Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas

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.

Graphical abstract

Figure 1.

Frequency of circulating T cells and CD5 expression after CD5.CAR T-cell infusion. (A) The overall frequency of total CD3⁺ T cells in the peripheral blood of patients after CD5.CAR T-cell infusion. Statistical significance was evaluated by one-way analysis of variance. Levels of CD3⁺ CD4⁺ (B) and CD3⁺ CD8⁺ (C) T cells in the peripheral blood. (D) Expression of CD5 and CD5.CAR in CD3⁺ T cells from the peripheral blood (top) and lymph node biopsy samples at the indicated time points.

Figure 2.

Kinetics of CAR T responses by PET-CT imaging. Preinfusion (A) PET-CT of patients with ATLL treated at DL2 and postinfusion (B) PET/CT 4 weeks after CD5 CAR T-cell administration. (C) Preinfusion PET/CT of a patient with AITL (no. 5); (D) PET/CT 4 weeks after infusion showing increased markedly hypermetabolic lymph nodes and increased uptake in subcutaneous nodules; (E) PET/CT 8 weeks after CD5 CAR T-cell administration showed resolution of nearly all of the previous hypermetabolic abnormalities and appearance of 1 new FDG-avid lesion (indicated by red oval).

Figure 3.

MAGENTA disease responses. Swimmer plot for the mature TCL cohort. LD, lymphodepletion; w/, with; w/o, without. SD, stable disease.

Figure 4.

Expansion and persistence of CD5.CAR T cells after infusion. (A) Levels of the CD5.CAR transgene per mL of blood. The area under the curve (AUC) for each dose level over the first 3 weeks is plotted on a bar graph. (B,C) Levels of the CD5.CAR transgene in patients no. 5 (B) and no. 31 (C), who received a second dose of CD5.CAR T cells. (D) CD5.CAR transgene levels and 3-week AUC in responders (Rs) and nonresponders (NRs). Statistical significance was evaluated using the unpaired Student t test.