Novel Study of Next-Generation BCMA-Targeted CAR-Modified T Cells for Multiple Myeloma Opens at MSK

Ola Landgren, MD, PhD

Professor of Medicine

Chief of Multiple Service

Memorial Sloan Kettering Cancer Center

Chimeric antigen receptor (CAR) T-cell therapy has been developed as a novel strategy whereby the immune system functions as the "drug" against cancer—by taking out a patient’s own T cells from peripheral blood, inserting a so called "vector" in the T cells in the laboratory, and giving back the modified T cells to the patient. This has been found to work dramatically well in the setting of acute lymphoblastic leukemia and now reports of the initial patients treated with multiple myeloma are showing the immense potential in this disease.

The first study using CAR T-cell therapy in patients with myeloma was developed by James Kochenderfer, MD, and colleagues at the National Institutes of Health (NIH). Their results, based on small numbers, show impressive rapid clearance of large myeloma burden, resulting in complete response for a patient who failed most other therapies. It was first communicated as a plenary presentation at the 2015 ASH Annual Meeting.

The work by the NIH team serves as proof-of-concept for CAR T-cell therapy as a valid treatment approach in multiple myeloma. Also, based on small numbers, researchers at the University of Pennsylvania have been able to follow up on the NIH approach and show similar results using their CAR T cells. This further confirms the potential of this treatment strategy in myeloma.

At Memorial Sloan Kettering Cancer Center (MSK), patients with relapsed/refractory leukemias and lymphomas have been treated successfully with CAR T-cell therapy for several years. In parallel with ongoing work on leukemias and lymphomas, Eric Smith, MD, PhD, and Renier J. Brentjens, MD, PhD, have further developed myeloma-directed CAR T cells at MSK. Their work has focused on improving efficacy and limiting toxicity by introducing new features of the CAR T cells.

The MSK myeloma CAR T-cell therapy has several features which are different from other existing myeloma CAR T cells. Specifically, MSK’s newest version of the CAR T-cell therapy for myeloma has a built-in "off switch" which can be used to deactivate the CAR T cells. This will be used if there are severe toxicities. Also, the CAR T-cell receptor at MSK is human, which may avoid anti-CAR immune responses seen with CARs containing mouse-derived elements. Furthermore, this construct was selected out of many evaluated, and confers many favorable characteristics onto T cells that may increase efficacy.

The clinical lead principal investigator for the new myeloma CAR T-cell therapy study is Sham Mailankody, MBBS. He works closely with Drs. Smith and Brentjens on the new study. In March 2017, the first myeloma patients will be treated with CAR T cells at MSK.

Regarding study population, it is open for patients who have been diagnosed with multiple myeloma and have refractory, persistent, or progressive disease after receiving at least two prior lines of therapy, including treatment with an immunomodulatory drug and a proteasome inhibitor.

Regarding study design, this is an open-label, dose escalating, nonrandomized, single-center, phase I study of EGFRt/BCMA-41BBz CAR T cells.

On a practical note, patients will undergo leukapheresis of peripheral blood for further T cell enrichment; activation and genetic modification using a retroviral vector encoding a B-cell Maturation Antigen (BCMA)-targeted CAR, and the EGFRt safety system (EGFRt/BCMA-41BBz). These T cells will be expanded and after the appropriate number of cells are generated, the modified T cells may be infused fresh or frozen for later use, according to standard operation procedures.

These modified T cell infusions will be administered 2 days following a single day of conditioning chemotherapy. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells. For patients who have obtained clinical benefit from the initial T cell therapy and did not experience any non-hematologic grade 4 toxicities, additional modified T cells may be re-infused after 30 days at the treating physician’s discretion.

For physicians or patients who are interested in this study, please contact Analisa Wills, Cellular Therapeutics Center, MSK, for referrals to the protocol. Phone: 212-639-5317