# A modular cell therapy platform for controlling immunological tolerance

> **NIH NIH DP2** · STANFORD UNIVERSITY · 2024 · $473,515

## Abstract

Project Summary/Abstract
The balance between immune tolerance and activation lies at the heart of most pathologies. Immunological
tolerance refers to the set of processes that prevent immune activation against non-pathogenic antigens. The
key distinguishing feature of tolerance compared to other forms of immunosuppression is that it operates to
inhibit reactivity only to specific antigens and does not render the host immunosuppressed with respect to
unrelated pathogens. Immune homeostasis relies upon precise tuning of this tolerance-activation axis, and
disruption of this balance results in autoimmunity or malignancy. To date, nearly all our treatments for
autoimmune disease result in some form of nonspecific immunosuppression. Conversely, while
immunotherapies represent the greatest paradigm shift in oncology in decades, they largely act to induce broad
immune activation in a nonspecific manner that often results in adverse events, including autoimmune
pathologies. In solid organ transplantation, our inability to induce complete graft tolerance often requires the use
of lifelong immunosuppressants. Thus, despite over a half-century of research into immunological tolerance,
there remains a pressing need to develop therapies capable of controlling antigen-specific
immunological tolerance for a wide range of diseases and clinical settings. In this proposal, we seek to
develop a new class of modular immunotherapies that couple intrinsic T cell biology with synthetic biology and
genome engineering to reeducate endogenous tolerance programs in the host. We hypothesize that by
activating or disrupting aberrant tolerance programs, we can treat autoimmune disease and metastatic
cancer. Lymph nodes are the anatomical hubs of peripheral tolerance induction, a feature that is coopted by
malignancies as they metastasize throughout the host. Unlike conventional engineered cell therapies whose
mechanism of action relies upon cytolysis of pathogenic cells, including tumors or autoreactive lymphocytes, the
engineered cell therapies that we propose instead function by trafficking to lymph nodes to alter
endogenous tolerance induction resulting in resolution of autoimmunity or treatment of metastatic cancer. To
achieve these goals, we will develop a T cell therapy that specifically homes to lymph nodes by coopting intrinsic
naïve T cell homing machinery. In the context of metastatic cancer, we will augment this approach with the
inclusion of chimeric antigen receptors (CARs) that break immune tolerance and induce activation upon ligation
of the CARs following trafficking to LNs. In the context of autoimmunity, our therapies will induce tolerance
following recognition of autoantigen presentation by antigen presenting cells in lymph nodes. Thus, at the
conclusion of this project, we will deliver a new class of modular immunotherapies that harnesses the
endogenous immune response in an antigen-specific manner. This approach has the potential to deliver
cures to patie...

## Key facts

- **NIH application ID:** 10899598
- **Project number:** 5DP2AI177915-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nathan Edward Reticker-Flynn
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $473,515
- **Award type:** 5
- **Project period:** 2023-08-04 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899598

## Citation

> US National Institutes of Health, RePORTER application 10899598, A modular cell therapy platform for controlling immunological tolerance (5DP2AI177915-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10899598. Licensed CC0.

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