CAR T Cells with a Dominant-Negative TGFβ Receptor Are Safe and Feasible

Use of chimeric antigen receptor (CAR) T cells targeting prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer (mCRPC) has shown promise, but their clinical use remains challenging due to a highly immunosuppressive tumor microenvironment characterized by high transforming growth factor-β (TGFβ) expression. As CAR T cells that express a dominant-negative form of the TGFβRII (TGFβRDN) showed improved tumor control in preclinical models, Narayan and colleagues developed and tested PSMA CAR T cells engineered with a TGFβRDN (CART-PSMA-TGFβRN) in patients with mCRPC in a single-institution phase I clinical trial to assess safety and feasibility as well as T-cell activity and tumor trafficking. Eighteen patients were enrolled, with 13 moving forward with the planned protocol. Cohort 1 [1–3 × 10⁷ m⁻² cells infused with no lymphodepletion (LD)] had no treatment-related adverse events (AE) above grade 3, while Cohort 2 (1–3 × 10⁸ m⁻² cells infused with no LD) had two patients develop grade 3 cytokine release syndrome (CRS), with one patient also developing neurotoxicity that resolved after additional supportive treatments. Cohort 3 (1–3 × 10⁸ m⁻² cells infused with LD) had one patient develop grade 4 CRS that resolved, but the patient ultimately died. After observing this dose-limiting toxicity, the protocol was amended to “Cohort -3” (1–3 × 10⁷ m⁻² cells infused with LD), where grade 2 CRS was observed but was able to be resolved with additional interventions. No additional non-CRS AEs above grade 3 were observed in Cohort -3. Kinetics of these CAR T cells indicated a peak in expansion at 14 days, with some patients in Cohort -3 demonstrating persistence of cells in the peripheral blood over 200 days after infusion. Reduction in PSA levels was observed in four patients, stable disease at the 3-month assessment was seen in five patients, and one patient showed tumor regression following treatment, but no partial responses were observed. Overall, this trial demonstrated the safety and feasibility of the use of these CART-PSMA-TGFβRN cells in mCRPC, with future studies seeking to enhance clinical efficacy and mitigate toxicities.

Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med 2022;28:724–34.

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