Early Clinical Results of a Novel Anti-CD20 Chimeric Antigen Receptor (CAR)-T Cell Therapy for B-Cell NHL Patients Who Are Relapsed/Resistant Following CD19 CAR-T Therapy

Background:

Relapse due to loss of the CD19 targeted epitope presents a therapeutic challenge of CD19 CAR-T therapy. These patients universally have poor outcomes. CD20 is a proven therapeutic target for B-Cell Non-Hodgkin Lymphomas (B-NHL), supported by previously approved and widely used monoclonal antibody therapy.

C-CAR066 is a novel 2nd generation chimeric antigen receptor T (CAR-T) therapy. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to CAR-Ts derived from scFVs of Leu16, Rituximab, and Obinutuzumab,

Methods:

NCT04036019 is a single arm, single-center, non-randomized phase I clinical trial conducted at Shanghai Tongji Hospital to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B cell lymphoma who were previously treated with anti-CD19 CAR-T therapy. The primary objective of the study is to evaluate incidence and severity of treatment emergent adverse events. The secondary objectives include determining overall response rate (ORR), PFS, and OS. C-CAR066 is manufactured in a serum free, semi-automated, and digitally closed system. C-CAR066 is administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen.

Results:

As of Aug 3, 2020, 7 patients (all DLBCL) were enrolled and infused with C-CAR066 with a dose range of 2.0 x 10⁶ to 5.0 x 10⁶ CAR-T cells. The manufacturing success rate was 100%. All patients had relapsed after anti-CD19 CAR-T treatment, only one of the patients had achieved CR following anti-CD-19 CAR-T therapy. C-CAR066 treatment was well tolerated with reversible grade 1~2 CRS in six patients, grade 3 CRS in another patient, and no neurotoxicity events. 6/7 patients showed clinical improvement (best overall response rate, BOR = 85.7%). The best overall responses include 3 CR and 3PR. All patients responded to C-CAR066 treatment and showed different degrees of tumor regression (45-100%). Furthermore, the expansion and proliferation of C-CAR066 CAR-T cells in the peripheral blood positively correlated with the extent of tumor regression.

Conclusion:

C-CAR066 has a favorable safety profile and shows promising early efficacy in patients with r/r NHL following CD19 CAR-T therapy. It confirms that C-CAR066 has a different mechanism of action compared to anti-CD-19 CAR-T therapy. These data provide strong scientific rationale to the strategy of targeting both CD20 and CD19 tumor antigens and to ask whether this leads to superior clinical benefit to targeting either CD19 or CD20 alone in NHL.