Optimized, computationally engineered CD70-targeting CAR-T cells for high-risk multiple myeloma

Multiple myeloma is a blood cancer diagnosed in over 30,000 Americans per year but still without any known cure. Over the past decade, harnessing the immune system to fight myeloma has become a highly promising therapeutic strategy. One of the most potent types of these “immunotherapies” are chimeric antigen receptor (CAR) T-cells targeting BCMA, a protein expressed on the surface of myeloma tumor cells. However, despite many myeloma patients achieving remission after these very potent engineered cellular therapies, essentially all patients still appear to eventually relapse. Among the patients who relapse most quickly after current BCMA CAR T-cells are those with “high-risk” tumor features. 

Here, we aim to develop a new type of CAR-T therapy that we predict will be particularly effective for these high-risk patients who are in urgent need of new therapeutic options. Specifically, we have identified the target CD70 as being enriched on the surface of tumor cells from high-risk myeloma patients. We have subsequently used protein engineering and artificial intelligence approaches to develop what we believe is the most potent CAR T targeting CD70 described to date. The goal of this proposal is to perform additional preclinical evaluation of our unique CD70-targeting CAR T-cell, including additional anti-tumor effectiveness studies in high-risk myeloma models and required safety studies. We will further validate for our CD70 CAR T-cells a novel manufacturing strategy pioneered by our colleagues at UCSF. This manufacturing approach uses advanced CRISPR genome engineering technology to generate CAR T cells which are more effective at low doses, ideally leading to high efficacy but low toxicity in patients. Finally, we will assemble regulatory documents compiling these data as needed to move toward the next steps on the path to clinical translation (“pre-IND” meeting). Our goal by the end of the 3-year award period is to be poised for a near-term clinical trial of this therapy for high-risk myeloma patients. Furthermore, we note that CD70 is a target expressed on the surface of other blood cancers, such as acute myeloid leukemia and T-cell lymphoma, as well as some solid tumors, such as renal cell carcinoma. Therefore, our efforts here to develop a “best in class” CD70-targeting CAR T-cell may ultimately benefit not only myeloma patients but many others in need.