S1634 A PHASE I FIRST‐IN‐HUMAN CLINICAL TRIAL OF CD19‐TARGETED 19–28Z/4–1BBL “ARMORED” CAR T CELLS IN PATIENTS WITH RELAPSED OR REFRACTORY NHL AND CLL INCLUDING RICHTER TRANSFORMATION
Authors: M.L. Palomba, C. Batlevi, I. Riviere, B. Senechal, X. Wang, J. Yang, P. Kane, Y. Bernal, R.R. Furman, C. Diamonte, E. Halton, J. Pineda, B. Renier, M. Sadelain, P. Jae
Journal: HemaSphere (2019)

Background: Second generation, CD19‐specific chimeric antigen receptor (CAR) T cell therapy containing either the CD28 or 41BB co‐stimulatory domain have demonstrated long‐term complete remission (CR) rates of 40–50% in relapsed or refractory (R/R) NHL and 20–30% in CLL. The suboptimal activity of the 2 nd generation CAR T cells in NHL and in particular CLL may be due, in part, to poor proliferation and cytolytic activity of T cells in the inhibitory tumor microenvironment. We have previously demonstrated that binding of 4–1BBL to its cognate receptor enhances T cell proliferation, IL‐2 secretion, survival and cytolytic activity of the T cells compared to 19–28z, 19–41BBz and 1928BBz (Zhao Z et al. Cancer Cell 2015;28:415–428). Herein, we report updated results ona study of adult patients with CLL and NHL treated with escalating doses of autologous 19–28z/4–1BBL + CAR T cells (NCT03085173). Aims: The primary objective of this study was to determine the toxicity and MTD of 1928z‐41BBL CAR T cells in patients with relapsed or refractory CD19+ hematologic malignancies. Secondary objectives was to assess the anti‐tumor efficacy and in vivo persistence of the CAR T cells. Exploratory objectives were to assess the level of MRD when applicable and to assess the impact of infused CAR T cells on endogenous anti‐tumor immune response and changes in cellular and cytokine tumor microenvironment. Methods: Pts with R/R NHL (DLBCL, follicular lymphoma (FL), transformed FL (tFL), Waldenström's macroglobulinemia (WM)), CLL including Richter's transformation and B‐ALL were eligible for the trial. Pts received conditioning chemotherapy of cyclophosphamide (Cy) alone or combined with fludarabine (Flu) followed by escalating doses of CAR T cells. CAR T cells were administered at dose level (DL) 1 (1x10 5 CAR T cells/kg), DL2 (3x10 5 CAR T cells/kg), DL 3 (1x10 6 CAR T cells/kg), and DL4 (3x10 6 CAR T cells/kg). Results: 28 pts were enrolled with R/R CLL (n = 9), de novo DLBCL (n = 9), tFL (n = 3), FL and WM (n = 4), Richter's transformation (n = 3) and a single pt with B‐ALL. Median age was 70 (range, 53–81), and median number of prior treatments was 5 (range, 2–17). 3 pts received DL1 CAR T cells, 3 pts DL2 CAR T cells, 3 pts DL3 CAR T cells and remaining 19 pts received DL4 CAR T cells. No dose‐limiting toxicity (DLT) was observed. All 28 pts are at least 2 weeks from T cell infusion and evaluable for toxicity. Overall, 11 pts experienced CRS (39.3%), which were mostly grade 1 (n = 6) and grade 2 (n = 4) and 11 pts (39.3%) experienced neurotoxicity (NTX), including 8 pts with grade 1–2 and 3 pts with grade 3 NTX. 16 of 28 pts (57%) achieved a CR, including 7 of 9 pts (78%) with large cell lymphoma, 2 of 3 pts with FL (67%), 3 of 10 pts (30%) with CLL, 2 pts with Richter's transformation (67%) and the one pt with B‐ALL. The pt with WM achieved a VGPR. With a median follow‐up of 169 days (24–534 days), 8 pts (29%) remain in CR. Peak CAR T cell expansion occurred at a median of 9 days after CAR T cell infusion (range, 2–82). CAR T cell detection beyond 160 days has been noted. Summary/Conclusion: Treatment with 19–28z/41BBL armored CAR T cells is safe. No severe CRS was observed and severe NTX occurred in 8% of the pts. The overall CR rate of 57% is encouragingCR rates were higher in pts with large cell lymphoma (78%) compared to CLL (20%), though small number of pts limits any firm conclusions. Pts with CLL may require higher doses of CAR T cells or incorporation of the CAR therapy in earlier lines of treatments. Detailed cytokine and CAR T cell expansion analysis as well as updated data will be presented. image