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Previous studies reporting the response to SARS-CoV-2 mRNA vaccination in alloHSCT recipients used serological and/or cellular assays, but no study has evaluated vaccine-induced neutralizing antibodies. We prospectively studied 28 alloHSCT recipients who received two BNT162b2 doses. Two patients groups were defined according to time from alloHSCT and immunosuppressive treatment, and had different baseline immunologic status. Study end-point was the evaluation of humoral and cellular responses one month after the second vaccine. All patients seroconverted. Anti-S IgG levels and neutralizing antibodies percentages were not significantly different between both groups. Using IFNγ ELISpot assay, five patients showed a strong increase, without correlation with the humoral response. Using flow cytometry lymphocyte proliferation assay, 14 patients exhibited responding T cells, without difference between both groups or correlation with anti-S IgG levels. A few low serological responders had a detectable CD4 + T cell proliferative response. This finding should be confirmed in a larger cohort.

CD4+ T cells and CD4+ chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4+ T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4+ CAR T cells. Mechanistically, mouse or human CD4+ CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4+ CAR T-cell efficacy and may be considered to guide the use of CD4+ T cells during immunotherapy.

CAR-T cells represent a new anti-tumor immunotherapy which has shown its clinical efficacy in B-cell malignancies. The results of clinical trials carried out in this context have shown that certain immunological characteristics of patients before (at the time of apheresis) and after the administration of the treatment, or of the CAR-T cells themselves, are correlated with the response to the treatment or to its toxicity. However, to date, there are no recommendations on the immunological monitoring of patients treated in real life. The objectives of this workshop were to determine, based on data from the literature and the experience of the centers, the immunological analyses to be carried out in patients treated with CAR-T cells. The recommendations relate to the characterization of the patient's immune cells at the time of apheresis, the characterization of the injected CAR-T cells, as well as the monitoring of the CAR-T cells and other parameters of immune reconstitution in the patient after administration of the treatment. Harmonization of practices will allow clinical-biological correlation studies to be carried out in patients treated in real life with the aim of identifying factors predictive of response and toxicity. Such data could have a major medico-economic impact by making it possible to identify the patients who will optimally benefit from these expensive treatments.

International audience; No abstract available

CAR-T cells represent a new anti-tumor immunotherapy which has shown its clinical efficacy in B-cell malignancies. The results of clinical trials carried out in this context have shown that certain immunological characteristics of patients before (at the time of apheresis) and after the administration of the treatment, or of the CAR-T cells themselves, are correlated with the response to the treatment or to its toxicity. However, to date, there are no recommendations on the immunological monitoring of patients treated in real life. The objectives of this workshop were to determine, based on data from the literature and the experience of the centers, the immunological analyses to be carried out in patients treated with CAR-T cells. The recommendations relate to the characterization of the patient's immune cells at the time of apheresis, the characterization of the injected CAR-T cells, as well as the monitoring of the CAR-T cells and other parameters of immune reconstitution in the patient after administration of the treatment. Harmonization of practices will allow clinical-biological correlation studies to be carried out in patients treated in real life with the aim of identifying factors predictive of response and toxicity. Such data could have a major medico-economic impact by making it possible to identify the patients who will optimally benefit from these expensive treatments.

Purpose Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. Methods We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. Results We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. Conclusion Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus., INSERM, University of Paris; Rockefeller University; St. Giles Foundation; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R37AI095983]; French National Research Agency (ANR) under the "Investments for the future" programFrench National Research Agency (ANR) [ANR-10-IAHU-01, ANR13-ISV3-0001-01, ANR-16-CE17-0005-01]; ECOS-NORD [C19S01-63407, SRC2017]; ANRHGDIFDFrench National Research Agency (ANR) [ANR-14-CE15-006-01]; ANR-IFNGPHOX [ANR-13-ISV3-0001-01]; GENMSMD [ANR-16-CE17-0005-01]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/11757-2, 2010/51814-0, 2012/51094-2]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)National Council for Scientific and Technological Development (CNPq) [303809/2010-8]; Instituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Commission [PI11/01086, PI14/00405]; European Regional Development Fund (ERDF)European Commission; Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX) [619-2013]; Diana Garcia de Olarte foundation PID; ColcienciasDepartamento Administrativo de Ciencia, Tecnologia e Innovacion Colciencias [713-2016, 111574455633]; "Poste d'accueil" INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm); Imagine Institute, The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, University of Paris, The Rockefeller University and the St. Giles Foundation, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (R37AI095983), and grants from the French National Research Agency (ANR) under the "Investments for the future" program (ANR-10-IAHU-01) and IFNGPHOX (ANR13-ISV3-0001-01 for JB and ACN), GENMSMD (ANR-16-CE17-0005-01 for JB) grants, ECOS-NORD (C19S01-63407 for JB and JFR), and SRC2017 (for JB). CO-Q is supported by ANRHGDIFD (ANR-14-CE15-006-01). AG was supported by the ANR-IFNGPHOX (ANR-13-ISV3-0001-01), GENMSMD (ANR-16-CE17-0005-01), and the Imagine Institute. AC-N and EBO-J are supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ grant 303809/2010-8). MMG and RC are supported by Instituto de Salud Carlos III, grants PI11/01086 and PI14/00405, co-financed by the European Regional Development Fund (ERDF). JFR and AAA are supported by Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX; 619-2013, Diana Garcia de Olarte foundation PID and Colciencias grant 713-2016 #111574455633). JR was supported by "Poste d'accueil" INSERM and Imagine Institute.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the virus causing causing Coronavirus disease 2019 (COVID-19) was reported for the first time in Wuhan (Hubei, China) in December 2019 (1, 2) and has become a major public health concern all over the world.…

Background . Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells represent a major therapeutic advance in the management of patients (pts) with relapsed/refractory aggressive large B-cell lymphoma (R/R aggressive LBCL) with reported overall response rates between 40% and 83% in the pivotal trials (ZUMA1, JULIET, TRANSCEND) as well as in the real-life cohorts with either axicabtagene ciloleucel (axi-cel, Yescarta) or tisagenlecleucel (tisa-cel, Kymriah). However, a significant number of pts will experience failure after infusion, 20% to 35% of these failures occurring early during the first month. Lenalidomide is reported to activate CD8 T-cells, to inhibit regulatory T-cells and to restore T-cell immune synapse. Here, we report our experience with early exposure to Lenalidomide (LEN) in the treatment of early failure ( Methods . Between June 2018 and June 2021, 142 patients with R/R aggressive LBCL were treated with commercial anti-CD19 CAR T-cells, axi-cel (n=70) or tisa-cel (n=72). With a median follow-up of 11.4 months [IQR, 4.4-20.4], 76 patients experienced a failure based on the Cheson 2014 response assessment criteria, including 36 (47%) within the first month. Among those 36 patients who progressed during the first month, LEN was initiated before D15 in 17 pts (EARLY LEN pts), and 19 were not treated by LEN (OTHER pts). Efficacy of early LEN was assessed by CT-scan and 18FDG-PET after the 1st cycle and at the end of treatment. CAR T-cells expansion was monitored in blood by flow cytometry. All pts gave informed consent. Results . Median age of the 17 EARLY LEN pts was 65 yo (IQR 59-71) and 7 (41%) male. Histology subtypes were 12 (71%) DLBCL, including 7 GCB and 5 non-GCB, 1 (6%) PMBL, 4 (24%) tFL; 10 (59%) were treated with at least 3 prior therapies including 2 high dose therapy plus autologous stem cell transplantation. All received bridging therapy with 16 (94%) of them receiving high intensity regimen with combined immunochemotherapy. At time of infusion, 14 (82%) presented with an advanced disease (stage III or IV), 14 (82%) an elevated LDH level, 7 (41%) had at least 2 extra-nodal sites; 3 (18%) with low age-adjusted International Prognostic Index (aaIPI), 2 (12%) with low-intermediate aaIPI, 6 (35%) with high-intermediate aaIPI, and 6 (35%) with high aaIPI. Median total metabolic volume (TMTV) was 144 mL [IQR, 109-45]). The best overall response rate was observed in 15 (88%) of the EARLY LEN patients, including best complete response in 6 and best partial response in 9. Compared to the OTHER pts, the median progression-free (PFS) was significantly improved, with a median PFS of 68 days (95% CI, 52- not reached) vs 35 days (95%CI, 28-70) (p=0.035). Among the 6 pts with LEN< D15 that obtained a CR, PFS was even better with 3 events at 20, 88 and 451 days. Median overall survival (OS) was 97 days (95% CI, 76-Not reached) in the EARLY LEN pts, compared to 107 days (95 CI, 53-192) in the pts who progressed during the first month (p = 0.033). In univariate analysis, the 13 EARLY LEN pts evaluable for expansion had a higher CAR T-cell expansion in blood during the first 28 days (mean AUC D0-D28=1184 days*CART Cells number/µL of total blood) than other pts relapsing (mean=66 , p=0.0490), including those treated with LEN after D15 (mean=313, p=0.0166). Otherwise, expansion of these 13 EARLY LEN pts was similar to expansion of patients without relapse (mean=737, p=0.214). Grade 3-4 neutropenia was observed in 13 (76%) pts, grade 3-4 thrombopenia in 11 (65%) and grade 3-4 anemia in 8 (47%). Cytopenias required LEN discontinuation for 2 pts (12%). Cytokine release syndrome occurred in 13 patients (76%) (10 axi-cel and 3 tisa-cel) with a median duration of 6 days, including 1 (6%) grade 3 and no grade 4. Immune effector cell-associated neurotoxicity syndrome occurred in 6 (35%) (2 axi-cel and 4 tisa-cel) with a median duration of 10 days, including 1 (6%) grade 3 and no grade 4. Conclusion. Early LEN exposure at time of CAR T-cell expansion led to a high response rate in very high-risk pts of relapse after CAR T-cells. Comprehensive analyses of these mechanisms using tumor transcriptomic and single cell analyses should help for a comprehensive analysis on the peculiar mechanism of action of LEN, including not only an anti-tumoral effect, but also an immunomodulatory effect. Figure 1 Figure 1. Disclosures Di Blasi: Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Introduction The French health agency granted access to KTE-X19 in its early access program (French ATUs) for patients with relapsed or refractory (R/R) mantle-cell lymphoma (MCL) who failed after at least one line of chemoimmunotherapy and Bruton's tyrosine kinase (BTK) inhibitor. DESCAR-T is the French national registry for all patients treated with CAR-T cells (commercial or early access program). DESCAR-T designed and sponsored by LYSA/LYSARC aims to collect "real-life" data about CAR-T cell eligible patients in all hematological malignancies. We report the first results of "real-life" use of KTE-X19 in R/R MCL. Methods. All patients with MCL and registered in DESCAR-T were eligible for the present study. The data collection started at time of the medical decision to treat with KTE-X19. All patients gave informed consent before DESCAR-T registration. Response was determined by investigators per the Lugano criteria. CAR-T cells were monitored in peripheral blood samples of 14 patients by multiparametric flow cytometry routine procedures, using the biotinylated CD19 CAR detection reagent (Miltenyi Biotec©). Results Our study started at the beginning of the French early access program on January 7 th 2020 until data extraction on June 18 th 2021. A total of 57 patients were registered, including 6 commercial use registrations of KTE-X19 (after the end of early access program). KTE-X19 product has been ordered for 55 patients of whom 47 have been infused with CAR-T cells. KTE-X19 was not ordered in 2 cases because of patient decision. It was not infused in 8 patients because of disease progression (n=3), manufacturing failure (n=3), cardiac disease (n=1) and uncontrolled infection (n=1). At the time of registration in DESCAR-T, median age of infused patients was 67 years (range 45-79), 93.6% of patients were male. Median number of prior lines of treatment was 3 (range 2-8) with 34% of autologous stem cell transplant. Initial Ki67 was high (>30%) in 78.6% of patients, 52.4% of patients had elevated LDH and 21.1% had a poor performance status (PS≥2) at inclusion.Median time between CAR-T order and infusion was 56 days (range 35-134) and 87.2% of patients had a bridging therapy. Median follow-up since CAR-T administration was 3.3 months (range 0-12.6). The best overall response rate for the 42 patients with at least one efficacy evaluation was 88%, including CR in 61.9%. PFS calculated from KTE-X19 infusion at 6 months was 57.9% (Figure A) and median duration of 5.3 months. Cytokine release syndrome (CRS) was observed in 78.7% of patients and a neurotoxicity in 48.9%. Transfer in ICU was needed in 27.7% of patients, with a median duration of hospitalization of 5 days. CRS or neurotoxicity of ≥ grade 3 were seen in 4 patients (8.5%), one patient presented both AEs. Among the 47 infused patients, 5 died, 4 of progressive disease and 1 of grade 5 CRS. Cellular kinetics parameters including area under the curve (AUC) representing the exposure from day 0 to day 28 (Figure B), maximal expansion post infusion (C MAX, Figure C) and time to maximal expansion (T MAX, Figure D) are shown. We observed a statistical trend to a shorter T MAX in responders. Conclusion This first analysis of "real-life" use of KTE-X19 supports results of clinical trials using CAR-T cells in R/R MCL. The safety profile and the overall response rate are also in line with previously published data. Taken together, the present "real-life" study experience supports the use of KTE-X19 in R/R MCL who failed after BTKi. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Abbvie: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria; Takeda: Honoraria, Research Funding. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Bouabdallah: Abbvie: Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings . Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Janssen: Honoraria; Genentech, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Houot: MSD: Honoraria; Gilead: Honoraria; Roche: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria; Jsnssen: Honoraria; CHU Rennes: Current Employment; Celgene: Honoraria.