P-015: A Novel CAR-T cell therapy targeting kappa myeloma antigen for the treatment of multiple myeloma

Introduction: Multiple myeloma (MM), the second most common blood cancer, is characterized by the accumulation of malignant plasma cells in the bone marrow. Chimeric Antigen Receptor (CAR)-T cell therapy has recently entered the standard of care for relapsed and refractory MM, following the recent FDA-approval of two CAR-T cell products, ide-cel® and cilta-cel®, which target the B cell maturation antigen (BCMA). However, despite impressive response rates, most patients relapse within 1-3 years, highlighting the need to develop novel CAR targets for this disease indication.

Methods: Kappa (κ) myeloma antigen (KMA) is a tumour specific membrane associated protein expressed on malignant plasma cells in patients with kappa light-chain restricted (κ-type) MM. KMA is absent on normal plasma cells and haematopoietic stem cells, making it an attractive and alternative target antigen for CAR-T cell therapy for MM. The monoclonal antibody, KappaMab (MDX-1097), binds to a conformational epitope on KMA, and has been assessed in phase I, IIa and IIb clinical trials in relapse refractory myeloma patients. Here, we have engineered a lentiviral vector encoding a second-generation CAR expressing a scFv from MDX-1097, fused to a 4-1BB co-stimulatory domain and CD3 zeta chain, to test in preclinical models of MM.

Results: We successfully generated human anti-KMA CAR-T cells with high and stable CAR expression and a predominately memory T cell phenotype. The CAR-T cells selectively killed KMA-expressing tumour lines and secreted interferon-gamma upon target recognition. Futhermore, a single dose of anti-KMA CAR-T cells demonstrated potent anti-tumour activity in a xenograft model. All mice treated with a 5e6 CAR-T cell dose were alive at 100 days post-treatment, had persisting circulating CAR-T cells and no evidence of disease.

Conclusions: Our data demonstrates that anti-KMA CAR-T cell therapy is a novel and potent treatment ready to enter a phase I clinical trial for patients with multiple myeloma.