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NIH grant 1R01CA313939-01: Advancing ProCAR therapy toward clinical application
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Nicholas Arpaia. Award: $635722.
Start: 2026-07-23T00:00:00.
PROJECT SUMMARY
Synthetic biology is ushering in a new era in medicine through the engineering of living cells. This
approach enables the development of engineered drug-delivery systems that can intelligently detect
and adapt to different environments, offering enhanced specificity and effectiveness beyond current
molecular-based methods. Although such living drugs have shown significant success, they face numerous challenges in treating solid neoplasms, including the absence of uniformly expressed
specific antigens, antigen loss as a resistance mechanism, and poor infiltration along with hostile
microenvironments that lead to T cell dysfunction. By designing cooperative interactions between
mammalian effectors and other modalities, such as engineered probiotics, these limitations can
potentially be overcome. Over the last few decades, microbiome and mechanistic studies have
elucidated the remarkable ability of certain bacteria to invade and thrive in immunologically and
metabolically distinct environments. Where mammalian effectors – whose activity is
antigen-dependent – struggle to target and infiltrate lesions, bacteria naturally home, colonize, and
remain indifferent to their antigenic profile. Harnessing advances in synthetic biology, probiotics can
be engineered as beacons which direct and enhance the activity of immune cells, such as
probiotic-guided ProCAR-T cells, which are guided by orthogonal antigens released from engineered
probiotics. This project proposal seeks to advance the bridge between a pro- and eukaryote
cooperative, cross-domain platform. Specifically, we will improve pharmacokinetics of the engineered
probiotics through genetic attenuations and gene circuits as well as enable long-range ProCAR-T
cell interactions through probiotic-payload production and ProCAR-T cell engineering. Because the
therapeutic activity of engineered probiotics and ProCAR-T cells depends on complex
interactions among the tumor, immune system, and host tissues, vertebrate animal models
are required to evaluate bacterial colonization, biodistribution, safety, and antitumor efficacy
in vivo. These studies cannot be adequately replicated using existing in vitro systems and
thus our project will involve the use of mouse models of cancer. This work represents a
fundamentally new approach to genetically engineering interactions between living medicines,
combining the advantages of redirected immune cells and bacteria, and lays the foundation for
next-generation engineered communities.document fetched 2026-08-02 08:24