CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1–positive B-Cell Lymphoma

Abstract

Purpose: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is effective against refractory or relapsed (R/R) B-cell lymphoma, but the efficacy is hindered by the existence of PD-1/PD-L1 pathway. Patients and Methods: Here, we generated a novel anti-CD19 CAR-expressing PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR). We then conducted a phase Ib study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1+ B-cell lymphoma. Results: We found that CD19-PD-1/CD28-CAR T cells had superior T-cell proliferation, cytokine production, and sequentially capability of killing PD-L1+ B-cell lymphoma cells in vitro and in vivo relative to the prototype, CD19-CAR T cells. Among 17 adult patients with R/R lymphoma who received the CAR T therapy, 10 patients had objective response (58.8%), including seven patients with complete remission (41.2%). At a median follow-up 15 months, median overall survival for all patients was not reached. Remarkably, no severe neurologic toxicity or cytokine release syndrome was observed. Conclusions: This first-in-human study demonstrates the tolerability, safety, and encouraging efficacy of CD19-PD-1/CD28-CART in PD-L1+ large B-cell lymphoma.

CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies

“…Recently, we have reported that CD19-PD-1/CD28-CAR T cells exhibited a superior capability of killing PD-L1 + B-cell lymphoma cells in vitro and in vivo relative to the prototype, CD19-CAR T cells. We also demonstrated that this therapy had a favorable safety profile and induced durable clinical responses in the patients with PD-L1 + R/R DLBCL [6]. An interesting aspect of the current study was that CD19-PD-1/CD28-CAR T was generally well-tolerated and resulted in a high response rate that was durable in R/R large B-cell lymphoma after failure of CD19-CAR T therapy.…”

B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

“…A phase Ib study involving patients with PD-L1 + large B-cell lymphoma demonstrated that the ORR of CD19-PD-1/ CD28-CAR T-cell therapy was 58.8%, and that the CR was 41.2%. No severe cytokine release syndrome or neurologic toxicity was reported in that study (17). One recent study reported that high levels of plasma-soluble PD-L1 and signal transducer and activator of transcription (STAT) 3 were related to worse progression-free survival and overall survival in patients with DLBCL (30).…”

“…A phase Ib study involving patients with PD-L1+ large B-cell lymphoma demonstrated that the ORR of CD19-PD-1/CD28-CAR T-cell therapy was 58.8%, and that the CR was 41.2%. No severe cytokine release syndrome or neurologic toxicity was reported in that study ( 17 ).…”

The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy

“…Our review of the literature, as summarised here, suggests other chemokine pathways that may also be re-purposed to drive CAR-T cell migration and activity, such as the CCL2/CCR2 pathway. CAR-T cells with switch-signalling receptors offer a novel way to convert T cell inhibitory signals, such as those provided by PD1 [ 227 ] to activation signals such as CD28, and a similar process could potentially be used to reverse the inhibitory capacity of glioblastoma-abundant cytokines such as TGF-β, an idea which has been reviewed recently [ 228 ]. An early preclinical study of CAR-T cells with a decoy receptor for TGF-β (a non-signalling ectodomain of the TGF receptor II) prolonged the life of U87 glioblastoma bearing mice and polarized GAM towards an M1 phenotype [ 229 ].…”