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: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah: Epizyme: Consultancy; Legend: Consultancy; Incyte: Consultancy; Umoja: Consultancy; Lily: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Boissel: Novartis: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Bondanza: Novartis: Ended employment in the past 24 months, Patents & Royalties: Author of patent related to abstract; AstraZeneca: Current Employment. Lu: Novartis: Current Employment. Zhu: Novartis: Current equity holder in publicly-traded company; NIBR: Current Employment. Engels: Novartis: Current Employment, Current equity holder in publicly-traded company. Brogdon: Novartis Institutes for Biomedical Research: Current Employment. Mataraza: Novartis: Current Employment, Current holder of stock options in a privately-held company. Davis: Novartis: Current Employment, Current holder of stock options in a privately-held company. Marchal: Novartis: Current Employment. Mariconti: Novartis: Current Employment. Moschetta: Novartis: Current Employment. Parseval: Novartis: Current Employment. Barba: Gilead: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Dickinson: Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria.

Secretory co-factors in next-generation cellular therapies for cancer

“…Expressing the membrane-bound cytokines is intended to enhance the potency of engineered cells themself and minimize the effect on surrounding cells, which is supposed to work as a conditioned culture even in vivo (115)(116)(117). Therefore, this strategy could strongly support recently spotlighted fast CAR T-cell manufacturing procedures that expect in vivo expansion of CAR T cells instead of conventional ex vivo expansion (118,119). Another synthetic chimera form of cytokines is a targettethered cytokine composed of a cytokine and an antibody fragment or a specific binding domain (68,120).…”

The frequency of differentiated CD3+CD27-CD28- T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma

“…: 1422/2015, 1607/2018), YTB323 [n=2; EC No. : 2055/2019 ( 39 )], or in routine applications of tisagenlecleucel (n=6) or axicabtagene ciloleucel (n=3). Analysis of data was approved by the EC of the Medical University of Vienna (EC No.…”

Recent Advances and Challenges in Cancer Immunotherapy

“…Recent studies utilizing IL7 and IL15 for the expansion phase of CART culture (instead of IL-2 utilized FDA-approved products) and a shorter 8-day manufacturing period have shown an increase in T stem-cell-like memory populations and have been hypothesized to improve expansion and overall effectiveness [ 86 ]. Commercial production of 4-1BB CAR19 using a 2-day, expansion-free approach has demonstrated encouraging results [ 87 ]. This shorter method boosted stemness and proliferative potential by expanding CAR T cells in vivo (in human), as opposed to ex vivo [ 87 , 88 ].…”

“…Commercial production of 4-1BB CAR19 using a 2-day, expansion-free approach has demonstrated encouraging results [ 87 ]. This shorter method boosted stemness and proliferative potential by expanding CAR T cells in vivo (in human), as opposed to ex vivo [ 87 , 88 ].…”