U01CA265713

Precise Tumor Targeting with Logic Car Circuits - Project Summary

This proposal describes a unique Supra Car system in human T cells to address in vivo off-tumor toxicity, using an established liver transgene expression mouse model. We will use our recently developed Split, Universal and Programmable (SUPRA) Car system that simultaneously encompasses multiple critical upgrades, such as the ability to finely tune T cell activation strength, sense and logically respond to multiple antigens, and independently regulate two T cell subtypes simultaneously.

Specifically, we will evaluate two types of circuits: (1) AND and (2) NIMPLY (A AND NOT B) logic Car circuits, which have been determined bioinformatically as the best type for circuits for discriminating tumors from healthy cells. The proposed experiments will test the hypotheses that (1) our modular and tunable logic Car T systems are uniquely suited for preventing on-target off-tumor toxicity in vivo, even when healthy tissues expressing a target antigen are near the tumor, and (2) the tumor specificity and activity of our Supra Car systems is enhanced by controlled delivery. Importantly, preliminary data support these hypotheses, and well-characterized materials and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise that encompass synthetic biology, immunology, animal tumor biology, and biomaterials.

The specific aims of this five-year proposal are as follows:

Aim 1: Evaluate and logic Supra Car specificity in vivo.
Aim 2: Investigate the tumor specificity and toxicity of NIMPLY logic Supra Car in vivo.
Aim 3: Determine the effect of adaptor protein delivery mechanism on tumor-targeting specificity.

Outcomes from this work will establish the clinical potential of logic Car systems and expand their use to additional cancers, including solid tumors.

Trustees Of Boston University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.286 - Discovery and Applied Research for Technological Innovations to Improve Human Health

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Biomedical Imaging and Bioengineering (NIBIB) [HHS - NIH]

Boston, Massachusetts 02215 United States

Single Zip Code

Collaborative Approaches to Engineer Biology for Cancer Applications (U01 Clinical Trial Not Allowed) (RFA-CA-20-054)

Amendment Since initial award the total obligations have increased 1351% from $175,000 to $2,539,139.