Enhancing the “fitness” of anti-BCMA CAR T cells for improved efficacy in multiple myeloma
Paul Beavis
PhDThe University of Melbourne
Project Term: July 1, 2024 - June 30, 2027
Chimeric antigen receptor (CAR) T cell therapy is a form of immune-based therapy where a patient’s own immune cells are genetically engineered to recognize and kill the tumor cells. This therapy has revolutionized the treatment of certain blood cancers and excitingly, two CAR T cell products were recently approved for the treatment of multiple myeloma.
Despite impressive initial clinical data showing responses in 73-98% of patients, most patients still relapse after CAR-T cell therapy within 3 years. Therefore, there is a significant unmet need to further enhance the effectiveness of CAR T cell therapy in this disease. In this project we will investigate whether an approach we have shown to make CAR T cells “fitter” and more effective in solid tumors is also effective in the context of multiple myeloma.
Chimeric antigen receptor (CAR) T cell therapy is a form of cancer immunotherapy whereby a patient’s immune cells are genetically engineered to recognize and kill cancer cells when administered back to the patient. CAR T therapy has transformed the treatment of several forms of blood cancer with clinical responses often >90%. Importantly responses are durable lasting for ~10 years and CAR T therapy is now the first therapy used in many types of blood cancer.
Recently studies have investigated the potential of CAR T therapy to treat Multiple Myeloma (MM), a disease associated with no cure and disease relapse. co-PI HARRISON led the recent CARTITUDE 4 trial (NCT04181827) that demonstrated responses in 73-98% of patients that had no remaining treatment options. The trial is ongoing, so the full extent of benefit is yet to be determined, but initial results show that risk of progression/death was reduced by 74% at 16 months post treatment. Although these results are highly encouraging, further refinements are needed as unfortunately in ~60% of patients the cancer eventually returned after CAR-T therapy.
In this project, we will leverage technology we have already developed and tested in the context of solid tumors i.e. breast/ovarian cancers. We recently developed a way to improve the effectiveness of CAR T by engineering them to produce a protein called FOXO1 (FOXO1 CAR T). Excitingly, the same observations were made by Dr. Weber’s group (Philadelphia, USA) who will collaborate with us on this project. FOXO1 CAR T are significantly more effective in the treatment of ovarian/ breast cancers and importantly, this was associated with 10-fold greater persistence relative to standard CAR T. Notably, in the CARTITUDE 4 trial it was observed that CAR T persistence directly correlated with improved patient outcomes. Given we have shown FOXO1 CAR T exhibit enhanced persistence, there is a strong rationale to investigate this approach in MM, which is the subject of this project.
We anticipate that by the conclusion of the project we will have sufficient data to support the initiation of a phase I trial that will treat 12 MM patients at the Peter MacCallum Cancer Centre. We are uniquely placed to achieve this as all infrastructure required for CAR T clinical trials exists and PI BEAVIS will be supported by co-PI HARRISON, a clinician researcher and world leader in the treatment of MM. Co-PI Prof Harrison has led multiple trials in MM to completion including those involving CAR T cells.
This project has the potential to make a significant impact in the treatment of MM and it is estimated that results from this work could be implemented into clinical practice within 2-3 years of the completion of the project. If successful, the project would lead to wider implementation of this approach. If the efficacy of CAR T could be improved from 40% to 90% (as per CAR T in other blood cancers) this would equate to improved treatment of ~15000 Americans per year.