Influence of Myeloma Cell Expressed CD28 and CD86 on BCMA CAR T Cell Efficacy and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)

CAR T cell therapy has emerged as a vital therapeutic option, offering extended treatment-free periods for patients with Multiple Myeloma (MM). However, despite impressive initial responses observed in large, randomized trials, relapse remains a significant challenge. Additionally, CAR T cell therapy is associated with toxic adverse events, including cytokine release syndrome (CRS), ICANS, and cytopenia in most treated patients. Enhancing the durability of responses while minimizing these toxicities could significantly improve outcomes for patients with advanced MM.

CD28, the prototypic T cell co-stimulatory receptor, stimulates T cell activation, proliferation, and function when ligated by B7 proteins CD80 or CD86. Interestingly, CD28 and CD86 are also expressed on MM cells, promoting their growth and survival. Therapeutically targeting the CD28-CD86 interaction with abatacept (CTLA4-Ig) has been explored to sensitize relapsed/refractory MM to chemotherapy (Clinical Trial: NCT03457142). Our recent findings indicated that endogenous CD28 on CAR-modified T cells influences their anti-myeloma activity and cytokine secretion (Lieberman et al. 2024). Transient CD28 inhibition with abatacept can block proinflammatory cytokine release without compromising CAR T cell efficacy in mouse models, suggesting that targeting CD28-CD86 interactions may limit CAR T cell toxicities while sensitizing MM cells to cytotoxic effects.

This study examines the impact of myeloma CD28 and CD86 expression on clinical outcomes in patients receiving BCMA-targeted CAR T cell therapy. We hypothesize that CD28 expression promotes myeloma cell survival during CAR T therapy, limiting efficacy, while CD86 expression promotes CRS and ICANS due to CD28 stimulation on CAR T cells.

Methods: Flow cytometry was used to examine CD28 and CD86 expression on CD138-positive cells from 23 myeloma patients who underwent BCMA CAR T cell therapy at a single institute from September 2021 to February 2024. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and differences were tested using the log-rank test.

Results: The median time from MM diagnosis to CAR T therapy was 6.3 years (range: 1-23 years) and the median follow-up was 184 days (range: 25-947 days). The median line of therapy pre-CART was 5. Among patients, 16 (65%) were IgG, 4 (17%) were IgA, and 3 (13%) were light chain MM. Eight patients (34%) had extramedullary disease. CD28 positivity was observed in 17 patients (74%), and CD86 positivity in 13 patients (57%). All patients underwent apheresis with successful CAR T cell manufacturing before the standard flu/cy lymphodepletion regimen. Twenty-one patients (91%) received bridging therapy, with a median duration of 66 days (range: 36-114 days). Nineteen patients (82%) achieved a very good partial response or better. Median PFS for CD28-positive patients was 84 days versus 190 days (p=0.026), and OS was 113 days while median OS had not been reached in CD28-negative patients (p=0.067). The highest CRS observed was grade 3 (median: 2, range: 0-3), occurring a median of 2 days post-therapy and lasting a median of 3 days. Fifteen patients (65%) received Tocilizumab, and nine patients (39%) received Dexamethasone. The highest ICANS observed was grade 2 (median: 1, range: 0-2). CD86 positivity predicted ICANS occurrence: only one CD86-negative patient experienced grade 1 ICANS (10%), compared to 7 CD86-positive patients (54%) (p=0.007). Similarly, only one CD28-negative patient experienced grade 1 ICANS (17%), compared to 7 CD28-positive patients (41%) (p=0.004). Six of 10 CD28/CD86 double positive patients experienced ICANS, versus 2 of 10 single positive and 0 of 3 double negative patients.

Conclusion: CD28 expression on MM cells predicts durable responses to BCMA CAR T cell therapy, suggesting that the CD28 MM survival signal may limit CAR T cell efficacy. Conversely, CD86 expression did not significantly impact survival but may contribute to ICANS and CRS. These findings, alongside preclinical data indicating CD28-induced proinflammatory cytokine secretion in the myeloma microenvironment, suggest that CD86 on myeloma cells may stimulate CAR T cell toxicity. Future clinical trials should explore CD28 inhibitors (e.g., abatacept, belatacept) to mitigate CRS and ICANS in myeloma patients undergoing CAR T therapy and potentially in those receiving bispecific antibodies.