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Engineering T Cell Receptors for Adoptive Cell Therapies

Award Number: R01CA178844
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2014
PERIOD OF PERFORMANCE END DATE: 12/31/2019

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Engineering T Cell Receptors for Adoptive Cell Therapies - DESCRIPTION (provided by applicant): Adoptive T cell therapy can be an effective and highly specific approach to the treatment of cancer. Introduction of receptors that recognize cancer antigens provides sufficient numbers of T cells with the appropriate specificity to destroy large, established tumors. The receptors used to date include either �� T cell receptors (TCRs) against pepMHC or antibody (scFv)-directed chimeric antigen receptors (CARs) against conventional cell surface cancer antigens. The purpose of this proposal is to improve upon current therapies and to develop a robust strategy that combines the advantages of each of these targeting approaches. The strategy involves a single-chain TCR (V�-linker-V�, called scTv) fused to signaling domains of CD28 (or 4-1BB) and CD3?. When endowed with a high-affinity scTv, this novel signaling receptor, which we call TCR-SCS (TCR-Single-Chain Signaling fusions), redirects activity of both CD4 and CD8 T cells. The TCR-SCS can be used without some of the risks associated with conventional �� TCRs. For example, TCR-SCS receptors limit self-peptide, off-target reactivities and they avoid mis-pairing with endogenous TCR chains. The reduced levels of off-target reactivities arise from the inability of the single-chain signaling protein to synergize with CD8, a process that enhances sensitivity in CD8 T cells but also increases the level of stimulation by other pepMHC. To enable the rapid use of these TCR-SCS receptors in human therapies, we will also use structure-guided design to engineer high-affinity TCRs against specific pep/HLA-A2 antigens. Our central hypotheses are that TCR-SCS (TCR-Single-Chain Signaling fusions) can be rapidly engineered against many different pepMHC target antigens, and that the TCR-SCS will mediate effective CD4 and CD8 T cell activity without off-target cross-reactivity. Accordingly, the specific aims are: Aim 1. To isolate human T cell receptors against diverse peptide/HLA-A2 antigens using a single TCR scaffold. The approach will involve a combination of structure-based design, taking advantage of computational analyses for library construction and advanced techniques of yeast display for the rapid isolation and evolution of the TCRs. Aim 2. To determine if a TCR-SCS (TCR-Single-Chain Signaling fusion) influences T cell persistence and function in mice. Because the TCR-SCS format is a completely novel approach, we will use the model system involving the peptide SIY, and the high-affinity m33 TCR-SCS against SIY/Kb, to further examine in vivo properties of transduced CD4 and CD8 T cells (collaboration with Dr. Hans Schreiber). Tumor models will include an inducible B-Raf/PTEN-/- melanoma that expresses SIY/Kb (collaboration with Dr. Tom Gajewski). Aim 3. To use TCR-SCS (TCR-Single-Chain Signaling fusions) with high-affinity, human TCRs against WT1 to target tumors. Established, transplanted WT1/HLA-A2 human tumors will be used to examine effectiveness of CD4 and CD8 T cells, transduced with WT1-specific TCR-SCS receptors (collaboration with Dr. Philip Greenberg). Preliminary studies with TCRs isolated in Aim 1 will also extend results to other human tumor antigens.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Cancer Treatment Research	000	5	5/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $320,517 )
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Cancer Treatment Research	000	5	12/19/2017	NON-COMPETING CONTINUATION	$288,465
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Cancer Treatment Research	001	5	5/23/2018	NON-COMPETING CONTINUATION	$32,052
														Subtotal = $320,517

Issue Date FY: 2017 ( Subtotal = $320,517 )
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Cancer Treatment Research	000	4	12/21/2016	NON-COMPETING CONTINUATION	$288,465
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Cancer Treatment Research	001	4	6/7/2017	NON-COMPETING CONTINUATION	$32,052
														Subtotal = $320,517

Issue Date FY: 2016 ( Subtotal = $320,517 )
2016	2016	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cancer Treatment Research	000	3	12/21/2015	NON-COMPETING CONTINUATION	$320,517
														Subtotal = $320,517

Issue Date FY: 2015 ( Subtotal = $320,517 )
2015	2015	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cancer Treatment Research	000	2	12/22/2014	NON-COMPETING CONTINUATION	$288,465
2015	2015	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cancer Treatment Research	001	2	1/27/2015	NON-COMPETING CONTINUATION	$32,052
														Subtotal = $320,517

Issue Date FY: 2014 ( Subtotal = $320,517 )
2014	2014	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cancer Treatment Research	000	1	12/23/2013	NEW	$320,517
														Subtotal = $320,517

Grand Total All Awards = $1,602,585

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Engineering T Cell Receptors for Adoptive Cell Therapies

Award Number: R01CA178844

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2014

PERIOD OF PERFORMANCE END DATE: 12/31/2019

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