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

Abstract

Background: The redundancy of CD28 and CD3 signaling in a CAR design incorporating all 3 immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a novel CD19 CAR construct with calibrated CAR signaling potential by mutating 2 of the 3 ITAMs, termed 1XX. In mouse models, 19-28z1XX CAR successfully induced tumor eradication at low CAR T cell doses with improved survival compared to conventional 19-28z CAR and with enhanced persistence of functional CAR T cells. We report on adult pts with DLBCL treated with 19(T2)28z-1XX CAR T cells (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. Pts received lymphodepleting chemotherapy followed by escalating doses of CAR T cells: 25–200 × 106. The primary objective was to evaluate safety and tolerability and determine the recommended phase 2 dose. Secondary objectives include overall response rate and duration of response. Results: Sixteen pts were treated on the dose escalation phase of the study. Median age was 62 (range, 50–80), and median number of prior treatments was 2 (range, 1–5). 4, 6, 3 and 3 pts were treated at DL1, DL2, DL3 and DL4 CAR T cells, respectively. 15 pts (94%) experienced cytokine release syndrome (CRS): grade 1 (n = 9), grade 2 (n = 6). No pts experienced ≥ grade 3 CRS. Two pts (13%) experienced neurotoxicity (NTX): 1 pt with grade 1 and 1 pt with grade 3. NTX was transient and reversible in both cases.Ten of 16 pts (63%) achieved a complete response (CR) and 2 pts (13%) achieved a partial response (PR), with overall response rate (ORR) of 75%. One pt who achieved initial PR spontaneously converted to CR without further treatment after month 6, resulting in best CR rate of 69%. Responses were seen across all dose levels. With a median follow-up of 155 days (range, 33–667), no pt in CR has experienced relapse including 7 pts with >6 months of follow-up (Figure 1). Peak CAR T cell expansion occurred at a median of 14 days after CAR T cell infusion (range, 7–83.3 days). CAR T cell detection beyond 350 days has been noted. DL 1 (25 × 10e6 cells) was chosen as the recommended dose for the expansion phase. Updated responses in the dose escalation cohort and the full expansion cohort, as well as PK data, will be presented. Conclusions: Treatment with 19(T2)28z1XX CAR T cells was safe. No severe CRS was observed and only 1 pt experienced transient grade 3 NTX. The overall CR rate was 69% and durable with no relapse observed with a median follow-up of 155 days. CRs were observed at DL1, which was chosen for the expansion phase. These findings corroborate our preclinical data and suggest that the 1XX signaling domain may lead to enhanced efficacy of CD19 CAR and allow infusion of a lower T cell dose with favorable toxicity profile. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. M. L. Palomba Consultant or advisory role: Synthekine, Cellectar, Kite, Bristol Meyer Squibb I. Riviere Consultant or advisory role: Fate Therapeutics, Akron Biotechnology Stock ownership: Mnemo Therapeutics, J. Li Employment or leadership position: Takeda L. Sellner Employment or leadership position: Takeda M. Sadelain Consultant or advisory role: Atara Research funding: Takeda, Mnemo Therapeutics S. Chen Employment or leadership position: Takeda Y. Zhao Employment or leadership position: Takeda J. H. Park Consultant or advisory role: Novartis, Kite, Kura, Astra-Zeneca, Servier, Curocell, Intella, Autolus, Allogene, Affymmune, Amgen Research funding: Genentech