Advancing the Next-Generation of Cellular Immunotherapy

University Hospitals Seidman Cancer Center was the first to provide a patient in Ohio with ABECMA® (idecabtagene vicleucel), the first CAR T-cell immunotherapy for adults with relapsed or refractory multiple myeloma. This CAR T-cell therapy is for the treatment of multiple myeloma in patients who have received at least four kinds of treatment regimens that have not worked or have stopped working.

ABECMA® is a medicine made from a patient’s own white blood cells, which are genetically modified to recognize and attack multiple myeloma cells. Research in this field is cultivating more treatment options for patients with hard-to-treat or relapsed multiple myeloma.

For instance, in late 2023, Reshmi Parameswaran, PhD, MS, scientist in the Division of Hematology and Oncology and member of the Case Comprehensive Cancer Center Immune Oncology Program received a $1 million Dr. Ralph and Marian Falk Medical Research Trust award for her work advancing novel approaches to treating B-cell cancers.

Dr. Parameswaran has developed a new treatment strategy for B-cell cancer patients, including those with multiple myeloma, who do not respond to conventional therapies or suffer a relapse, Of the 250,000 B-cell cancer patients diagnosed in the United States each year, an estimated 100,000 patients need a more effective therapy option.

Validating the Tumor-Killing Potential and Safety of BAFF-CAR NK Cells

In her work, Dr. Parameswaran has engineered powerful modified immune cells that more effectively target and kill cancer cells while sparing normal cells, thus minimizing the side effects experienced by patients. To do this, she purifies “Natural Killer (NK)” cells—white blood cells with tumor-killing capabilities. A slice of DNA called “BAFF CAR” is then inserted, which gives the NK cells more “specificity” and “power” to kill cancer cells, sparing normal cells. NK cells from any donor can be used to make BAFF CAR-NK cells. When the need for them arises, these specialized cells can be thawed and injected into patients. Her lab is working to validate the tumor-killing potential and safety of BAFF-CAR NK cells using mouse models with support from the Falk Trust.

Understanding the Mechanism of Tumor Microenvironment-Mediated Drug Resistance

Other projects of interest in Dr. Parameswaran’s lab include elucidating the mechanism of tumor microenvironment-mediated drug resistance in leukemia patients and understanding novel regulators of immune cell cytotoxic function. This entails the following:

1. Development of new CAR-T and CAR-NK therapies for solid and liquid tumors. 
2. Advancement of adoptive natural killer (NK) cell transfer, which has shown promise in cancer therapy, but has been hampered by insufficient cytotoxic activity of adoptively transferred NK cells in patients. To further this approach, Dr. Parameswaran’s lab is studying the role of tumor microenvironmental factors, transcription factors, post-translational modifications, as well as dietary ingredients in regulating the cytotoxic function of NK cells, to maximize the effectiveness of NK cell transfer.
3. Basic research studies to better understand and target the mechanisms of drug resistance in ALL cells and find ways to target these cells. For instance, B-lineage acute lymphoblastic leukemia (B-ALL) arises by malignant transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, which promotes their survival and drug resistance. Dr. Parameswaran’s lab aims to identify ways to more effectively target these cells and improve patient care.

Development of a CAR-T Cell That Targets Multiple Myeloma and Other B-Cell Cancers

Reshmi Parameswaran, PhD, MS, led a research team to develop a b-cell activating factor (BAFF) that binds three receptors, BAFF-R, BCMA, and TACI, which are primarily expressed on mature B cells. The researchers developed a BAFF ligand-based chimeric antigen receptor (CAR) and generated BAFF CAR-T cells with a non-viral gene delivery technique. They demonstrated that BAFF CAR-T cells can attach to each of the three BAFF receptors and effectively kill multiple B-cell cancers, including multiple myeloma, in vitro and using various xenograft models. Their findings were published in the January 11, 2022, issue of Nature Communications.