key: cord-0846377-rv465tym authors: Gatto, Lidia; Franceschi, Enrico; Nunno, Vincenzo Di; Brandes, Alba Ariela title: Potential protective and therapeutic role of immune checkpoint inhibitors against viral infections and COVID-19 date: 2020-06-29 journal: Immunotherapy DOI: 10.2217/imt-2020-0109 sha: ea587beddcec9ff1b3ac78acddc0f24dbdfb09f4 doc_id: 846377 cord_uid: rv465tym nan ative lung injury, with the formation of a clear liquid jelly and hyaline membrane. Tissue-resident macrophages overactivation is implicated in the release of a storm of cytokines leading to multiorgan dysfunction, such as pancytopenia, disseminated intravascular coagulation, hepatobiliary and central nervous system dysfunction. The crux of the pathogenesis is the overproduction, by tissues macrophages, of IL-1b, which drives the acute phase response to infection, the Th17 differentiation and the immunopathogenic response observed in acute respiratory distress syndrome and COVID-19 [6] . IL-1b and TNF-α both induce TH17 cell responses and vascular permeability. The overactivation of T cells, manifested by an increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury. TH17 cells produce IL-17 and GM-CSF, both associated with autoimmune and inflammatory disease. IL-17 promotes the production of G-CSF, IL-6, IL-1b and TNF-α that lead to systemic inflammatory symptoms, including fever. Chemokines like MIP2A, IL-8, IP10, MIP3A engage immune infiltrates [7] . IFN-γ is pleiotropic cytokine that enhances IL-6 production in monocytes and activates a large downstream cascade through the Janus kinase 1/Janus kinase 2 signaling. IL-6 promotes recruitment of neutrophils and cytotoxic T cells and has a crucial role: it inhibits the ability of lung dendritic cells to trigger naive T cells, thereby minimizing the adaptive immune response [6] . Huang et al. have performed comparison between patients who had been admitted to the intensive care unit and those who had not, observing that serum levels of IL2, IL7, IL10,G-CSF, IP10, MCP1, MIP1A and TNF-α are higher in intensive care units patients, suggesting that the cytokine storm is associated with disease severity [8] . Cancer immunotherapy works by reducing the suppression of the effector T cells, respiratory epithelial cells especially CD8 + , thereby restoring the cellular immunocompetence and improving tumor-specific immune responses. The main adverse effects of immune checkpoints inhibitors are related to excessive production of pro-inflammatory cytokines IL-6 and TNF-α; the immune-mediated lung injury, termed checkpoint inhibitor pneumonitis, occurs in about 3-5% of patients receiving ICI; however, the real-world incidence may be higher, especially now that ICI are used outward of clinical trials [9] . Thus, a potential synergy between the lung toxicity from ICI and the SARS-CoV-2 related interstitial-pneumonia has been hypothesized in patients receiving anticancer immunotherapy [3] . Patients receiving ICI are in a hyperimmune condition and can develop aberrant reactions in case of COVID-19 infection due to the overlap between the two pathogenetic mechanisms of lung injury. Is it possible to estimate the risk of contracting infections of cancer patients treated with immunotherapy compared with patients treated with chemotherapy and compared with the general population? Although our observations have no epidemiological background, we are quite surprised by the limited number of patients undergoing immunotherapy contacting us due to COVID-19. ICIs are currently widely used in oncology due to dramatic and durable responses in a variety of tumor types, but there are few data on their possible use in the treatment of human infectious diseases. Besides immunosurveillance in cancer, the pivotal function of immune system is the protection against pathogens, bacteria, viruses and fungi. As it occurs, even in chronic viral infections, for example, HIV and HBV infection, T cells undergo a continuous lasting antigen exposure, which is the driver of a phenomenon of 'anergy' in T cells called T-cell exhaustion. Exhausted CD8 T cells have reduced effector function and poor proliferative capacity and their primary characteristic is the overexpression of inhibitory receptors CTLA4 and PD-1/PD-L1 [10] . The efficacy of monoclonal antibodies against PD-1 and PD-L1, that have notably revolutionized the treatment of cancer, suggests that therapeutically targeting these pathways would also be effective for preventing and treating a range of infectious diseases. Several studies have suggested that ICIs empower T-cell responses giving immunity protection during many chronic viral, bacterial or parasitic infection, including malaria, HIV infection, HBV infection and TB. In numerous mouse models of cancer and chronic infection, PD-1-targeted therapy suppresses tumor growth and reduces viral load. Similar results have been observed in primates [11] . Many clinical trials on the use of immune checkpoint blockade in chronic viral infection are designed and performed in individuals with malignancies. Gane et al. have recently published a Phase Ib study of Nivolumab (anti PD-1) with and without GS-477, an HBV therapeutic vaccine, in chronic HBV-patients. They observed that Nivolumab was well-tolerated, leading to HBsAg decline in most patients. In one patient they obtained complete HBsAg seroconversion and HBsAg loss [12] . Gay et al. reported the role of an anti-PD-L1 antibody (BMS-936559) in HIV-infected patients in a Phase II study, obtaining an enhance of HIV-1-specific immunity in most of the participants. This is the only trial of an ICI in HIV patients without cancer disease [13] . Interestingly, the inhibition of the immune checkpoint system CD200-CD200R1 has shown positive effects on coronaviruses, restoring IFN production and increasing virus clearance [14, 15] . Immunotherapy (Epub ahead of print) future science group A trial with another ICI anti-PD1, Camrelizumab, is also ongoing in COVID-19 patients. Although the data from clinical trials in infectious diseases are still weak, checkpoint inhibitors are proving to have great potential in controlling viral infections and reducing viral load. Whereas on one hand the checkpoint blockade can contribute to 'fuel' the cytokine storm in case of coexistence of COVID-19, on the other hand, the recovery of immunocompetence could play a protective or even therapeutic role against the viral infection. We can therefore hypothesize two scenarios: • The first 'pre-infectious phase': the population treated with ICI is more 'resistant' to the attack of COVID-19; • The second 'infectious phase': patients receiving immunotherapy, when contracting the COVID-19, may develop more serious respiratory symptoms and complications, sustained together by the 'cytokine storm' and the ICI-immune mediated injury. Evidence-based guidelines on the correct management of cancer ICIs during the COVID-19 outbreak are currently lacking and experts are only providing generic practical recommendations [16] [17] [18] [19] such as: • To delay ICI in case of durable and long-lasting responses, considering the growing evidence of a durable benefit from immunotherapy after treatment outage; • To prefer regimens with longer interval, for example, durvalumab 4-weekly administration (instead of 2-weekly), nivolumab 480 mg every 4 weeks or pembrolizumab 400 mg every 6 weeks, in order to reduce the frequency of hospital visits; • To delay durvalumab (within 42 days) for III stage lung cancer after concomitant chemoradiotherapy; • To postpone immunotherapy in case of flu symptoms, in particular fever, cough, myalgia and fatigue. All presumed cases should be tested with nasopharyngeal swab-PCR for definite diagnosis. If a patient results positive to SARS-CoV-2 and is asymptomatic, 28 days of delay and two negative tests (at 1-week interval) should be considered before restarting the treatment. The issue whether to continue or delay immunotherapy during the coronavirus outbreak is crucial, since these agents may be detrimental in the case of virus-related pneumonia, but at the same time they are quite effective and potentially curative in cancer, especially in melanoma. A multicentric registry should be strongly encouraged to understand the impact of the COVID-19 infection on cancer patients and in particular on patients undergoing immunotherapy, and to identify the risk factors for poor outcome. The COVID-19 pandemic represents a unique challenge but also a learning opportunity. The complex immune responses for patients on immunotherapy treatment against noncancer antigens are largely unknown and giving an incorrect interpretation is a possibility. ICIs have only minimally been studied in human infectious diseases; therefore, it is not excluded that they may soon revolutionize the treatment against infectious agents, including COVID-19. Unfortunately, in the era of ICIs, the clinical advances in the oncology field are yet to be matched with those in the infectious, but there are broad perspectives for investigations and developments in future. COVID-19) situation report -52 Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors COVID-19 infection: the perspectives on immune responses COVID-19: consider cytokine storm syndromes and immunosuppression COVID-19 and lung cancer: risks, mechanisms and treatment interactions TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor fedratinib Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities Immune checkpoint blockade in infectious diseases Immune checkpoints and their inhibition in cancer and infectious diseases Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy The CD200-CD200R1 inhibitory signaling pathway: immune regulation and host-pathogen interactions CD200 receptor controls sex-specific TLR7 responses to viral infection Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: young oncologists' perspective Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic How we treat patients with lung cancer during the SARS-CoV-2 pandemic: primum non nocere Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.