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Background Chimeric antigen receptor (CAR) T-cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods We recruited 114 patients with B-cell malignancies, comprising 77 acute lymphoblastic leukemia (ALL) and 37 non-Hodgkin lymphoma (NHL) patients, who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T-cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), event-free survival (EFS) and overall survival (OS) were assessed. All statistical tests were 2-sided. Results We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T-cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR) adjusting by multiple testing. Using the sites linked to CR, the EPICART signature was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher’s exact test, P<.001) and enhanced EFS (HR = 0.36, 95% CI = 0.19 to 0.70, P=.002; log-rank P=.003) and OS (HR = 0.45, 95% CI = 0.20 to 0.99, P=.047; log-rank P=.04;). Most important the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35) where it was associated with CR (Fisher’s exact test, P<.001) and enhanced OS (HR = 0.31, 95% CI = 0.11 to 0.84, P=.02; log-rank P=.02). Conclusions We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria.

Background: Chimeric antigen receptor-engineered (CAR) T-cell therapy remains associated with significant toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Recently, the recombinant IL-1 receptor antagonist anakinra has emerged as a promising approach after failure of tocilizumab and corticosteroids to treat CRS/ICANS (Norelli, Nat Med 2018; Giavridis, Nat Med 2018). Here, we describe the safety and efficacy of two anakinra dose regimens to treat refractory CRS and/or ICANS after CAR T-cell therapy. Methods: We retrospectively analyzed data from 26 patients with B-cell or plasma cell malignancies treated at 9 institutions with anakinra for CRS and/or ICANS after CAR T-cell therapy. Details regarding CAR T-cell product and disease type are shown in the Table. CRS/ICANS grade was determined by applying the ASTCT criteria at the time of peak symptom severity. We defined response to anakinra as an improvement in CRS and/or ICANS symptoms per the attending physician's evaluation. Results: Patients, disease, and CAR T-cell product are shown in the Table. Anakinra was administered at 100-200mg/day subcutaneously (SC) in 13 patients (pts) (50%; low-dose), or at 8mg/kg/day SC or intravenously (IV) in 13 pts (50%; high-dose). Most pts were treated with anakinra for steroid-refractory ICANS (n=23); two pts were treated for tocilizumab-refractory CRS (n=2) and one for both (n=1). All but one patient received anakinra concurrently with corticosteroids. Median peak CRS and ICANS grade by ASTCT criteria was 2 (range, 1-4), and 4 (range, 0-5), respectively. Median CRS and ICANS duration was 5 days (range, 1-10) and 15.5 days (range, 1-38), respectively. Median time from CAR T-cell infusion to anakinra initiation was 9 days (range, 5-31). The median duration of anakinra treatment was 8.5 days (range, 1-47). The median time to anakinra initiation from CRS or ICANS onset was comparable in pts receiving high-dose compared to low-dose anakinra (4 versus 4 days, respectively; p=0.8). Comparable peak CRS (median grade, 2 versus 2, p=0.9) and ICANS (median grade, 4 versus 4, p=0.2) were measured in both groups. Other toxicity-directed therapies were administered in 8 pts receiving low-dose anakinra (siltuximab, n=8; intrathecal chemotherapy, n=2, etoposide n=1). The only infectious event reported after anakinra initiation was HHV6 encephalitis (n=1). Two pts with infections confirmed prior to anakinra initiation died after anakinra treatment: CMV pneumonia (n=1), Escherichia coli bacteremia (n=1). In one patient the anakinra administration route was changed from SC to IV due to a subcutaneous hematoma; in one patient anakinra was discontinued due to elevated liver enzymes. We observed anti-tumor responses (partial or complete) to CAR T-cell therapy in 15 pts (58%; B-ALL, n=1/1; DLBCL, n=9/15; MCL, n=3/4; MM; n=1/1; PMBCL, n=1/3), including complete responses in 11 pts (42%). In high-dose anakinra pts, the ORR was 77% (complete response, 53%). CRS/ICANS improvement was observed after anakinra initiation in 73% of pts with a median duration of treatment of 3 days (range 1-7). Higher response rates were seen in pts who received high-dose compared to low-dose anakinra (100% versus 46%, respectively; p=0.005) and the non-relapse mortality rate at day 30 was significantly lower in pts treated with high-dose anakinra compared to low-dose anakinra (0% versus 69%; p=0.001%). In addition, a shorter time to anakinra initiation from CRS or ICANS onset was associated with CRS/ICANS improvement (median, 2 versus 5 days in responders versus non-responders, respectively; p=0.04). Conclusion After failure of tocilizumab and/or corticosteroids, early administration of high-dose anakinra (8mg/kg/day IV or SC) was associated with rapid resolution of CRS/ICANS symptoms after use of tocilizumab and/or corticosteroids, with a manageable toxicity profile, and with a non-relapse mortality rate at day 30 of 0%. In contrast, 38% of patients treated with low-dose anakinra died from infections. We observed complete responses to CAR T-cell therapy in pts treated with high-dose anakinra, suggesting limited impact on in vivo CAR-T cell function. In summary, high-dose anakinra is a feasible and promising approach after failure of conventional CRS and ICANS-directed therapies. Prospective trials of anakinra to prevent or treat CRS and ICANS are ongoing. Figure 1 Figure 1. Disclosures Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Corral: Gilead: Consultancy; Novartis: Consultancy; Gileqd: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Maziarz: Allovir: Consultancy, Research Funding; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Vor Pharma: Other: Data and Safety Monitoring Board; Incyte Corporation: Consultancy, Honoraria; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Omeros: Research Funding; Intellia: Honoraria; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Turtle: AstraZeneca: Consultancy, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Allogene: Consultancy. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy.

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