Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion—A Phase 2, Prospective Interventional Study

Patients with large B-cell lymphoma (LBCL) in stable or progressive disease (SD/PD) at lymphodepletion prior to chimeric antigen receptor T cell (CAR-T) therapy have an inferior outcome. we hypothesized that enhancing in-vivo expansion of CAR-T cells could overcome this grim prognosis leading to improved outcomes. We conducted a phase 2 prospective trial (NCT05385263) investigating the addition of nivolumab to enhance CAR-T cell expansion and response in patients with SD/PD-LBCL. Eligible patients received 1 dose of nivolumab between day +5 and +9 post CAR-T infusion. An additional dose of nivolumab was administered on day +19 only to patients whose CAR-T cell levels in peripheral blood were below 100 cells/µL at day +7. Twenty patients were enrolled and received anti-CD19 CAR-T (Axicabtagene ciloleucel, n = 12; tisagenlecleucel, n = 8). Eight were ineligible to receive nivolumab due to active CAR-T-associated toxicities. Overall, the protocol was safe. One-month PET-CT showed an 84% overall response rate (complete response, 53%). The cumulative incidence of progression-free survival at 6 and 12 months were 50% (95% CI 36%-64%) and 42% (95% CI 26%-58%), respectively. The cumulative incidence of overall survival at 6 and 12 months were 85% (95% CI 72%-98%) and 51% (95% CI 31%-71%), respectively. Nivolumab administration significantly reduced PD-1 expression on all immune cells. CAR-T cell expansion was similar between nivolumab-eligible and noneligible patients. Notably, there was a significant enrichment of CD45RO-CD27+ CD8+ cells and CD45RO-CD27+ CD8+ CAR-T cells in the nivolumab-eligible group compared to those ineligible, suggesting that specific cell enrichment could potentially contribute to an enhanced response rate. We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response rates.