Outcomes of CD20-targeting CAR T-cell therapy in patients with advanced melanoma: MB-CART20.1 Melanoma phase I trial.

BACKGROUND

Previous studies identified CD20+ cells within the melanoma tumor microenvironment, including tumor-associated B-cells and putative cancer stem cells (CSC), as potential therapeutic targets. We therefore evaluated CD20-targeting CAR T-cells in patients with advanced melanoma.

METHODS

This prospective, open-label phase I trial evaluated a 3 +3 design in patients with advanced melanoma, refractory to approved treatments, to assess safety and preliminary activity of autologous anti-CD20 CAR T-cells (MB-CART20.1). Following lymphodepleting chemotherapy, patients received a single MB-CART20.1 infusion. Primary endpoints were safety and tolerability; secondary endpoints included kinetics and early evidence for antitumor activity. Three patients received dose level 1 (DL1) (1.0 ×10⁵ cells/kg) and four patients DL2 (1.0 ×10⁶ cells/kg).

RESULTS

No DLTs occurred at DL1, while two patients experienced DLTs at DL2 (grade 3 ICANS and grade 4 hepatotoxicity). Overall, 43 serious TEAEs were reported across all seven patients. Stable disease was observed in three patients at week 16; all had progressed by month 6. All had received immune checkpoint inhibitors within 6 months before leukapheresis and showed reduced exhaustion marker expression on CD8+ T-cells. In addition, the frequency of CD19+CD24+CD27+ Breg cells trended to associate with progressive disease and inversely correlate with toxicity. MB-CART20.1 showed robust in vivo expansion however, severe DLTs at DL2 without durable clinical benefit led to early trial termination.

CONCLUSIONS

In advanced melanoma, MB-CART20.1 was associated with marked expansion and toxicity, suggesting that Breg depletion and the melanoma-typical treatment history might have driven distinct CAR T-associated immunotoxicities.