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Principal Investigator: Ingunn Margarete Stromnes
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $336,835
Funding agency: National Cancer Institute
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a 5-year overall survival of <10%.
Lethality is due to late diagnosis, early metastasis and therapeutic resistance. A hallmark characteristic of PDA
is the robust fibroinflammatory and suppressive tumor microenvironment that compresses blood vessels and
restricts drug access. This tumor microenvironment is also believed to interfere with immunotherapies, which are
transforming the standard of care for many other cancer indications. Tumor-antigen specific T cells are
responsible for mediating the therapeutic effects of immunotherapy. While much has been learned about
suppressive cells within the pancreatic tumor microenvironment, factors that impact the differentiation program
of antigen-specific T cells and their antitumor activity is markedly understudied in this disease. We created a
novel engineered T cell therapy that shows marked anti-tumor and anti-stromal activity in an aggressive and
difficult to treat genetically engineered PDA animal model that recapitulates many aspects of the human disease,
including response to immunotherapy. T cells engineered to express a tumor-reactive T cell receptor specific to
mesothelin, which is highly expressed by tumor cells yet poorly expressed by normal cells, is safe, destroys the
stroma, alters myeloid cell composition, induces objective responses, and significantly prolongs animal survival.
Notably, engineered T cells preferentially accumulate in primary tumors and metastasis, challenging the dogma
that PDA is immune privileged. Based on this efficacy, candidate T cell receptors specific to mesothelin for use
in patients have been identified leading to a Phase 1 clinical trial. However, despite engineered T cell persistence
and significant antitumor activity in vivo, a principle obstacle to cure is the progressive loss of engineered T cell
function within the suppressive pancreatic tumor microenvironment. While T cell functionality and differentiation
are well-studied in other cancer indications, little is understood regarding how the pancreatic tumor
microenvironment impacts tumor antigen-specific T cells. Here, we incorporate innovative tools we have
developed to identify mechanistically how engineered T cells mediate stromal remodeling, how the tumor adapts
and evades anti-tumor T cells, and then use this knowledge to develop a cutting edge engineered T cell therapy
for patient treatment with strategic advancements as compared to most cell engineering approaches. Our
Specific Aims are to: (1) Identify how engineered T cells mediate stromal remodeling, (2) Identify the contribution
of TCR affinity and the tumor microenvironment on T cell differentiation and functionality, and (3) Test the safety
and efficacy of a novel cell engineering approach for targeting solid tumors. Our studies will identify
characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during
immunotherapy to create safe and durable clinical opportunities for pancreatic cancer patient treatment.
Terms: <Adoptive Cell Transfers><Advanced Cancer><Advanced Malignant Neoplasm><Affinity><Animal Model><Animal Models and Related Studies><Animals><Antigen Presentation><Antigens><Antitumor Response><Assay><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Blood Vessels><Bypass><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Cause><Cancer Etiology><Cancer Model><Cancer Patient><CancerModel><Cancers><Carcinoma><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Death><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Therapy><Cell-Extracellular Matrix><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chronic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cytolytic T-Cell><Cytometry><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Defect><Diagnosis><Disease><Disorder><Drugs><ECM><Early-Stage Clinical Trials><Endothelial Cells><Epithelial cancer><Extracellular Matrix><Fibroblasts><Gene Modified><General Transcription Factor Gene><General Transcription Factors><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Human><Immune><Immune Evasion><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><In Vitro><Intracellular Communication and Signaling><KI mice><Knock-in Mouse><Knowledge><Learning><Legal patent><MHC Receptor><Macrophage><Major Histocompatibility Complex Receptor><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Mediating><Medication><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><Neoplasm Metastasis><Normal Cell><PD 1><PD-1><PD1><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Patents><Patients><Pharmaceutical Preparations><Phase 1 Clinical Trials><Phase I Clinical Trials><Preclinical Testing><Predisposition><Primary Neoplasm><Primary Tumor><Production><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Signaling><Recombinant DNA Technology><Regulatory T-Lymphocyte><Reporter><Resistance><Role><Safety><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Soluble Mpf/Mesothelin-Related Protein><Specificity><Subcellular Process><Susceptibility><T cell based therapeutics><T cell based therapy><T cell differentiation><T cell directed therapies><T cell infiltration><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Testing><Therapeutic><Therapeutic Effect><Toxic effect><Toxicities><Toxicity Testing><Toxicity Tests><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Treatment Efficacy><Treg><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><Xenograft Model><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell therapy><adoptive cellular therapy><anti-tumor effect><anti-tumor immunity><anti-tumor response><antigen-specific T cells><antitumor effect><antitumor immunity><base editor><biological signal transduction><cancer antigens><cancer immunity><cancer metastasis><cancer microenvironment><cell engineering><cell mediated therapies><cell type><cell-based therapeutic><cell-based therapy><cellular engineering><cellular therapeutic><cellular therapy><check point blockade><checkpoint blockade><chimeric antigen receptor><comparable efficacy><comparative efficacy><compare efficacy><cytokine><drug/agent><effective therapy><effective treatment><engineered T cells><epithelial carcinoma><exhaustion><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene modification><gene-editing toolkit><genetically engineered><genetically engineered T-cells><genetically modified><human disease><immune check point blockade><immune checkpoint blockade><immune evasive><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vivo><innovate><innovation><innovative><intervention design><intervention efficacy><killer T cell><knockin mice><lung cancer><malignancy><mesothelin><model of animal><mortality><mouse model><murine model><mutant><necrocytosis><neoplasm/cancer><neoplastic cell><novel><overexpress><overexpression><pancreatic cancer patients><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><patients with pancreatic cancer><phase I protocol><pre-clinical><pre-clinical testing><preclinical><progenitor><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><public health relevance><regulatory T-cells><resistance to therapy><resistant><resistant to therapy><response><safety testing><scRNA-seq><screening><screenings><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><standard of care><stem><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic T-cell platform><therapeutic efficacy><therapeutic resistance><therapy design><therapy efficacy><therapy resistant><thymus derived lymphocyte><tool><transcription factor><transgenic T- cells><treatment design><treatment resistance><tumor><tumor cell metastasis><tumor microenvironment><tumor xenograft><tumor-specific antigen><vascular><vector><xenograft transplant model><xenotransplant model>