RBD- specific Th1 responses are associated with vaccine-induced protection against SARS-CoV-2 infection in patients with hematological malignancies.

The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.

Efficacy, safety and ancillary analyses of pembrolizumab in combination with nintedanib for the treatment of patients with relapsed advanced mesothelioma

BackgroundWe report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab).MethodsPatients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma.Results30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29;24.1%), Stable Disease (SD, n=17/29;58.6%) and Progressive Disease (n=5/29;17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months.ConclusionsWith a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM.Trial RegistrationClinicalTrialsgov, NCT02856425. Registered August 4, 2016 — Prospectively registered,https://clinicaltrials.gov/ct2/show/NCT02856425?term=PEMBIB&draw=2&rank=1.Ethics ApprovalThe protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

The immuno-oncological challenge of COVID-19.

Coronavirus disease 2019 (COVID-19) and its causative virus, SARS-CoV-2, pose considerable challenges for the management of oncology patients. COVID-19 presents as a particularly severe respiratory and systemic infection in aging and immunosuppressed individuals, including patients with cancer. Moreover, severe COVID-19 is linked to an inflammatory burst and lymphopenia, which may aggravate cancer prognosis. Here we discuss why those with cancer are at higher risk of severe COVID-19, describe immune responses that confer protective or adverse reactions to this disease and indicate which antineoplastic therapies may either increase COVID-19 vulnerability or have a dual therapeutic effect on cancer and COVID-19.

Immune responses during COVID-19 infection.

Over the past 16 years, three coronaviruses (CoVs), severe acute respiratory syndrome CoV (SARS-CoV) in 2002, Middle East respiratory syndrome CoV (MERS-CoV) in 2012 and 2015, and SARS-CoV-2 in 2020, have been causing severe and fatal human epidemics. The unpredictability of coronavirus disease-19 (COVID-19) poses a major burden on health care and economic systems across the world. This is caused by the paucity of in-depth knowledge of the risk factors for severe COVID-19, insufficient diagnostic tools for the detection of SARS-CoV-2, as well as the absence of specific and effective drug treatments. While protective humoral and cellular immune responses are usually mounted against these betacoronaviruses, immune responses to SARS-CoV2 sometimes derail towards inflammatory tissue damage, leading to rapid admissions to intensive care units. The lack of knowledge on mechanisms that tilt the balance between these two opposite outcomes poses major threats to many ongoing clinical trials dealing with immunostimulatory or immunoregulatory therapeutics. This review will discuss innate and cognate immune responses underlying protective or deleterious immune reactions against these pathogenic coronaviruses.

Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.