Endogenous T-Cell Activation Has Potential Role After CAR T in Myeloma

In an analysis of therapeutic interventions following the failure of chimeric antigen receptor (CAR) T-cell therapy, Rahul Banerjee, MD discusses the potential mechanism for checkpoint inhibition following CAR T-cell therapy in patients with multiple myeloma. The study of nivolumab (Opdivo) failed to achieve responses in the majority of patients but yielded intriguing results in a minority that point to an endogenous T cell response rather than reactivating the CAR T cells.

Key Findings on T-Cell Dynamics

The phase 1 trial (NCT04205409) enrolled heavily pretreated patients with myeloma or lymphoma following failure of CAR T-cell therapy, where there is a significant unmet need. Banerjee highlights a significant discovery regarding the mechanism of action in patients who experienced durable responses. The data suggested that the durable responses in 2 of 11 patients showed no correlation with PD-L1 expression at study entry and response did not correlate with the presence or expansion of CAR-transduced cells at the time nivolumab was initiated. In patients achieving long-term disease control, the “normal” endogenous T-cells rather than persistent engineered CAR T-cells expanded and appeared to be responsible for the anti-tumor effect.

Hypothesis on Post-CAR T-Cell Crosstalk

Banerjee notes that the response rate in this specific setting of approximately 18% was numerically higher and more durable than previous prospective studies of checkpoint inhibitors in hematologic malignancies, such as a prior myeloma study where only one transient response was observed among roughly 27 patients.

He hypothesizes that CAR T-cell therapy may prime the immune system by inducing a limited endogenous T-cell response through “crosstalk” between the engineered cells and the patient’s native immune system. Even if the CAR T-cells eventually fail or persist in low numbers, they may have already unleashed a latent native immune response that nivolumab is then able to amplify and bring to the forefront, leading to unexpectedly durable disease control in a minority of patients.