A Next-Generation, Off-the-Shelf CAR-iNKT Cell Therapy for Multiple Myeloma
Abstract
Objective and Rationale: Multiple myeloma (MM) is a malignant monoclonal plasma cell disorder characterized by osteolytic bone lesions, anemia, hypercalcemia, and renal failure. It is the second most common hematological malignancy, affecting millions of people worldwide. Although novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous hematopoietic stem cell transplantation have improved the treatment, MM remains an incurable disease with a high relapse rate. About 12,000 MM patients die each year in the United States, demonstrating the desperate need for innovative and effective therapies. Autologous transfer of chimeric antigen receptor-engineered T cells (CAR-T) targeting B-cell maturation antigen (BCMA) has shown impressive clinical responses for treating relapsed/refractory MM in ongoing clinical trials and is expected to get regulatory approval in 2020 as a fourth-line treatment for MM. Despite its promise, the current autologous BCMA-targeting CAR-T (BCAR-T) cell therapy has significant limitations: its efficacy needs to be improved; and importantly, it falls into the category of autologous cell therapy. Such a conventional alpha-Beta T cell-based cell product risks inducing graft-versus-host disease (GvHD) when adoptively transferred into allogeneic hosts; therefore, personalized BCAR-T cells need to be manufactured for each patient and can only be used to treat that single patient, making the therapy extremely costly and difficult to deliver to all MM patients in need. Allogeneic “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat a broad base of MM patients, therefore, are in great demand. Invariant natural killer T (iNKT) cells are a small population of unconventional alpha-Beta T cells. These cells have several unique features, making them ideal cell carriers for developing allogeneic CAR-directed cell therapy for MM. Compared to conventional CAR-T cells, CAR-engineered iNKT (CAR-iNKT) cells can attack tumor cells using multiple mechanisms and at higher efficacy; can more effectively traffic to and infiltrate tumor sites; can alter tumor immunosuppressive microenvironment; and most importantly, do not induce GvHD. However, human blood contains extremely low numbers of iNKT cells (0.001%-1%), making it very difficult to reliably grow large numbers of allogeneic iNKT cells for CAR-engineering. Moreover, allogeneic iNKT cell products expanded from blood may contain bystander allogeneic conventional alpha-Beta T cells and thus, risk inducing GvHD. Recently, we have successfully overcome this critical hurdle by establishing a novel Ex Vivo Hematopoietic Stem Cell (HSC)-Derived CAR-iNKT Cell Culture Method, which can produce therapeutic levels of pure and potent CAR-iNKT cells suitable for allogeneic cell therapy. Based on this method, in this project we propose to develop a next-generation, off-the-shelf BCMA-targeting CAR-engineered iNKT (BCAR-iNKT) cell therapy for MM. Impact: The proposed project, if successful, will have a major impact on two of the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas: Immunotherapy and Blood Cancers. A potential near-term impact of the proposed project is an off-the-shelf BCAR-iNKT cell therapy for MM that is potent, economic, and ready to deliver to all MM patients in need, without gender/age/genetic restricts. The new therapy has the potential to save lives and/or improve life quality of MM patients. It is projected that this new therapy can enter clinical trials in 3 years, by the end of the proposed project. Relevance to Military Health: Military personnel are at greater risk for developing MM due to exposure to chemicals (e.g., Agent Orange) during deployment. MM remains an incurable blood cancer, and novel therapies are therefore in great demand. This project can potentially lead to an off-the-shelf cell therapy for MM that can fill in the gap of MM treatment and thus,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110882
Entities
People
- Lili Yang
Organizations
- United States Army
- University of California, Los Angeles