Antitumor Efficacy and Safety of Unedited Autologous CD5.CAR T Cells in Relapsed/Refractory Mature T-cell Lymphomas

Authors

LaQuisa C Hill
Rayne H Rouce
Mengfen J Wu
Tao Wang
Royce Ma
Huimin Zhang
Birju Mehta
Natalia Lapteva
Zhuyong Mei
Tyler S Smith
Lina Yang
Madhuwanti Srinivasan
Phillip M Burkhardt
Carlos A Ramos
Premal Lulla
Martha Arredondo
Bambi Grilley
Helen E Heslop
Malcolm K Brenner
Maksim Mamonkin

Publication Date

3-28-2024

Journal

Blood

DOI

10.1182/blood.2023022204

PMID

38145560

PMCID

PMC10997912

PubMedCentral® Posted Date

3-28-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Immunotherapy, Adoptive, Neoplasm Recurrence, Local, T-Lymphocytes, Chronic Disease, Lymphoma, T-Cell, Antigens, CD19, Clinical Trials and Observations, Immunobiology and Immunotherapy, Lymphoid Neoplasia

Abstract

Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5⁺ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.