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Next-generation Cellular Therapy in the Works at UH Seidman Cancer Center

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BAFF CAR-NK cells show promise

Innovations in Cancer | February 2024

A research team from UH Seidman Cancer Center and Case Western Reserve University School of Medicine is developing a next-generation cellular immunotherapy that early results suggest could be safer, more effective, more convenient and less expensive than existing options.

Reshmi Parameswarn, PhD UH Seidman Cancer CenterReshmi Parameswaran, PhD

The innovation at issue is BAFF CAR-NK cells – B cell activating factor ligand-based chimeric antigen receptor natural killer cells. Reshmi Parameswaran, PhD, a scientist in the Division of Hematology and Oncology at UH Seidman Cancer Center and Assistant Professor of Medicine at Case Western Reserve University School of Medicine, and colleagues have developed these cells to target three antigens expressed by B cell cancers: BCMA, TACI and BAFF-R.  

Results to Date

“Preliminary data demonstrates the BAFF CAR-NK cells efficiently kill B cell cancers and secrete significantly low amounts of cytokines compared to CAR-T cells,” Dr. Parameswaran. “This is expected to minimize the serious side effect of cytokine release syndrome in patients without compromising the tumor killing potential. At the same time, our preliminary data demonstrates efficient tumor killing by the BAFF CAR-NK cells against mantle cell lymphoma, multiple myeloma and chronic lymphocytic leukemia in cellular models.”

With a new $1 million grant from the Dr. Ralph and Marian Falk Medical Research Trust, the team is conducting further efficacy and safety studies using mouse models and plans to submit its work to the FDA as an investigational new drug. They hope to begin clinical trials within three years.

Clear Advantages

Importantly, Dr. Parameswaran says, BAFF CAR-NK cells can be generated from random donors, frozen and used when needed. The CAR T process, on the other hand, requires collecting the patient’s own T-cells, re-engineering them and reinfusing them, with what can be a lengthy manufacturing process.

“BAFF CAR-NK cells are an “off-the-shelf” product,” she says. “Manufacturing costs are significantly reduced as patient cell harvesting is eliminated.”

The three antigens targeted by BAFF CAR-NK cells – as opposed to a single CD19 receptor targeted by CAR T applications – also make them ideally suited for avoiding the problem of antigen escape – a major factor in relapse.

“With three antigen targeting, we anticipate mitigating antigen escape,” she says.

In fact, it’s very likely patients who’ve been treated with CAR T therapy and whose cancer has lost the CD19 receptor after CD19 CAR T treatment can be effectively treated with BAFF CAR- NK cells, Dr. Parameswaran says. In addition, BAFF CAR-NK cells have the potential to treat patients with multiple myeloma, where CD19 is absent.

Reducing devastating side effects can also not be under-estimated as a potential advantage of BAFF CAR-NK cells, she says.

“These CAR-T therapies have drawbacks,” she says. “CAR-T-cells release cytokines that can cause cytokine release syndrome, neurotoxicity, fevers, low blood pressure, and low blood oxygen that are often serious enough to discontinue therapy.”

Dr. Parameswaran says she and her team are determined to tackle these problems and improve options for patients.

“About 250,000 B cell cancer patients are diagnosed each year in the U.S., with half relapsing without a therapeutic option to stop progression,” she says. “We need a better therapeutic tool. We believe our new cost-effective treatment strategy for B cell cancer patients, for those not responding to conventional chemotherapies, designed to target multiple proteins found on the surface of cancerous B cells killing tumor cells with minimal side effects, could be the tool we need to get better outcomes.”

For more information, please email Reshmi Parameswaran, PhD at rxp278@case.edu.

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