# Binding and Presentation of Lipid Antigens by CD1

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $467,196

## Abstract

CD1d-restricted NKT cells with invariant TCR chains (iNKT cells) are a unique and conserved
component of the mammalian immune system. Studies in mice have shown dramatic in vivo effects of
iNKT cell activators, such as the CD1d-presented glycolipid antigen -galactosylceramide (GalCer), in
a wide variety of animal models, but despite remarkable therapeutic effects with iNKT cell activators in
murine models of cancer and other diseases, this area has been slow to progress to more advanced clinical
development. This application addresses issues that are likely to be major limitations in advancing iNKT
cell-based therapeutics, and seeks to provide practical solutions to these impediments. We hypothesize
that attempts to move iNKT cell therapeutics into the clinic for applications such as cancer
immunotherapy or as vaccine adjuvants have been slowed by three specific issues, all of which will be
directly addressed by the current proposal. The first is the suboptimal design of synthetic iNKT cell
activators, which we will overcome using recent discoveries from our work on the structure-activity
relationship of GalCer analogues. The second issue is the tendency of iNKT cell agonists to induce
deletion and hypo-responsiveness of the responding cells (“anergy”), making them at best “single shot”
therapeutics. We will use recently developed novel glycolipid delivery methods to overcome this
limitation. We also propose studies based on recent gene expression profiling in iNKT cells to identify
the cell surface receptors that control post-activation anergy, which will provide mechanistic insights into
the anergic response and strategies to overcome it. A third issue addressed by the proposal relates to the
inadequacy of standard mouse models for development of potential iNKT cell therapeutics, for which we
will implement human CD1d knock-in mice as the first practical, humanized model for in vivo evaluation
of iNKT cell-based immunotherapies. Overall, this competing renewal application proposes innovative
solutions to major impediments in the ongoing effort to harness the potential of iNKT cell-based
therapeutics. Successful completion of the aims of the proposal should advance our understanding of
iNKT cell biology, while also helping to drive progress in the area of cancer immunotherapy.

## Key facts

- **NIH application ID:** 9975679
- **Project number:** 5R01AI045889-21
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Steven A Porcelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,196
- **Award type:** 5
- **Project period:** 1999-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975679

## Citation

> US National Institutes of Health, RePORTER application 9975679, Binding and Presentation of Lipid Antigens by CD1 (5R01AI045889-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975679. Licensed CC0.

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