Cheloni and Karagkouni et al. characterized endogenous (non-CAR) T cells in patients with LBCL treated with anti-CD19 CAR T cells, who experienced either long-term response (LtR) or relapse (R). T cells from LtR patients (cf. R patients) were less differentiated at leukapheresis, had higher expression of cytotoxic and pro-inflammatory genes (which increased after CAR T infusion), and showed expansion of cytotoxic TCR clonotypes. R patient T cells, NK cells, and monocytes expressed genes associated with immune regulation and dampened responses. Clonotypic T cell expansion 4 weeks after CAR T treatment predicted patient response better than CAR T peak expansion.
Contributed by Alex Najibi
ABSTRACT: While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.
Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Bos
Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (5) Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. (6) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (7) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (8) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (9) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Kite, a Gilead Company, Santa Monica, CA, USA. (12) Kite, a Gilead Company, Santa Monica, CA, USA. (13) Kite, a Gilead Company, Santa Monica, CA, USA. (14) Kite, a Gilead Company, Santa Monica, CA, USA. (15) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (16) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Spatial Technologies Unit, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. (17) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Harvard Medical School, Boston, MA, USA. davigan@bidmc.harvard.edu.
