Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma

Abstract

Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment for patients with refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), and combination with PD1 inhibitors may further improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas. In a single-center study, we evaluated the safety and efficacy of a combination therapy with CD19 CAR-T cells and an anti-PD-1 antibody (nivolumab) in patients with relapsed/refractory B-NHL. A total of 11 patients with refractory/relapsed B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab. The primary end points were safety and feasibility. The infusions were safe, and no dose-limiting toxicities occurred. Grade 1 or 2 cytokine release syndrome (CRS) was observed in 25% (3/11) and 50% (6/11) of the patients, respectively, and only one patient (1/11) experienced neurotoxicity. The objective response rate (ORR) and complete response (CR) rate were 81.81% (9/11) and 45.45% (5/11), respectively. The median follow-up time was 6 (1~15) months. The median progression-free survival (PFS) time was 6 months (1~14 months), and 3 patients continued to have a response at the time of this writing. Our study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in refractory/relapsed B-NHL.

Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer

“…Clinically, using CD19-targeting CAR-T cells combined with anti-PD-L1 antibodies in patients with R/R DLBCL showed promising results with a 90% ORR and six patients in CR [91]. Additionally, an anti-PD-1 antibody, Nivolumab combined with anti-CD19 CAR-T cells also demonstrated impressive clinical efficacy with an ORR of 81.8% and CR of 45.5% in a total of 11 patients with R/R NHL [92]. In children with R/R B cell ALL, preliminary results of combinational therapy with PD-1 blockade and CAR-T cells were promising [93].…”

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

“…A growing body of evidence indicates that CAR-T cells from non-responders or (early) relapsers are more prone to exhaustion and display increased expression of immune checkpoint molecules, such as PD-1 [56,74]. Conceptually, immune checkpoint blockade could help to restore the function of these exhausted CAR-T cells and several studies combining CAR-T cells with checkpoint inhibitors are now underway [75][76][77]. To avoid the toxicities of systemically administered checkpoint inhibitors, CAR-T cells have also been genetically modified to locally release a PD-1 blocking antibody [78].…”

Determinants of Resistance to Checkpoint Inhibitors

“…The combination of immune checkpoint blockade to ACT in a preclinical model of melanoma has shown that ICIs can aid in the reversion of immunosuppressive TMEs and confer long-term protection against recurrence of solid tumors [174]. Additionally, ICIs can reinvigorate the immune system and support the persistence of CAR T cells in preclinical and clinical models [175][176][177]. Adjuvant immune checkpoint blockade appears to enhance the potency of CAR T-cell therapy and may extend the success observed in hematologic cancers to solid cancers.…”