A First-in-Human Study of YTB323, a Novel, Autologous CD19-Directed CAR-T Cell Therapy Manufactured Using the Novel T-Charge TM platform, for the Treatment of Patients (Pts) with Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL)

Abstract Background: Despite unprecedented efficacy of existing CAR-T cell therapy, many pts fail to respond to the therapy, or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell therapy utilizing the FMC63 domain for CD19 recognition and 4-1BB costimulatory domain. YTB323 is manufactured with an innovative simplified process, called T-Charge TM, which reduces the ex vivo culture time to about 24 hours and takes <2 d to manufacture the final product. The T-Charge TM platform preserves naive and stem cell memory T (T scm) cells in the final product (preclinical data will be reported separately), which is expected to result in longer CAR-T cell persistence, and in turn higher response rates and longer durability of response. Methods: This Phase I, multicenter, dose-escalation study (NCT03960840) is evaluating safety and preliminary efficacy of YTB323 in pts with B-cell malignancies. Results presented here focus on the DLBCL cohort. Eligible pts are adults with measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior therapies, including autologous hematopoietic stem cell transplantation (aHSCT). Pts received single-dose YTB323 at dose level 1 (DL1; 1-2.5×10 6 CAR+ cells), DL2 (5-12.5×10 6 CAR+ cells), or DL3 (25-40×10 6 CAR+ cells). Bridging therapy prior to YTB323 was optional. Primary endpoints are rate of dose-limiting toxicities (DLTs) in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Secondary endpoints are cellular kinetics, overall response rate (ORR) by local investigator assessment, duration of response, and overall survival. Results: As of April 16, 2021, 15 pts with r/r DLBCL were infused with YTB323: 4 at DL1, 10 at DL2, and 1 at DL3 (Fig, n=14 for DL1 and DL2). Median age was 65 years; most (60%) received 2 prior lines of therapy and 4 (27%) had prior aHSCT. All adverse events were reported regardless of study drug relationship. Of the 15 pts evaluable for safety, 4 pts (27%) reported at least one Grade (Gr) 3 AE, 6 (40%) at least one Gr 4 AE, and 2 (13%) at least one Gr 5 AE. Most commonly reported Gr 3/4 AEs were thrombocytopenia (n=2, 13%), neutropenia (n=3, 20%), and decreased neutrophil count (n=3, 20%). Seven pts (47%) had neurological AEs, of which 2 events (13%) were considered serious-1 event each of Gr 3 peripheral neuropathy (unrelated) and Gr 2 seizure (immune effector cell-associated neurotoxicity syndrome Grade 3, related to treatment). Four pts (27%) experienced cytokine release syndrome (CRS), including 3 (20%) Gr 1/2 and 1 (7%) Gr 4 (Lee et al, 2014), which met DLT criteria. Tocilizumab and corticosteroids were administered for CRS management in 2 (13%) and 1 (7%) pts, respectively. There have been 4 deaths on trial, all unrelated to YTB323: 2 due to disease progression and 2 to sepsis (1 at DL1 and 1 at DL3). Median time to onset of CRS was 9 d (range, 9-9 d) for DL1 and 11 d (range, 8-17 d) for DL2. Preliminary dose-dependent response was observed. At DL1, 4 pts were evaluable for efficacy at Mo 3 and the ORR and CR rates were both 25% (95% CI, 0.6%-80.6%). At DL2, 8 pts were evaluable for efficacy at Mo 3, including 2 pts in CR prior to YTB323 infusion; ORR and CR rates were both 75% (95% CI, 34.9%-96.8%). Dose-dependent expansion (C max and AUC 0-28d) was observed following infusion with mean peak expansion (C max) at DL2 of 13.6% CAR+ in CD3+ cells or 32,100 copies/µg DNA. Although long-term persistence cannot be evaluated yet, of the 8 pts at DL2 with 3-mo follow-up, 3 had detectable CAR expression by flow cytometry (≥1%). Time of peak expansion (T max) coincided with peak cytokine levels (~16 d post infusion). The novel manufacturing methodology of YTB323 allowed preservation of CD4 and CD8 naive/T scm cells in the final product as ascertained by flow cytometry. Bulk and single-cell RNAseq analysis demonstrated that YTB323 retained a naive stem-like phenotype. Conclusions: YTB323 recruitment is ongoing at DL3; RP2D remains to be identified. At DL2, YTB323 showed promising efficacy and a favorable safety profile. Current data support continued development of YTB323 in r/r DLBCL pts. Clinical trial information: CYTB323A12101 Figure 1 Figure 1. Disclosures Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consulta