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Principal Investigator: Aryana Razmara
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $41,568
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Although immunotherapy, especially immune checkpoint inhibition (ICI) with PD-1/PD-L1 inhibitors, has rapidly
become the fourth pillar in cancer therapy with increasing breakthrough advances, barriers still exist to its
success. Given their ability to rapidly exert their cytotoxic effects on heterogeneous tumor cells with minimal
adverse events, natural killer (NK) cells have emerged as promising tools to expand the benefits of cancer
immunotherapy, including for patients who never start or stop responding to ICI. However, lack of consistent
responses in human NK cell trials, especially for solid tumors, calls for innovative methods to successfully
translate novel NK immunotherapy approaches to the clinic. Dogs with cancer are an excellent way to assess
novel immunotherapies because they recapitulate fundamental clinical and genetic features of human cancers,
including the development of spontaneous tumors in the setting of an intact immune system. To speed translation
of NK immunotherapy approaches, the proposed project will test an innovative treatment of allogeneic NK
adoptive transfer in combination with a novel caninized anti-PD-L1 antibody developed by our comparative
oncology group. Using a co-clinical Phase II trial format, dogs with locally advanced melanoma will be treated
with radiation therapy (RT), adoptive transfer of expanded/activated allogeneic NK cells from healthy beagle
donors, and immune checkpoint blockade using our dog anti-PD-L1 antibody. As the first trial to use NK cell
transfer in combination with ICI on spontaneous tumors in a clinical setting, the results of this study will provide
potentially transformative insights into mechanisms of both therapies and will evaluate barriers for future first-in-
human trials on solid tumors. Since NK cell activity is known to be mediated by the PD-1/PD-L1 axis with PD-L1
being a critical inhibitory NK marker, the proposed study will offer critical insight into potential mechanisms of
overcoming NK dysfunction responsible for unimpressive responses with NK cell immunotherapies alone.
Furthermore, RT is part of the standard of care for unresectable malignancies and has been shown to have
important immunomodulatory effects, including sensitization of tumor cells to NK cytotoxicity. The Canter Lab is
a leader in canine clinical trials as well as their use as tools to perform multidimensional analyses of NK cells.
Similarly, the potentially high impact of this novel immuno-oncology (IO) therapy will be studied through extensive
correlative studies including flow cytometry to follow the regional differences of donor and endogenous NK cells,
killing assays to assess changes in cytotoxicity, and RNA sequencing to characterize differential gene expression
of relevant immune populations. Although we hypothesize meaningful clinical and immunologic effects from this
novel therapy, we will nevertheless gain key insights into the dog as a comparative model for future dog and
human IO studies. Thus, beyond the potential for significant scientific and clinical impact, the completion of this
study will provide me with cutting edge training in comparative cancer immunotherapy to prepare me for a
successful career as a veterinary scientist in cancer immunology and NK immunotherapy.
Terms: <Address><Adoptive Transfer><Adverse Experience><Adverse event><Allogenic><Antigen-Antibody Complex><Assay><Autologous><B7-H1><B7H1><Bioassay><Biological Assay><Biopsy><Blood><Blood Reticuloendothelial System><Body Tissues><Bone Sarcoma><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD274><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Model><Cancer Patient><Cancer Treatment><CancerModel><Cancers><Canine Species><Canis familiaris><Cell Body><Cells><Cellular immunotherapy><Clinic><Clinical><Clinical Trials><Combination immunotherapy><Combined Modality Therapy><Correlative Study><Cytotoxic cell><Data><Development><Differential Gene Expression><Disease><Disorder><Dogs><Dogs Mammals><Dose><Dysfunction><Effector Cell><Evaluation><Expression Signature><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Future><Gene Expression Profile><Genetic><Genomics><Germinoblastic Sarcoma><Germinoblastoma><Goals><Granzyme><History><Homing><Human><Immune><Immune Complex><Immune mediated therapy><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunooncology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><K lymphocyte><Knowledge><Ligands><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocytic><Lymphoma><Lytotoxicity><Malignant Lymphoma><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modeling><Modern Man><Modification><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NK Cell Activation><NK Cells><NK cell immunotherapy><NK cell therapy><NK cell-based immunotherapy><NK cytotoxicity><Natural Killer Cell Activation><Natural Killer Cell Immunotherapy><Natural Killer Cell toxicity><Natural Killer Cells><Natural Killer cytotoxicity><Neoplasm Metastasis><Oncologist><Oncology Group><Organ><Osseous Sarcoma><Osteogenic Sarcoma><Osteosarcoma><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD-L1 antibody><PD-L1 blockade><PD-L1 inhibitors><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL-1><PDL1><PDL1 antibody><PDL1 blockade><PDL1 inhibitors><Pathway interactions><Patients><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Physiopathology><Population><Pre-Clinical Model><Preclinical Models><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Progression-Free Survivals><RNA Seq><RNA sequencing><RNAseq><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Recording of previous events><Research><Residencies><Reticulolymphosarcoma><Safety><Sampling><Scientist><Secondary Neoplasm><Secondary Tumor><Single cell seq><Skeletal Sarcoma><Solid Neoplasm><Solid Tumor><Speed><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Toxic effect><Toxicities><Training><Translating><Translations><Tumor Cell><Unresectable><Up-Regulation><Upregulation><Variant><Variation><aPD-L1 antibodies><adoptive T cell transfer><adoptive T-cell therapy><anti-PD-L1 antibodies><anti-PD-L1 blockade><anti-PD-L1 monoclonal antibodies><anti-PDL1 antibodies><anti-cancer immunotherapy><anti-cancer therapy><anticancer immunotherapy><cancer immunology><cancer immunotherapy><cancer metastasis><cancer microenvironment><cancer therapy><cancer-directed therapy><canine><canine animal model><canine model><career><cell-based immunotherapy><check point blockade><check point inhibition><checkpoint blockade><checkpoint inhibition><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 effect><clinical relevance><clinically relevant><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><companion animal><companion cat><companion dog><companion pet><comparative><cytokine><cytotoxic><cytotoxicity><developmental><dimensional analysis><dog model><domestic dog><dual immunotherapy><exhaustion><experience><first in man><first-in-human><flow cytophotometry><gene expression pattern><gene expression signature><gene signatures><genetic signature><global gene expression><global transcription profile><histories><immune cell therapy><immune check point blockade><immune check point inhibition><immune checkpoint blockade><immune checkpoint inhibition><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immune-oncology><immuno oncology><immuno therapy><immunologic reactivity control><immunology oncology><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><innovate><innovation><innovative><insight><lymph cell><lymph gland><lymph nodes><lymphnodes><malignancy><mouse model><multi-modal therapy><multi-modal treatment><murine model><natural killer cell based immunotherapy><natural killer cell therapy><neoplasm immunology><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncoimmunology><osteochondrosarcoma><osteoid sarcoma><palliative><pathophysiology><pathway><phase 2 trial><phase II protocol><phase II trial><pilot trial><predict responsiveness><predicting response><primary end point><primary endpoint><programmed cell death ligand 1><programmed cell death ligand 1 inhibitors><programmed cell death protein ligand 1><programmed cell death protein ligand 1 inhibitors><protein death-ligand 1><radiation treatment><regional difference><response><response to therapy><response to treatment><safety assessment><single cell next generation sequencing><single cell sequencing><skills><species difference><standard of care><success><therapeutic T-cell platform><therapeutic response><therapy response><thymus derived lymphocyte><tool><trafficking><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><translation><translational study><treatment response><treatment responsiveness><treatment with radiation><tumor><tumor cell metastasis><tumor immunology><tumor microenvironment><αPD-L1 antibodies>