Immune checkpoint inhibitors increase T cell immunity during SARS-CoV-2 infection.

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.

[An example of Clinical Investigations Center reorganization during the COVID-19 pandemic French national lockdown]. / Un exemple de réorganisation dans le fonctionnement d'un Centre d'investigations cliniques en période de confinement national suite à la pandémie COVID-19.

BACKGROUND: The Clinical Investigations Center of Saint-Louis Hospital (CIC-1427) is a structure dedicated to clinical trials and mainly early phase trials (first-in-man administration, phase 1 and 2). These trials are conducted in a French Regional Health Agency (ARS) authorized structure. In March 2020, faced to the global COVID-19 pandemic and the French national lockdown measures, the CIC-1427 had to rapidly adapt its operating procedures to ensure the safety of both patients and staff. STUDY OBJECTIVE: Ensuring optimal management of patients included in early phase clinical trials, while respecting the good clinical and professional practices (GCP/GPP) of the CICs protocol sponsors' requirements, patients' safety and clinical research multidisciplinary staff safety (nurses, caregivers' assistants (AS), clinical research assistants (CRA), clinical trial coordinators (CTC), project leaders, health executive and investigating physicians), in the context of the health crisis related to COVID-19. METHODS AND RESULTS: Due to their activity, requiring on-site presence, each staff member of the CIC-1427 clinical research team had to adapt their daily activity to the constraints of the health crisis. New specific procedures were quickly developed to deal with the pandemic. Most of the on-site medical visits were replaced by virtual consults with biological assessments in the local laboratories. "Remote monitoring" replaced on-site monitoring visits. Treatments were sent to each patient's home via couriers after agreement of the CPPs of each protocol (Committee for the Protection of Persons). The essential visits were maintained on site thanks to the unfailing involvement of our clinical care team, with implementation of a specific sanitary protocol. CONCLUSION: The involvement of our entire multidisciplinary research team ensured that each patient was able to benefit from a personalized follow-up and to continue the treatment on-trial. The newly introduced procedures also allowed collection of a maximum of safety and efficacy data for clinical trial sponsors while complying with good regulatory practices. This set of procedures developed during the first epidemic wave, fundamentally helped setting the frame for a better coping during the subsequent pandemic waves.

Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients.

In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to be a new standard of treatment. Few data are available on anti-PD1 safety in patients who develop IPI-related severe adverse events (AEs) (grade≥3). The aim of this study was to compare the anti-PD1 safety and efficacy in patients with previous severe toxicity to IPI versus in those showing moderate and no previous IPI-related AEs. This single institution-based observational study included all patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for unresectable stage III or IV melanoma. The patients enrolled were classified according to the occurrence of IPI-related AEs: group A: no previous IPI-related AEs; group B: mild to moderate IPI-related AEs; and group C: severe to life-threatening IPI-related AEs. The main outcome measure was safety of the anti-PD1 among the three groups. The secondary endpoints included response parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients. The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4, and 66.7% among the patients in groups A, B, and C, respectively. The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.

Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma.

To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A 57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF, NRAS, and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression.

Atypical severe immune-related adverse effects resulting from sequenced immunotherapy in melanoma.

We report unusual severe toxicity in three patients treated at our institution with sequenced immunotherapy for metastatic melanoma. These three patients illustrate the unusual potential toxicity of sequential administration of anti-programmed cell death 1 followed by ipilimumab, and the need for careful monitoring of these toxicities associated with sequential immunotherapies. Data from forthcoming trials and national databases such as MELBASE, recently implemented in France, will be helpful in providing further insights into the risks and benefits of sequential immunotherapy schedules.