Rebecca Cottman, PhD, on Creating Regulated Gene Circuits to Enhance Cell Therapy Cytotoxicity

“A cytokine that can be preclinically has been shown to enhance CAR-mediated tumor killing is IL12. This particular cytokine has been applied in the clinic, but unfortunately, in unregulated applications either by injection or alongside adaptive T cell therapies. And in both cases, we've seen unacceptable risk of toxicity in patients. Senti has addressed this critical limitation by developing a gene circuit that uses a small molecule-regulated transcriptional switch to control the expression of IL22. And potentially, in conjunction with other CAR therapies or on its own, can lead to minimizing the risks to patients while maximizing that therapeutic window for application of IL12 in cytotoxic CAR therapies.”

While cytokines such as interleukin-12 (IL-12) have shown potential to enhance tumor cell cytotoxicity of chimeric antigen receptor (CAR) T-cell therapies, these are often accompanied by high levels of toxicity in treated patients. Senti Biosciences has developed a gene circuit using tamoxifen metabolites (endoxifen) that is able to induce robust, controllable expression of IL-12 in the brain and other tissues.

Preclinical, proof-of-concept data were presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by Rebecca Cottman, PhD, scientist, Senti Biosciences. CGTLive spoke with Cottman to learn more about the data presented and how Senti’s small molecule-regulated gene circuits have potential to be used in a variety of diseases and tissues to help enhance both gene and cell therapies. She discussed the course of the research and the different iterations of transcriptional switches Senti developed until reaching one sensitive to therapeutic levels of small molecules.

Click here to read more coverage of the ASGCT 2023 meeting.

REFERENCE

Cottman R, Johnson V, Hung M, et al. Engineering Pharmacologically Relevant, FDA-Approved Small-Molecule-Regulated Gene Circuits for Therapeutic Applications in the Brain. Presented at: ASGCT 2023 Meeting; May 16-20; Los Angeles, California. Abstract #150