Posted: Wednesday, June 21, 2023
The ability to assess T-cell exhaustion attributable to CAR (chimeric antigen receptor) T-cell therapy may be possible, according to a study presented at the European Hematology Association (EHA) 2023 Hybrid Congress (Abstract S188). “The limited durability of responses and the development of treatment resistance present significant challenges,” said Julia Frede, PhD, of Dana Farber Cancer Institute and Harvard Medical School, Boston, and colleagues. “Limited expansion and persistence of CAR T cells, T-cell exhaustion, and a hostile immune microenvironment are key factors that restrict the efficacy of CAR T-cell therapies,” they noted.
The researchers used droplet-based, single-cell RNA sequencing and immune profiling on CD45-positive immune cells from the bone marrow of four patients with relapsed or refractory multiple myeloma to assess the immune status of targeted cells. The patients were receiving B-cell maturation antigen–targeted CAR T-cell therapy, with samples taken at 1 and 6 months after treatment. Longitudinal single-cell RNA sequencing of CAR T cells and CD8-positive T cells was was also conducted, using samples from 24 patients in the KarMMA-2/KarMMa-3 trials.
The investigators reported a temporary expansion of the myeloid compartment after 1 month of CAR T-cell therapy. Significant changes were identified in the CD8 T-cell compartment, including an increase in GZMB-positive CD8 effector T cells and a decrease in CD8-naive and memory T-cell populations. The researchers initially observed a clonal antitumor response that eventually led to T-cell exhaustion, reduction in self-renewal potential, and depletion of tumor-reactive T-cell repertoire. After 6 months of therapy, expansion of preexisting T-cell clones was undergoing terminal differentiation. The authors noted that this may lead to compromised responses in future immunotherapies. Finally, TCF7, IKZF1, and PRDM1 were identified as transcription factors regulating divergent cell states and may be targeted for future therapies.
Disclosure: Full disclosure information for the study authors was not provided.