# Using microfluidics to realize patient-specific anti-cancer immunotherapies

> **NIH NIH DP1** · STANFORD UNIVERSITY · 2023 · $1,080,800

## Abstract

Project Summary
T cells play a central role in the immune response, detecting antigenic peptides cradled within MHC molecules
(pMHCs) displayed on the surface of diseased cells via specific interactions with cell-surface T cell receptors
(TCRs). This recognition triggers downstream T cell activation and cytotoxic killing. In vivo, T cells are
exquisitely sensitive and specific, able to be activated by a single antigenic peptide displayed by a diseased
cell. Immunotherapies attempt to harness this sensitivity and specificity to eliminate cancerous cells by either
transfusing patients with T cells engineered to display TCRs specific for tumor-associated antigens
(neoantigens) or injecting peptide ‘vaccines’ to stimulate expansion of neoantigen-specific T cell clones.
Predicting which neoantigen/TCR combinations will activate a potent T cell response in a patient remains a
formidable challenge. There are a vast number of potential pMHC/TCR complexes: MHC molecules are
encoded by 23,000 HLA alleles, each MHC displays a ~9 amino acid peptide (209 possibilities), and each
patient can express >1020 possible TCRs. While many techniques leverage next-generation sequencing to
screen millions of pMHC/TCR combinations for high-affinity binders, these screens can test only a small
fraction of possible combinations.
Moreover, the strength of pMHC/TCR binding does not predict activation:
many high-affinity peptides do not activate T cells, and many potent agonists bind with only moderate affinities.
T cells generate pN to nN forces on pMHC/TCR complexes as they crawl over antigen-presenting cells, and
emerging evidence has established that these biomechanical forces are essential for sensitive and specific
TCR-pMHC recognition: pMHC/TCR complexes that drive potent activation form ‘catch’ bonds that strengthen
under force, while those that do not form ‘slip’ bonds more likely to break. Thus, developing improved
immunotherapies requires new technologies capable of testing large numbers of candidate pMHC/TCR
interactions for their ability to form catch bonds and activate T cells under physiological forces.
My lab is uniquely qualified to address this critical need. In prior work, we developed a microfluidic platform that
enables recombinant cell-free expression, purification, and quantitative in vitro characterization of >1,500
proteins in hours and at low cost. Here, we will apply this powerful technology to systematically investigate
which pMHC/TCR combinations form ‘catch’ bonds that predict activation (Platform 1) and which neoantigens
are efficiently displayed by 1000s of different MHC sequences encoded by variable HLA alleles (Platform 2).
To further test candidate pMHC/TCR combinations in their cellular context, we will apply a novel droplet-based
technology we invented to co-encapsulate 10s of millions of T cell/APC pairs and sort them based on activation
(Platform 3).

## Key facts

- **NIH application ID:** 10702214
- **Project number:** 1DP1CA290563-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Polly Morrell Fordyce
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,080,800
- **Award type:** 1
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702214

## Citation

> US National Institutes of Health, RePORTER application 10702214, Using microfluidics to realize patient-specific anti-cancer immunotherapies (1DP1CA290563-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10702214. Licensed CC0.

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