Protein receptors salted over surfaces of Natural Killer (NK) immune cells act as search-and-destroy navigation systems to identify and control some cancers and pathogens. Now scientists hope to engineer a powerful new receptor for NK cell surfaces, allowing more precise, aggressive targeting of multiple myeloma, a tenacious cancer of plasma cells, and providing another crucial option for a revolutionary treatment called CAR therapy.

In CAR therapy, T immune cells are extracted from a patient’s blood. Then the cells are engineered in the lab by adding a chimeric antigen receptor—or CAR. The redesigned cells – called CAR-T cells – are multiplied and reinfused into the bloodstream. CAR-T cells have proven highly effective in finding and destroying some types of cancer cells.

But CAR-T therapy can have severe side effects. And because CAR-T has strict matching requirements, it must be custom-made for each patient. That is a slow process, and some patients languish on wait lists.

Scientists are looking for other treatment options. One idea is to design a CAR for NK cells optimized against multiple myeloma.

“NK cells would not have the same matching requirements for NK therapy compared to T cells,” said Stacey Finley, PhD, the Nichole A. and Thuan Q. Pham Professor at the USC Viterbi School of Engineering. “There’s evidence that NK cells in CAR therapy could be safer and cause less side effects.”

In 2022, the research team of Finley and Nick Graham, PhD, associate professor at the Mork Family Department of Chemical Engineering & Materials Science, received a five-year grant from the NIH National Cancer Institute’s Cancer Systems Biology Consortium to enable an efficient design of optimal CAR-NK cells.

“We are trying to understand the kind of signaling activated by the naturally occurring receptors on the surface of NK cells,” said Finley. “We might be able to use that knowledge to test how different receptors on NK cells could be combined, or how components of different receptors might be combined, to design a CAR as a basis in infusion treatment of multiple myeloma.”

But during the grant proposal process, the researchers hit a snag.

“When we first submitted the grant to NIH, reviewers said that we needed a more rigorous statistical analysis to ensure that the study is designed properly,” said Finley. “We needed enough statistical power to answer questions about whether one CAR design is better than others. That’s when I looked at resources available at the Southern California Center for Clinical and Translational Science Institute (SC CTSI), and I connected with Melissa.”

She's referring to Melissa L. Wilson, MPH, PhD, associate professor in the Department of Preventive Medicine at the University of Southern California and member of the Biostatistics, Epidemiology, and Research Design (BERD) group at SC CTSI.

“Melissa helped us think about how we could improve our proposed study so it could better answer our research questions,” said Finley. “From our discussions with Melissa, we realized that we needed to increase the number of samples and be clearer in the comparisons we would make.”

Wilson found the experience of working with Finley to be fruitful as well. The key to success is to make use of statistical services early in the process.

“Stacey came to BERD with plenty of time to spare, so I was able to really delve into the grant and see where some of the statistical aspects could be clarified,” said Wilson. “The project is extremely exciting, and it was a pleasure to work on something so important to the future of cancer treatment.”

The study will be conducted in two stages.

“If design A of a CAR is proven statistically most effective in killing tumor cells, then it could pass the first threshold and could be used in the next stage on animals," said Finley. "Melissa helped us to design both stages and to do the statistical analysis for both. She helped write the portion of the grant describing the statistical analysis and the portion describing how many animals we needed in the study, and what the different aims of the mouse study would look like.”

Although this teamwork was critical in producing a successful major grant proposal, the process was surprisingly smooth.

“It was very easy to work with Melissa," said Finley. "We had several meetings and phone conversations and then went back and forth on email and editing the proposal. The ease with which we got this collaboration going was quite nice.”