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Programming Metabolically Fit TILs for Immunotherapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA239952-01A1
Agency Tracking Number: R41CA239952
Amount: $224,559.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NCI
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-02-15
Award End Date (Contract End Date): 2021-01-31
Small Business Information
3064 RIVERWOOD DRIVE
Mount Pleasant, SC 29466-8170
United States
DUNS: 081243721
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 SHIKHAR MEHROTRA
 (843) 792-0940
 ogretmen@musc.edu
Business Contact
 BESIM OGRETMEN
Phone: (843) 792-0940
Email: ogretmen@musc.edu
Research Institution
 MEDICAL UNIVERSITY OF SOUTH CAROLINA
 
1 SOUTH PARK CIRCLE - BUILDING 1SUITE 506
CHARLESTON, SC 29407
United States

 Nonprofit college or university
Abstract

ABSTRACT
Advances in molecular biology and genetic engineering have led to the design and use of modified T cells
recognize tumors to achieve significant tumor control upon adoptive cell transfer (ACT) to patients. These T
cells are either transduced with tumor antigen reactive T cell receptors (TCR), or chimeric antigen receptors
(CARs). Recently, a surge in studies with neo-antigen reactive T cells or T cells recognizing novel mutated
antigens has also shown promise. While the implementation of these studies requires significant technical
resources, the appearance of antigen loss variants also leads to less effective tumor control when using
effector T cells reactive to single tumor antigen or target molecule. Thus, there is a resurgence in using TILs,
which have endogenous T cells reactive to multiple tumor epitopes, for ACT. While most studies have used the
conventional approach to expand TILs using high dose IL2, some recent studies using IL15 or IL21 showed
improved tumor control. Preclinical studies have also shown that different subsets of both helper CD4+ T helper
(Th) cells and CD8+ T cytotoxic (Tc) cells hold promise for clinical use in ACT protocols. Importantly, T helper
cell subsets with the ability to secrete IL-17 (Th17) have been shown to possess stem cell like phenotype that
attributes to their long-term persistence and leads to improved tumor control tumors as compared to the Th1
subsets (that secrete IFNγ, IL2, TNFα). However, contrary to these observations there are reports that Tc1
cells exhibit improved tumor control as compared to Tc17 cells. These differences in T cell subsets response to
control tumors, is compounded by the fact that in the suppressive tumor microenvironment a large fraction of
these Th or Tc subsets acquire FoxP3+ regulatory phenotype, become dysfunctional or undergo cell death
leading to tumor reversion. Thus, ex vivo programming conditions that can render a stable phenotype with
reduced `plasticityandapos; and not only controls primary tumors, but also results in formation of anti-tumor memory will
be of immense importance in ACT. We have recently established that programming conditions that bring
together `anti-tumor effector functionandapos; of Th1 cells and `stemnessandapos; of Th17 cells lead to a superior hybrid Th1/17
(and Tc/17) cells exhibiting long-term tumor control. Thus, we hypothesize that ex vivo expansion and
programming of TILs to hybrid T1/17 (Th1/17 and Tc1/17) phenotype will lead to robust anti-tumor control even
with fewer adoptively transferred cells. Following specific aims are proposed to establish and develop our
approach for commercialization: Specific Aim 1: To determine if human melanoma tumor derived TILs could be
ex vivo programmed to potent anti-tumor hybrid T1/17 phenotype. Specific Aim 2: To establish if hybrid TILs
are superior to conventional TILs in controlling melanoma tumor growth in vivo. We believe that this proposal
will help adopt the novel ex vivo programming conditions for generating robust anti-tumor TILs that could be
used future in adoptive T-cell immunotherapy clinical trials.NARRATIVE
Adoptive transfer of T cells that can recognize tumor and cause tumor cell death is a promising approach, and
has gained momentum after novel anti-tumor T cells could be engineered by viral transductions of tumor
reactive T cell receptor (TCR), or chimeric antigen receptors (CAR). However, many confounding factors as
susceptibility to immunosuppression, or T cellandapos;s inability to persist and undergo activation induced cell death
due to chronic antigen stimulation in a tumor microenvironment still persist. In this application, we propose to
program tumor infiltrating T cells, using our recently published methodology in Cell Metabolism, with robust
anti-tumor and glutaminolysis dependent phenotype that could help the TILs to compete for nutrients in highly
glycolytic tumor microenvironment and achieve robust tumor control upon adoptive transfer.

* Information listed above is at the time of submission. *

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