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

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...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.892-892
Main Authors: Park, Jae H., Palomba, Maria Lia, Devlin, Sean M., Valtis, Yannis K., Sikder, Devanjan S, Senechal, Brigitte, Wang, Xiuyan, Cathcart, Elizabeth, Liotta, Kelly, Yu, Alina, Stocker, Kelsey, Zhang, Honglei, Schoder, Heiko, Leithner, Doris, Li, Jia, Sellner, Leopold, Mansilla-Soto, Jorge, Riviere, Isabelle, Sadelain, Michel
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Language:English
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Summary: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 (25x10 6), DL2 (50x10 6), DL3 (100x10 6) and DL4 (200x10 6 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
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-187623