Prolonged manufacturing times for autologous CAR T cell therapies can be incompatible with rapidly progressive disease (PD), resulting in increased need for bridging therapy to achieve disease stabilization. Bridging therapy was required for most patients receiving cilta-cel and ide-cel in clinical trials (75 and 87%, respectively) (7, 9, 11, 12). Although use of bridging therapy may not affect ORR, CRR, or PFS, it is associated with worse overall survival (15). Similarly, as wait times for CAR T cell product increase, so does risk of mortality as effectiveness of the therapy decreases (16, 17), highlighting the need for improved CAR T cell products with faster and more reliable manufacturing.
Another issue associated with traditionally manufactured CAR T cell products is T cell exhaustion due to extended periods of in vitro stimulation and expansion during manufacturing (18). Higher levels of exhausted T cells were also observed in the leukapheresis material and final products from patients who later experienced PD (18). T cell exhaustion can result in poor persistence of CAR T cells in the body, thereby impeding function as the proliferation and survival of transferred T cells strongly correlate with their antitumor activity (19–22). Specific T cell populations have varying abilities to expand and persist in vivo. Memory (CD8+CD45RO−CD27+) and naive T cell (TN cell) subsets are associated with improved clinical response, given their ability to proliferate and persist after infusion, whereas effector T cell subsets comparatively exhibit lower self-renewal and survival capabilities (19, 23, 24). Although these patient-specific parameters are initially established in leukapheresis material, preservation of such cell populations in the final product via manufacturing techniques may improve the antitumor activity of a patient’s CAR T cell therapy (18, 19, 23, 24).
Durcabtagene autoleucel (PHE885) is an autologous, BCMA-targeting CAR T cell therapy carrying a CAR construct with a fully human anti-BCMA single-chain fragment variable (scFv) fused to 4-1BB/CD3ζ signaling domains manufactured on a next-generation platform. Prior work has shown that this platform can successfully manufacture product in fewer than 2 days by eliminating the need for ex vivo expansion, thereby preserving overall T cell stemness (the ability of T cells to self-renew and mature), which results in a final product with greater proliferative potential and fewer exhausted T cells (18). Here, we present the findings of part A of the phase 1 study (NCT04318327) of durcabtagene autoleucel in r/r MM, along with correlative analyses of the product before and after infusion.
