Dr Rafiq on Novel Strategies for CAR T-Cell Engineering in Solid Tumors

Sarwish Rafiq, PhD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine; program leader, CAR T Basic/Translational Research, Winship Center for Cancer Immunology, Winship Cancer Institute of Emory University, discusses how novel methods for engineering metabolically fit, memory rich CAR T-cells may address barriers to CAR T-cell efficacy in solid tumors.

At the Frontiers in Cancer Immunotherapy 2024 Symposium, Rafiq presented and shared 2 novel approaches to CAR T-cell engineering. The first multi-cytokine particle approach is a CAR T-cell extrinsic method, which involves engineering microparticles to enhance the manufacturing process of CAR T cells, Rafiq states. Since CAR T cells are extracted from patients, modified ex vivo, and then reinfused, this approach focuses on improving the quality of the cells during the manufacturing stage, she details. The engineered microparticles help in enriching the cells for memory phenotypes, which are associated with more durable responses in patients, Rafiq explains.

The second approach is a T-cell intrinsic method where CAR T cells are engineered to secrete their own antagonistic peptide against a novel immune checkpoint, Rafiq says. This modification alters the metabolism and activation profile of the CAR T cells, resulting in a more potent product, she describes.

Before these approaches can be used to manufacture CAR T cells for patients, additional GMP grade studies are needed, Rafiq continues. These studies will indicate whether the extrinsic approach can be implemented in a manufacturing facility to produce CAR T cells. For the intrinsic approach involving vasoactive intestinal peptide receptor antagonists, current research is focused on syngeneic mouse models, which involve the use of mouse CAR T cells in mice that have an intact immune system and tumors, Rafiq says. This research aims to determine if an endogenous immune response can be engaged and to assess any potential on-target off-tumor toxicities from antagonizing the receptor, she explains.

Additionally, studies addressing toxicity with the secreting CAR T cells are necessary to ensure their safety for patients, Rafiq notes. These steps are crucial for advancing these innovative CAR T-cell approaches from experimental stages to clinical application, she concludes.