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Abstract
Objective CC-97540 (BMS-986353) is an investigational CD19 CAR T-cell therapy utilizing the lisocabtagene maraleucel CD19-directed CAR T construct with a 41BB co-stimulatory domain and an epidermal growth factor receptor safety switch and is manufactured using the optimized NEX-TTM platform (figure 1A). Here, we present preclinical and phase 1 clinical data demonstrating CD19-specific cell targeting, CC-97540 CAR T expansion, and hypogammaglobulinemia in patients with relapsed or refractory non-Hodgkin lymphoma (RR NHL), suggesting that transformational clinical responses from an immune reset may be achieved at similar doses in patients with systemic autoimmune diseases (AID) like systemic lupus erythematosus (SLE).
Methods In vitro studies tested target cell killing using Incucyte® S3 Live-Cell Analysis System (Sartorius 4647) with endogenous and engineered cell lines expressing various levels of CD19. CC-97540 was analyzed in vivo using a NALM6 xenograft model.
A multicenter phase 1 trial (NCT04231747) is investigating CC-97540 in patients with RR NHL. Following leukapheresis, patient T cells are purified and engineered followed by limited ex vivo expansion. After lymphodepleting chemotherapy (3 days fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2]), patients receive a single infusion of CC-97540 at 10×106 (dose level [DL] 1) or 25×106 (DL2) CAR T cells.
Results CC-97540 depletes CD19-expressing target cells completely in vitro and in vivo (figure 1B,C). As of March 20, 2023, 18 patients with RR NHL have been enrolled in NCT04231747; 16 have been treated (DL1: n=10; DL2: n=6). Transgene levels demonstrated robust cellular expansion, followed by a decrease in serum IgG and IgA levels (figure 2A–C). Despite persistent hypogammaglobulinemia, absolute lymphocyte, neutrophil, and platelet counts had transient decreases with subsequent rapid recovery (figure 2D–F).
Conclusions CC-97540 is a NEX-TTM investigational CAR T product that can achieve deep CD19-specific cellular depletion in vitro and in vivo. In patients with RR NHL, hypogammaglobulinemia was induced at low CC-97540 doses, indicating that an immune reset and clinical remission may be observed at similar doses in patients with systemic AID like SLE. CC-97540 is being tested in the phase 1, multicenter, open-label study evaluating the safety and tolerability in patients with severe, refractory SLE (NCT05869955).
Funding Bristol Myers Squibb.
Overview of the (A) construct of CC-97450 and CD19 target cell depletion (B) in vitro and (C) in vivo. (A) Vector design includes scFv that specifically binds to an epitope on the extracellular domain of CD19, CD28tm (an intracellular CD33 signaling domain), an intracellular 41BB co-stimulatory domain, and the huEGFRt safety switch. (B) Cytotoxicity: the functional capacity of CC-97540 to kill CD19-expressing cell lines was performed with K562-CD19/NLR target cells expressing CD19 co-cultured with CC-97540. (C) Endogenous CD19-expressing NALM6 xenograft NSG mice were treated intravenously with CC-97540 at 1.0 x 106 cells per mouse and compared to control (NALM6 no treatment) (n = 8 per group). Disseminated tumor growth was assessed by imaging NALM6 firefly luciferase-positive bioluminescence. 3’LTR, 3’ long terminal repeat; CD28tm, CD28 transmembrane domain; E:T, effector-to-target ratio; huEGFRt, non-functional, truncated human epidermal growth factor receptor safety switch; p/s, photons/sec; scFv, single-chain variable fragment; T2A, ribosomal skip sequence
CC-97540 pharmacokinetic and pharmacodynamic profile from patients with R/R NHL in the CC-97540-NHL-001 phase 1 clinical trial (NCT04231747). Median CC-97540 transgene levels following infusion over time are shown in red and blue lines for DL1 and DL2 with individual patient values shown in grey. The dotted line indicates the lower limit of quantification (40 copies/ug). Time courses of transgene levels were measured by droplet digital polymerase chain reaction in whole blood and plotted using Rstudio (Version 1.4.1103–4; Posit Software, PBS, Boston, MA, USA). Mean values for serum IgG, IgA, absolute neutrophil count, absolute lymphocyte count, and platelets following CC-97540 infusion are shown in red and blue lines for DL1 and DL2, respectively, with individual patient values shown in grey. Dotted lines for IgG and IgA panels represent low normal immunoglobulin levels. IgG and IgA measurements taken after intravenous immunoglobulin supplementation were excluded (GraphPad Prism 9, GraphPad Software, La Jolla, CA, USA)
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