-1 checkpoint blockade.The patient not only recovered from COVID-19 with no long-term adverse effects despite the presence of comorbidities but also a pronounced reduction in tumor burden was seen 2 months after ICIs were stopped due to infection.The case provides evidence for a virally mediated abscopal effect in patients with COVID-19 and cancer.

Conclusion
In summary, this report adds to the growing body of evidence that PD-1 blockade may be safe and effective for patients with cancer and COVID-19.Furthermore, the documentation of continuing tumor response even after cessation of therapy adds insight into the crosstalk between anti-viral and anti-tumor immunity, the mechanisms of which should be further explored to enhance the efficacy of both immunotherapy and COVID-19 treatments.

Statements
COVID-19, the disease caused by the novel 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global health emergency.Although highly effective vaccines have been developed since the virus first emerged in Wuhan, China, and subsequently spread to infect millions of people worldwide within 15 months, non-universal access and compliance, emerging variants, and recurrent local outbreaks necessitate ongoing social and physical distancing measures in several regions to slow the spread.COVID-19 causes a multi-organ inflammatory syndrome characterized by acute respiratory distress, disseminated coagulation, and a "cytokine storm" [1].Anti-inflammatory interventions such as corticosteroids and interleukin (IL)-6 modulation have reduced mortality in severe COVID-19.However, robust T-cell responses are also essential for viral clearance, and dysfunction in the lymphocyte compartment has been linked with worse outcomes [2-4].T cell responses are known to be dysregulated in patients with cancer, and immune checkpoint inhibitor (ICIs) antibodies targeting the PD-1/PD-L1 axis offer deep and durable responses to many patients with a variety of solid tumors.ICI therapy's known mechanisms and toxicities may include inflammatory pulmonary manifestations reminiscent of COVID-19 pneumonitis, causing speculation at the beginning of the pandemic that checkpoint blockade could cause worse outcomes in SARS-CoV-2-infected cancer patients.Emerging data suggest that developments in ICI-treated patients are no worse than individuals with comparable comorbidities receiving conventional anticancer treatment [5,6].More data is needed to understand the safety and efficacy of ICI therapy in patients with cancer and COVID-19, especially the interplay between anti-viral and anti-tumor immunity.Here, we describe a case report of a patient with advanced cutaneous squamous cell carcinoma (CSCC) who became infected with SARS-CoV-2 while on the anti-PD-1 therapy cemiplimab.The patient recovered completely after hospitalization, interruption of ICI, and treatment with steroids.

:
Figure 1).At presentation, the patient's Eastern Cooperative Oncology Group (ECOG) performance status score was 1. Baseline comorbidities were chronic obstructive pulmonary disease (COPD), managed with formoterol every 12 hours, and hypertension, for which the patient was treated with lercanidipine.Systemic immunotherapy consisted of the anti-PD1 cemiplimab at a dosing schedule of 350 mg every 3 weeks.At the first assessment, significant size reductions were seen for the parotid lesion, the frontal lesions, and the lateral cervical lymph nodes (see Figure1).Therapy was well-tolerated, and no immune-related adverse events (irAEs) were observed while on treatment.The patient received 8 cycles of cemiplimab before testing positive for COVID-19 during routine

Figure 1 :
Figure 1: Images of cutaneous squamous cell carcinoma lesions at (a), showing reductions in size and ulceration from baseline while on-treatment with cemiplimab (b), and continued improvement after therapy was halted due to SARS-CoV-2 infection (c)