Engineering Spatially Targeted Cell Therapies via Metabolite Sensing GPCRs

Stanford researchers have discovered programmable mechanisms to mobilize T and Natural Killer (NK) cells to solid tumors. The therapeutic cells are engineered to detect bioactive molecules released by tumors, migrate along these tumor-derived biochemical gradients, and, in turn, achieve marked enhancement of tumor infiltration and therapeutic efficacy.

The invention addresses a critical barrier in cell therapies and immunotherapies, which have transformed cancer treatment but remain ineffective for many patients, in part due to insufficient immune recruitment and infiltration into solid tumors. While cell engineering efforts have primarily focused on protein-protein interactions, this invention has uncovered the untapped potential of bioactive metabolites and their cognate G protein-coupled receptors (GPCRs) as programmable levers for mobilizing immune cells to solid tumors.

Aberrant tumor metabolism is a well-established and prevalent cancer hallmark, which is already routinely used by oncologists for cancer detection and diagnosis. Using a tumor homing GPCR (thGPR), the invention enables the engineering of therapeutic cells to sense, migrate to, and target solid tumors based on their abnormal metabolic activity. Given the unique diffusion ranges, tissue partitioning, and clearance of small lipophilic metabolites, metabolite sensing GPCRs provide spatial information orthogonal to, and synergistic with, other axes, such as Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) signaling, which recognize target cells upon contact. thGPRs can be expressed in therapeutic cells via ex vivo or in vivo genetic editing or targeted RNA/protein delivery and have already been shown by the investigators to significantly enhance the in vivo efficacy of NK, CAR NK, CAR T, and TCR-based therapies, leading to tumor control and elimination, as evidenced by durable and complete responses in preclinical studies.

thGPRs were directly compared to dozens of genes with well-established roles in immune cell migration, including chemokine receptors, integrins, and proteases, and repeatedly outperformed these alternative strategies. Studies have thus far been performed in breast and ovarian cancer mouse models, where the thGPRs have been independently identified as top hits in NK CRISPR activation tumor infiltration screens, demonstrating a high degree of convergence and generalizability. Preclinical in vivo models are now being extended to additional cancer types. While the results obtained thus far, along with the well-established pan-cancer metabolic abnormalities, strongly suggest that the lead thGPRs will be relevant across a broad set of cancer types, the researchers are also testing metabolic biomarkers and developing rapid functional assays to determine the optimal thGPRs for a given cancer type or patient.

The invention creates modular mechanisms for spatially targeted cell therapies, where tumor-specific, tissue-specific, or pathology-specific metabolites serve as navigation cues to dynamically control immune cell location.

The work opens a new domain for the design and development of spatially targeted cell therapies and can provide a basis for a whole new class of therapies.

Stage of Development
Research - in vivo

Stage of Research
In vivo data from studies across therapeutic modalities, including xenograft models with human T cells and NK cells and immunocompetent syngeneic models with mouse T cells, have demonstrated a marked improvement in tumor infiltration and therapeutic efficacy.