Chimeric Antigen Receptors/Genetically Modified T-Cells
Authors: Kochenderfer James N. 
Published: October 2019

Multiple myeloma (MM) is a usually incurable malignancy of plasma cells. While the therapy of MM has improved greatly in the past 15 years, therapies with novel mechanisms of action are needed for MM. Allogeneic stem cell transplantation has been shown to have a potent anti-myeloma effect, and allogeneic donor lymphocyte infusions can cause remissions of MM. These results from allogeneic transplantation show that MM can be vulnerable to cellular immunotherapies, but allogeneic transplants have substantial rates of mortality and morbidity. Anti-CD19 CAR T cells have been shown to have powerful activity against B-cell malignancies. The success of anti-CD19 CAR T cells against B-cell malignancies has motivated investigators to develop genetically-modified T-cell therapies for MM. CD19 has been targeted as a therapy for multiple myeloma. A clinical trial of anti-CD19 CAR T cells for MM is underway. Part of the rationale for targeting CD19 is that CD19 might be expressed on a myeloma stem cell, which might be a mature B cell. The NY-ESO antigen has been targeted by human-leukocyte-antigen-restricted T cells in a clinical trial enrolling MM patients. B-cell maturation antigen (BCMA) is expressed by most cases of MM. We conducted the first-in-humans clinical trial of CAR T cells targeting BCMA at the National Cancer Institute. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells on this dose-escalation trial. Among the 6 patients treated on the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9x106 CAR+T cells/kg bodyweight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM with 80% bone marrow plasma cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T-cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients also had prolonged cytopenias. In summary, our findings demonstrated strong anti-myeloma activity of CAR-BCMA T cells. One of the best attributes of the CAR T-cell field is that there are multiple avenues for improving CAR T-cell therapies. New CAR designs are being tested. Any part of the CAR might be improved including development of new fully-human single chain variable fragments (scFv) for the antigen-recognition component of the CAR, testing different hinge and transmembrane domains, and defining the optimal costimulatory moieties. Another avenue for improving CAR T-cell therapies is improving T-cell culture methods. Optimizing clinical application of CAR T cells, especially enhancing toxicity management, is another important avenue of improving CAR T-cell therapies. Finally, identifying new CAR target antigens is a critically important area of CAR research. In summary, genetically-modified T cells hold great promise to make a profound improvement in the therapy of multiple myeloma.

Disclosures
Kochenderfer: bluebird bio: Patents & Royalties, Research Funding; Kite Pharma: Patents & Royalties, Research Funding.