CO-engineering car t cells and car macrophages with synthetic cytokine signaling for glioblastoma immunotherapy

The National Cancer Institute awarded The Leland Stanford Junior University $100,228 on February 13, 2027, under the Cancer Research Manpower program (CFDA 93.398) to support biomedical training and research in cancer immunotherapy. Performance extends through September 21, 2029, at Stanford's Palo Alto, California location.

The award funds research on co-engineered CAR T cells and CAR macrophages for glioblastoma treatment. The project applies a synthetic cytokine receptor (SCR) platform to design immune cell systems where T cells and macrophages interact synergistically rather than in isolation. Aim 1 characterizes SCR macrophages with molecular phenotypes and functions associated with positive glioblastoma outcomes. Aim 2 performs combinatorial assays of CAR T cells and CAR macrophages transduced with the SCR, assessing killing capacity and phenotypic markers in both large in vitro screens and preclinical mouse models of glioblastoma. The training plan embedded in the proposal enables the applicant to gain technical expertise in synthetic biology and therapeutic cell engineering. The program supports workforce development for careers in basic, clinical, and prevention research relevant to the National Cancer Program.

Abstract

Current cell therapies use individual immune cells in isolation from one another, which contrasts the natural immune system where multiple specialized cells cooperate to overcome infections and cancer. Inspired by this concept, this proposal seeks to design immune cell systems that leverage the unique advantages of t cells and macrophages for the treatment of glioblastoma, a devastating and common brain cancer affecting over 200,000 people globally every year. However, a major challenge in synthetic biology and immunotherapy design is coordinating systems of therapeutic cells that synergistically interact and do not antagonize one another in a generalizable and programmable way. To address this problem, this proposal employs an innovative synthetic cytokine receptor (SCR) platform, which preliminary studies have demonstrated can leverage constitutive and customizable cytokine signaling to allow precise control over cell phenotype. The SCR can be used to design t cells with variable cytotoxicity, proliferation, and memory, as well as to design macrophages with a range of pro- and anti-inflammatory polarization. The SCR will be used to systematically vary car t and car macrophage phenotype to discover design rules of synthetic immune cell systems and to discover effective therapies against glioblastoma models. Aim 1 seeks to further characterize and discover SCR macrophages with molecular phenotypes and functions associated with positive outcomes in glioblastoma. Aim 2 is centered on performing combinatorial assays of car t cells and car macrophages transduced with the SCR, assessing the killing capacity and phenotypic markers of these therapeutics in the context of both large in vitro screens and preclinical mouse models of glioblastoma. The training plan within this proposal is tailored to allow the applicant to gain technical experience in the generation of large, unbiased datasets of primary human immune cell functions, preclinical mouse models, as well as career development skills in scientific communication and mentorship. These development goals will fill gaps in the applicant's training that will ultimately unlock future opportunities to be a leading translational synthetic biologist. The proposed research leverages innovative synthetic cytokine receptor technology and holds significant return on investment by advancing broadly applicable synthetic immune system engineering frameworks. Uncovering principles of synthetic cell system design will unlock new therapy modalities for glioblastoma, and ultimately lead to a paradigm shift in cell therapy that will use precisely controlled systems of genetically engineered cells for applications across cancer, autoimmune diseases, and regenerative therapies.