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This novel technology enables refined temporal control of protein-protein interactions that can be used to regulate cell therapies, including CAR T-cells and “cell factories”.

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Chimeric antigen receptor (CAR) T cells have so far shown limited efficacy on brain and solid tumors. UCSF investigators have developed a method of manufacturing recombinant immune cells by pre-treating them with a combination of small molecules to increase the number of CAR T cells in the tumor microenvironment and improve the survival of animal models bearing glioma in the brain relative to CAR T cells that have not received the pre-treatment. These results may be applicable to other solid tumors.

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Natural Killer (NK) cells are innate lymphocytes with the ability to lyse tumor cells. One limitation of NK cells when encountering tumor cells is that they can’t control their own proliferation and expansion to increase their numbers at the tumor site. Current approaches to increase NK cell numbers and stimulate NK-cell anti-cancer functions include systemic administration of recombinant cytokines (IL-15, IL-2, or IL-12) that exhibit systemic or local toxicity or constitutive expression of IL-15 in transduced NK cells. Researchers at UCSF have engineered NK cells with a chimeric cytokine receptor (CCR) that provides autocrine signaling through the secretion of IFNγ, which subsequently enhances NK cell proliferation and function to support NK cell anti-cancer immune response specifically at the tumor site while avoiding recombinant cytokine- related toxicity. 

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In cancer care, specific characteristics of T cells can be used to measure a patient’s response to immunotherapy. Using single-cell RNA-sequencing coupled with TCR sequencing, scientists at UCSF and Harvard detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in the blood. Their method reveals specific protein signatures (biomarkers) on the surface of T cells that can be therapeutically targeted to treat melanoma and other forms of cancer. It presents a very attractive alternative to obtaining invasive biopsy samples from the tumor, and can be done much more quickly.  

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