Enhancing CAR-T Therapy With Nivolumab: Final Analysis

Patients with rapid progressive disease (PD) progressive diffuse large B-cell lymphoma (DLBCL) disease, at the time of lymphodepletion (LD), face challenges in achieving complete remission (CR) and exhibit a 6-month progression-free survival (PFS) rate of only 20-30%. Prior research suggests that enhancing in-vivo expansion of chimeric antigen receptor T (CAR-T) cells could potentially mitigate this grim prognosis and enhance treatment outcomes (Bone Marrow Transplant 57 (Suppl 1), 11–15 (2022)).

Ron Ram and the team aimed to assess the efficacy of adding nivolumab to CAR-T therapy to improve clinical response in patients with rapid PD DLBCL by activating the immune system and promoting greater CAR-T cell expansion.

They performed an inclusive analysis by recruiting patients with PD DLBCL documented by PETCT before LD for a prospective phase 2 trial (NCT05385263). Patients received nivolumab (3mg/kg) between days 5-9 post CAR-T infusion. Those with <100 CAR-T cells/microL on day +7 received an additional dose of nivolumab on day +19. Endpoints encompassed safety, disease response rate (DRR) assessment and durability of response (DOR). Ancillary studies focused on identifying CAR-T kinetics and flow cytometry analyses of inhibitory receptors.

About 20 patients were recruited and received anti-CD19 CAR-T (Axicabtagene ciloleucel, n=12 and tisagenlecleucel, n=8). The median age was 67 (range, 40-77) years, with 6 (30%) patients having an ECOG score >1. Median LDH prior to LD was 528 (range, 367-1279) U/L. Eight (40%) patients were not eligible to receive nivolumab (off-protocol group) due to ongoing active CRS (n=6) and/or ICANS (n=3). Twelve patients were eligible for nivolumab administration (on-protocol group, 7 received only 1 dose due to sufficient day +7 expansion levels, n=4; ongoing toxicity, n=2; patient’s preference, n=1).

Among patients given nivolumab, 8 AEs were attributed to nivolumab (fever, n=4; rash, n=2, diarrhea, n=1; neutropenia, n=1). No SAEs related to nivolumab were observed. One patient died due to delayed prolonged cytopenia and recurrent sepsis. Correlative analyses in the first 10 patients showed that 67% showed re-expansion of CAR-T cells evaluated by flow cytometry. Expression of PD-1 on both mononuclear cells and CD3⁺ cells was significantly reduced in patients given nivolumab, compared to the control group [10.2% vs 21% (P=0.0075) and 6.5% vs 19.7% (P=0.0009), respectively] with no difference in the expression of PD-1 on CAR-T cells (P=0.52), and activation markers/T cell subpopulation between the 2 groups.

Among all patients, ORR was 80% (CR, n=12, 60% and PR, n=4, 20%) and PD (n=3, 15%). One patient had non-relapse mortality and was not evaluated. These results compared favorably with our historical control of patients with PD at LD (CR, n=16, 39%, PR, n=10, 24%, and PD, n=15, 37%). At 6-months, 48% of patients were progression-free and 85% alive. The 3-month EORTC QLQ-C30 questionnaire, compared to the baseline questionnaire, showed improved overall health perception (P=.025) and overall quality of life (P=.059), with no difference between patients on-protocol and off-protocol.

The study concluded that adding nivolumab tailored by expanding CAR-T cells in patients with progressive disease at LD is safe and yields impressive early response rates. However, the durability of response remains suboptimal, suggesting that future trials addressing this challenge may further enhance treatment outcomes.

The trial was sponsored by the Tel-Aviv Sourasky Medical Center.

Source: https://ebmt2024.abstractserver.com/program/#/details/presentations/964

Clinical Trial: https://clinicaltrials.gov/study/NCT05385263

Ram R, Amit O, Perry C, et al. (2024). “ADDITION OF NIVOLUMAB TAILORED BY EXPANSION OF CAR-T CELLS IN PATIENTS WITH PROGRESSIVE DLBCL AT LYMPHODEPLETION – A PHASE 2, PROSPECTIVE INTERVENTIONAL STUDY – FINAL ANALYSIS.” Presented at EBMT 2024 (Abstract GS02-09).