key: cord-1002852-6hsbzm59 authors: Di Cosimo, Serena; Malfettone, Andrea; Pérez-García, José Manuel; Llombart-Cussac, Antonio; Miceli, Rosalba; Curigliano, Giuseppe; Cortés, Javier title: Immune checkpoint inhibitors: A physiology-driven approach to the treatment of COVID-19 date: 2020-06-04 journal: Eur J Cancer DOI: 10.1016/j.ejca.2020.05.026 sha: 4db3607a0dea04c4e1c3da4ae5bdd39a8435c9f1 doc_id: 1002852 cord_uid: 6hsbzm59 While confirmed cases of infections of the deadly coronavirus disease 2019 (COVID-19) have exceeded 4.7 million globally, scientists are pushing forward with efforts to develop vaccines and treatments in an attempt to slow the pandemic and lessen the disease’s damage. Although no proven effective therapies to treat COVID-19 patients or for managing their complications currently exist, the rapidly expanding knowledge regarding severe acute respiratory syndrome–coronavirus 2 and its interplay with hosts provide a significant number of potential drug targets, and the potential to repurpose drugs already tested in other diseases. Herein we report the biological rationale of immuno-activating drugs and a brief summary of literature data on the potential therapeutic value of immune checkpoint inhibitors that have been recently tested beyond cancer treatment for their potential to restore cellular immuno-competence. • Severe COVID-19 patients present with lymphocytopenia and T cell exhaustion. • Persistent stimulation by SARS-CoV-2 leads to the inhibition of immune system. • Immune blockade in cancer patients supports host protective immunity. • ICIs safely restore immuno-competence in sepsis and viral infections. • Immune stimulants should be considered as the first-line option in severe COVID-19. There is increasing recognition that a state of impaired host immunity accompanied by a significant cell 89 degeneration in secondary lymphoid tissues follows the initial hyperinflammatory phase of COVID-19. First, critically ill high-risk COVID-19 patients often present with lymphocytopenia: A fall in total 91 lymphocyte number to 0.6 x 10 6 /mL is associated with a mortality rate of 75%. 2 Second, COVID-19 92 patients have high levels of serum IL-6, IL-10, and TNF-α and express increased levels of exhaustion 93 markers PD-1 and T cell immunoglobulin mucin-3 on the surface of their peripheral T cells, which in turn 94 impair T cell effector functions and prevent functional memory. 9 Finally, compared to cases of Several studies reported no increase of incidence or severity of immune-related adverse events 13,14 and, 108 as an additional finding, it has been described a lower overall rate of influenza among vaccinated patients 109 when compared to rates of laboratory-confirmed influenza. 14 Other data show that ICI-induced 110 pneumonitis is a very rare phenomenon (2.5-5%) with anti-PD-1/PD-L1 single-agent to 7-10% with dual 111 checkpoint blockade and most patients experienced clinically significant, new, or worsening immune-112 related adverse events after the first 6 months of treatment. 15 ICIs revealed that heterozygous HLA-I genotypes were associated with better survival than homozygosity 148 for one or more HLA-I genes, and treatment efficacy was diminished by loss of HLA-I heterozygosity. 20 149 These findings highlight that genetic variability in immune system may affect susceptibility to (and 150 severity of) SARS-CoV-2; therefore, strategies to boost immune responses at this stage are certainly 151 important for individuals particularly vulnerable to COVID-19. We believe that there is sufficient evidence to support clinical trials combining IL-6R antagonists with 153 PD-1 inhibitors to improve outcomes in COVID-19 patients. We propose that an earlier intervention with 154 anti-PD-1 therapy will minimize the need for intensive care support. Clinical features of patients infected with 2019 novel coronavirus 183 in Wuhan, China. The Lancet Clinical course and risk factors for mortality of adult inpatients with 185 China: a retrospective cohort study. The Lancet Comorbidities and multi-organ injuries in the treatment of COVID-188 19 Cancer patients in SARS-CoV-2 infection: a nationwide 190 analysis in China. The Lancet Oncology SARS-CoV-2 Transmission in Patients With Cancer at a 192 Tertiary Care Hospital in Wuhan, China Immunological insights on influenza infection and 195 vaccination during immune checkpoint blockade in cancer patients Elevated exhaustion levels and reduced functional 198 diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients Functional exhaustion of antiviral lymphocytes in COVID-19 Reduction and Functional Exhaustion of T Cells in Patients with 204 Coronavirus Disease 2019 (COVID-19). medRxiv Study of the Lymphocyte Change between COVID-19 and 207 Non-COVID-19 Pneumonia Cases Suggesting Other Factors besides Uncontrolled Inflammation 208 Contributed to Multi-Organ Injury. Infectious Diseases (except HIV/AIDS) Immune checkpoint inhibition in sepsis: a Phase 1b 211 randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 212 nivolumab Immune Checkpoint Inhibition in Sepsis: A Phase 1b Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 215 BMS-936559)*. Critical Care Medicine Immunogenicity and safety of influenza vaccination in 218 cancer patients receiving checkpoint inhibitors targeting PD-1 or PD-L1 Influenza Vaccine in Cancer Patients Receiving Immune Checkpoint Inhibitors Epidemiological and clinical characteristics of 99 cases of 2019 224 novel coronavirus pneumonia in Wuhan, China: a descriptive study Effective Treatment of Severe COVID-19 Patients with Tocilizumab Role of PD-1 during effector CD8 T cell differentiation Mouse models of acute and chronic hepacivirus 231 infection Human leukocyte antigen susceptibility map for SARS-233 Patient HLA class I genotype influences cancer Immune checkpoint inhibitors: A physiology-driven approach to the treatment of COVID-19 SDC: fees for medical education from Novartis and Pierre-Fabre JMPG: consultant/advisory board member for Roche, Lilly; travel, accommodation paid by Roche MSD; stock or other 11 ownership in MedSIR and Initia-Research; consultant/advisory board member for Lilly Genomic Health, GSK; speakers' bureau honoraria from Lilly Pierre-Fabre, Agendia; 14 travel GC: consultant/advisory board member for Roche JC: stock or other ownership in MedSIR; consultant/advisory board member for Roche Daiichi Sankyo; research funding to the Institution from Roche, Ariad pharmaceuticals Puma C, Queen Mary University of London. 25 AM and RM declare no competing interests