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Principal Investigator: Hokyung Kay Chung
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $159,840
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PROJECT SUMMARY/ABSTRACT
Recently, remarkable progress has been made in cancer treatment employing adoptive cell transfer (ACT) of
tumor-specific “killer”, CD8+ T cells. Various engineered T cells including chimeric antigen receptor T (CAR-T)
cells, have shown great potential as new forms of cancer therapies. However, a hostile tumor microenvironment
(TME) impedes T cell infiltration and survival and induces T cell dysfunction (i.e., ‘exhaustion’), making the
beneficial effects of the therapy transient. Exhausted T cells (TEX) arise when T cells are stimulated by antigen
for prolonged periods, which drives a defined differentiation process involving major transcriptional and
epigenetic changes in T cells. Thus, there have been attempts to promote intratumoral T cell
trafficking/proliferation but challenges with poor long-term survival and efficacy of adoptively transferred T cells
in solid tumors still remain. Therefore, the goal of this proposal is to engineer T cells that better infiltrate and
survive inside tumors to provide robust, durable anti-tumor T cell immunity.
By combining (1) the expertise of the Dr. Kaech lab in effector and memory T cell development, (2) that
of the Dr. Wang lab in integrative analysis of epigenomic/genomic data, and (3) that of Dr. Chung in protein
engineering, this research will provide novel solution to the current limitation in ACT. Preliminary research
generated epigenetic and transcriptional atlas of CD8+T cells and analyzed the transcription factor networks of
the most tumoricidal, tumor-infiltrating “effector” T cell state, the long-lasting “resident-memory” T cell state and
dysfunctional “exhausted” T cell state. Based on the understanding of T cell differentiation states, this proposal
aims to design key transcription factor programs that drive desired T cell states and devise new methodologies
to redirect T cell exhaustion state to toggle desirable effector and memory states and to temporally and
combinatorically control the cell-state specific TFs of the adoptively transferred T cells in situ.
This new class of T cell engineering platform is termed SMARTER (Specific Modifiers Assisted
Reprogramming of T cell Engineered with Regulability). To generate SMARTER T cells, in Aim 1, a new platform
will be devised to systemically identify novel cell-state-specific transcription factors. In Aim 2, synthetic machinery
will be developed to rewire exhaustion signals to specific differentiation program. Lastly, in Aim 3, a clinically
useable synthetic biology methods will be developed to enable temporal and combinatorial control of the cell-
state-specific modifiers. This SMARTER platform will effectively transform T cells into “intelligent and tenacious
soldiers”. These enhanced T cells will not only effectively infiltrate and kill cancer cells, but also retain the
immunological memory of their “foes” and reside long-term at the tumor site, leading to complete remission.
Terms: <Adopted><Adoptive Cell Transfers><Antigens><Antitumor Response><Atlases><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding><Bio-Informatics><Bioinformatics><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Reprogramming><Cell Signaling><Cell membrane><Cells><Clinical><Code><Coding System><Combinatorics><Cytoplasmic Membrane><Disease remission><Doctor of Philosophy><Drugs><Dysfunction><Effectiveness><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Eragrostis><Evaluation><Fostering><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Transcription><Goals><Human><Immune mediated therapy><Immune memory><Immunity><Immunologic Memory><Immunological Memory><Immunologically Directed Therapy><Immunology><Immunotherapy><In Situ><Individual><Infiltration><Intracellular Communication and Signaling><Knowledge><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Medication><Memory><Methodology><Methods><Modern Man><Modification><Molecular Interaction><PD 1><PD-1><PD1><Pathway interactions><Ph.D.><PhD><Pharmaceutical Preparations><Physiopathology><Plasma Membrane><Process><Proliferating><Protein Engineering><RNA Expression><Receptor Protein><Receptor Signaling><Recombinant DNA Technology><Rejuvenation><Remission><Research><Resistance><Route><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Site><Soldier><Solid Neoplasm><Solid Tumor><Specificity><T cell based therapeutics><T cell based therapy><T cell differentiation><T cell directed therapies><T cell infiltration><T cell targeted therapeutics><T cell therapy><T cells for CAR><T memory cell><T-Cell Development><T-Cell Ontogeny><T-Cell Transformation><T-Cells><T-Lymphocyte><T-Lymphocyte Development><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Teff><Teff cell><Testing><Therapeutic><Tissues><Training><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Tumor Antigens><Tumor Immunity><Tumor-Associated Antigen><Tumor-infiltrating immune cells><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell therapy><adoptive cellular therapy><anamnestic reaction><anti-cancer therapy><anti-tumor immunity><anti-tumor response><antitumor immunity><biological signal transduction><cancer antigens><cancer cell><cancer immunity><cancer microenvironment><cancer therapy><cancer-directed therapy><cellular reprogramming><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><clinical relevance><clinically relevant><combinatorial><cytotoxic><design><designing><driving><drug/agent><effector T cell><engineered T cells><epigenetically><epigenomics><exhaust><exhaustion><genetic protein engineering><genetically engineered><genetically engineered T-cells><genomic data><genomic data-set><genomic dataset><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point blockade><immune checkpoint blockade><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><improved><in vivo><in vivo Model><infiltration of tumors by immune cells><innovate><innovation><innovative><intratumoral immune cell><intratumoral immune infiltrate><malignancy><memory T lymphocyte><neoplasm/cancer><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><pathophysiology><pathway><plasmalemma><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><protein design><receptor><resident memory T cell><resistant><secondary immune response><shRNA><short hairpin RNA><single cell next generation sequencing><single cell sequencing><sle2><small hairpin RNA><synthetic biology><systemic lupus erythematosus susceptibility 2><therapeutic T-cell platform><thymus derived lymphocyte><tissue resident memory T cell><trafficking><transcription factor><transcriptional reprogramming><transgenic T- cells><translational applications><translational opportunities><translational potential><tumor><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumor-specific antigen>