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892 A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Improving CAR-T Therapies for B Cell Malignancies
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies
Monday, December 11, 2023: 3:30 PM

Jae H. Park, MD1, Maria Lia Palomba, MD2, Sean M. Devlin, PhD3*, Yannis K. Valtis, MD1, Devanjan S Sikder4*, Brigitte Senechal4*, Xiuyan Wang, PhD4*, Elizabeth Cathcart5*, Kelly Liotta6*, Alina Yu6*, Kelsey Stocker6*, Honglei Zhang7*, Heiko Schoder, MD8*, Doris Leithner, MD9*, Jia Li10*, Leopold Sellner11*, Jorge Mansilla-Soto1*, Isabelle Riviere11* and Michel Sadelain, MD PhD12

1Memorial Sloan Kettering Cancer Center, New York, NY
2Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY
4Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
5Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
6Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York
7Memorial Sloan Kettering Cancer Center, New York
8Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York
9Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
10Takeda Development Center Americas, Inc., Cambridge, MA
11Takeda Development Center Americas, Inc., Lexington, MA
12Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Autologous CD19 CAR T cell therapies have demonstrated favorable clinical responses in relapsed or refractory (R/R) diffuse large B-cell lymphomas (DLBCL), but only a subset of patients (pts) experience durable remissions. We hypothesized that the redundancy of CD28 and CD3ζ signaling in a CAR design incorporating all 3 CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX, and hypothesized that a 1XX CAR would afford durable responses at lower dose and fewer toxicities compared to CARs comprising 3 ITAMs. We previously presented the data from the dose-escalation portion of the phase I clinical trial of 19(T2)28z-1XX CAR T cells in DLBCL (Park J et al. ASH 2022). We have now completed accrual and report the updated results from both dose escalation and expansion portion of the study with a longer follow-up (NCT04464200).

Methods: This is a single-center, phase I, dose-escalation and expansion trial of 19(T2)28z1XX CAR T cells in adult pts with R/R DLBCL conducted at Memorial Sloan Kettering Cancer Center. Pts received fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by a single infusion of CAR T cells. There were 4 dose levels in the dose escalation cohort: dose level (DL) 1 (25x106), DL2 (50x106), DL3 (100x106) and DL4 (200x106 CAR T cells). The primary objective of the trial was to evaluate safety and tolerability and determine the recommended phase 2 dose. Key secondary objectives include assessment of overall response and complete response rates.

Results: 28 pts have been enrolled and treated; 16 pts on the dose escalation and 12 pts on the dose expansion phase of the study. Median age was 62 (range, 48-86). 20 pts (71%) had primary refractory disease, 3 pts (11%) had prior autologous HSCT, and 2 pts (7%) had prior autologous CD19 CAR T therapy. In the dose-escalation phase (n=16), 15 pts experienced grade 1-2 CRS (94%) and no pt experienced ≥grade 3 CRS. Two pts (13%) experienced ICANS: 1 pt with grade 1 and 1 pt with grade 3 (Table 1). Eight pts received tocilizumab and 5 pts received corticosteroid. Complete response (CR) was observed in 11 of 16 pts (69%) and partial remission (PR) in 1 pt (6%) with overall response rate (ORR) of 75%. Responses were seen across all dose levels (Table 1). The lowest dose (DL1: 25x106) was selected for dose-expansion based on exposure-response analysis and 12 additional pts were treated at that dose level. In a pooled analysis of 16 pts who received DL1 dose (4 in dose escalation and 12 in dose expansion), 12 pts and 1 pt experienced grade 1-2 (75%) and grade 3 CRS (6%), respectively. Only 1 pt experienced ICANS (6%) at grade 3 (same pt who had grade 3 CRS), which was reversible and transient (Table 1). 11 pts received tocilizumab and 9 pts received corticosteroids. Twelve pts achieved CR (75%) and 2 pts (12%) PR with the best ORR of 87% (Table 1). A lower metabolic tumor volume (MTV) at screening but not at post-bridging was associated with a higher likelihood of achieving CR (p=0.039). With a median follow-up of 345 days (range, 33-1024), 4 pts experienced relapse (1 CR and 3 PR pts) and 16 pts have ongoing CR > 6 months (Figure 1). While CAR T cell persistence analysis is ongoing, 5 pts have CAR T cells detected beyond one year in ongoing CR including a patient treated at DL1 with detectable CAR T cells at 2 years.

Conclusions: Treatment with 19(T2)28z1XX CAR T cells was shown to be safe with durable remissions with low rates of severe CRS (4%) and ICANS (7%). The overall CR rate of 71% is encouraging and appears durable with the majority of CR patients in ongoing remission > 6 months at a median follow-up of 345 days and with persisting CAR T cells. With more patients treated at DL1 with a longer follow-up, the study demonstrates a high efficacy of 19(T2)28z1XX CAR T cells at a dose significantly lower (25x106) than those of approved CD19 CAR T cells (100-300x106) and support that the 1XX single ITAM signaling domain may lead to enhanced efficacy of CD19 CARs and allow infusion of a lower T cell dose with favorable toxicity profiles.

Disclosures: Park: Autolus Therapeutics: Research Funding; Curocell: Consultancy; Affyimmune: Consultancy; Amgen: Consultancy; Genentech, Inc.: Research Funding; Artiva Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bright Pharmacetuicals: Consultancy; Be Biopharma: Consultancy; BeiGene: Consultancy; Fate Therapeutics: Research Funding; Servier: Consultancy, Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intella: Consultancy; Incyte: Research Funding; Takeda: Consultancy, Research Funding; GC Cell: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Research Funding; Pfizer: Consultancy; Kite: Consultancy; Minerva Bio: Consultancy. Palomba: MustangBio: Honoraria; Seres Therapeutics: Honoraria, Patents & Royalties; Rheos: Honoraria; Novartis: Honoraria; Pluto Immunotherapeutics: Honoraria; Synthekine: Honoraria; GarudaTherapeutics: Honoraria; Smart Immune: Honoraria; Thymofox: Honoraria; Kite: Honoraria; Juno: Honoraria, Patents & Royalties; Ceramedix: Honoraria; Cellectar: Honoraria; BMS: Honoraria. Valtis: EastRx: Consultancy. Schoder: Aileron Therapeutics: Honoraria. Li: Takeda: Current Employment. Sellner: Takeda: Current Employment. Mansilla-Soto: Takeda: Patents & Royalties: Licensed patents. Riviere: Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company. Sadelain: Takeda: Research Funding; Minerva: Current equity holder in private company; Atara: Research Funding; Mnemo: Current equity holder in private company, Research Funding; Fate: Research Funding.

OffLabel Disclosure: 19(T2)28z-1XX CAR T cells

*signifies non-member of ASH