Project Details
Description
The invariant Natural Killer T cells (iNKT cells) comprise a well-defined subset of unconventional, innate-like
lymphocytes that are important effector and regulatory cells in both humans and mouse models. Unlike
conventional T cells, iNKT cells express T cell antigen receptors of limited diversity and respond mainly to
foreign and self-glycolipid antigens presented by the MHC class I-like CD1d protein. Activities of iNKT cells
include tumor immunosurveillance and induction of tumor regression, strongly implying the potential for
iNKT cell-directed therapies for cancer. Synthetic glycolipid antigens that potently activate iNKT cells, such
as synthetic α-galactosyl ceramides, have attracted considerable attention as potential anti-tumor agents.
However, progress in development of effective iNKT cell directed therapies has been hindered by issues
related to toxicities and off-target effects, and is complicated by the fact that glycolipids are taken up and
presented by a variety of different cell types to generate complex and unpredictable outcomes.
Furthermore, the development of long-term unresponsiveness (anergy) and depletion of iNKT cells by
multiple exposures to strong activators like α-galactosyl ceramides makes repeated administration
ineffective. Approaches to activating iNKT cells that circumvent these obstacles are needed to exploit the
potential of these cells for cancer immunotherapy. The goal of the current proposal is to address these key
issues and accelerate the movement of iNKT cell-directed immunotherapy for cancer towards clinical
translation. Three specific aims are proposed that will build on our extensive background work that has
identified covalently stabilized soluble αGalCer-CD1d conjugates as iNKT cell activators for generating
targeted anti-tumor effects without causing iNKT cell anergy or off target toxicity. This approach will be
combined with other modalities to improve the anti-tumor effects of iNKT cell activators, including the
incorporation of costimulatory signals and combination with inhibitory immune checkpoint blockade. An
extensive body of preliminary work supports our approaches, which will be tested in vivo in relevant mouse
models of cancer. The project will benefit enormously from close interactive working relationships with a
superb group of collaborators with expertise in synthetic chemistry, protein engineering and the biology of
immune checkpoint molecules. The current proposal has direct relevance for clinical translation of basic
iNKT cell biology into immunotherapeutics, and will accelerate development of iNKT cell directed therapies
for cancers that are unresponsive to currently available treatment.
Status | Active |
---|---|
Effective start/end date | 7/1/99 → 6/30/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $562,714.00
- National Institute of Allergy and Infectious Diseases: $337,268.00
- National Institute of Allergy and Infectious Diseases: $327,721.00
- National Institute of Allergy and Infectious Diseases: $467,196.00
- National Institute of Allergy and Infectious Diseases: $249,413.00
- National Institute of Allergy and Infectious Diseases: $335,044.00
- National Institute of Allergy and Infectious Diseases: $336,488.00
- National Institute of Allergy and Infectious Diseases: $255,879.00
- National Institute of Allergy and Infectious Diseases: $382,338.00
- National Institute of Allergy and Infectious Diseases: $415,000.00
- National Institute of Allergy and Infectious Diseases: $271,738.00
- National Institute of Allergy and Infectious Diseases: $467,196.00
- National Institute of Allergy and Infectious Diseases: $256,900.00
- National Institute of Allergy and Infectious Diseases: $406,742.00
- National Institute of Allergy and Infectious Diseases: $467,196.00
- National Institute of Allergy and Infectious Diseases: $410,850.00
- National Institute of Allergy and Infectious Diseases: $211,317.00
- National Institute of Allergy and Infectious Diseases: $336,311.00
- National Institute of Allergy and Infectious Diseases: $263,822.00
- National Institute of Allergy and Infectious Diseases: $467,416.00
- National Institute of Allergy and Infectious Diseases: $406,742.00
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