R33CA302206

Next generation platforms for interrogating TCR specificity - Project abstract: Peptide-MHC tumor antigens provide actionable value for cancer detection, and therapeutic targeting.

But the process of identifying tumor antigens and then detecting them on tumor tissue at the protein level, and then targeting them therapeutically remains a major bottleneck.

Technologies that can interrogate, and mimic, how T cell receptors recognize the composite peptide-MHC surface are important for clinical translation to antigen-specific immunotherapies.

We wish to optimize development of two validated complementary methods for the identification, and subsequent detection and targeting of pMHC tumor antigens at the protein level.

In the first approach, the PI has developed a technology, yeast peptide-MHC display, to identify peptide ligands of ‘orphan’ TCRs in the natural immune system or from pathogenic systems (e.g. cancer, autoimmunity, infectious disease).

We have deployed this technology to discover new tumor antigens, but the platform has several technical liabilities that limit its impact.

We wish to engineer improved ‘next generation’ versions of the pMHC display technology that will increase the speed and yield of screening and help solve the problem of MHC restriction ambiguity by TCRs.

In the second approach, to make the best use of new ligands from AIM #1, we wish to optimize experimental and computational platforms for the rapid isolation of high-affinity “TCR mimic” antibodies and machine-learning designed pMHC mini-binders, respectively, that specifically recognize pMHC ligands and enables us to track tissue expression and induce selective killing of cells expressing these antigens.

While exome sequencing reveals neoantigens, it does not tell us if the antigen is expressed on the tumor cell surface.

Using our validated technology we are able to quantify the number of tumor antigens expressed on the tumor cell.

The pMHC display tumor antigen discovery platform goes with the TCR-mimic binder discovery as a “one-two punch” for protein-level detection and targeting of cancer antigens.

We request support to further develop the platforms to increase hit rates and make the workflow more user friendly for adoption by the wider community.

The Leland Stanford Junior University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. 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.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Advanced Development and Validation of Emerging Molecular and Cellular Analysis Technologies for Basic and Clinical Cancer Research (R33 Clinical Trial Not Allowed) (RFA-CA-24-009)