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Principal Investigator: Zachary Scott Morris
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2021
Award: $765,000
Funding agency: National Cancer Institute
ABSTRACT
We are developing a combined modality therapeutic approach to eradicating metastatic cancers that are
immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). Using an “in situ vaccine”
regimen consisting of 12 Gy focal external beam radiation therapy (EBRT) and intratumoral (IT) injection of
tumor-specific antibody (mAb) + IL2, we have eradicated solitary, large, cold syngeneic tumors in mice. This in
situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation resulting in
increased T-cell infiltration and potent T-cell memory. However, the presence of an identical but untreated
second tumor (2°) on a mouse’s opposite flank inhibits the effect of this treatment, preventing eradication of the
primary (1°) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2° tumor causes tumor-
specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1° tumor. We refer to this as concomitant
immune tolerance (CIT). We can overcome CIT, and eliminate both tumors by giving IT mAb-IL2 to the 1°
tumor and EBRT to both the 1° and 2° tumors. Delivering as little as 2 Gy EBRT to the 2° tumor can overcome
CIT. Clinically, delivery of EBRT (even low dose) to all sites of metastatic disease is problematic, but this can
effectively be achieved using molecular targeted radiation therapy (MTRT). MTRT is increasingly entering
clinical oncology practice and our UW team has led preclinical and clinical testing of a novel class of MTRT
using alkylphosphocholine (APCh) analogs that selectively deliver radiation to cancers in vivo. These show
tumor-selective uptake in virtually all mammalian tumor cells and tumor locations tested (including > 90 tumor
lines and in patients across various clinical trials). In a syngeneic murine melanoma model, we have observed
a potent synergy between systemically administered ICI and MTRT delivered using our next-generation APC
analog, 90Y-NM600. In a project that builds upon the ongoing collaborative progress of our multidisciplinary
team, we will now systematically optimize the potency of combining MTRT with immunotherapy to enhance
the immune response against immunologically cold tumors. In murine models, we will: 1) expand on
preliminary data showing potent synergy with the combination of MTRT and ICI, 2) evaluate the capacity of
MTRT to overcome CIT and enhance systemic anti-tumor immune response in the setting of multiple tumors
where one is treated with in situ vaccine (EBRT + IT mAb-IL2) alone or in combination with ICI. Because
murine models do not replicate the size and spatial distribution of human metastatic cancer and because these
factors strongly influence the dosimetry of MTRT, we will test the immunomodulatory effects of MTRT + in situ
vaccine in large breed companion canines (pet dogs) with naturally occurring metastatic melanoma. The
insights and treatment regimens developed in these studies should enable rapid translation to clinical
testing in patients and potentially for any type of metastatic cancer.
Terms: <90Y><Address><Aldesleukin Gene><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Animals><Antibodies><Antigen Presentation><Bears><Biology><Cancer Model><CancerModel><Cancers><Canine Species><Canis familiaris><Cell Body><Cells><Checkpoint inhibitor><Clinical><Clinical Data><Clinical Evaluation><Clinical Oncology><Clinical Research><Clinical Study><Clinical Testing><Clinical Treatment><Clinical Treatment Moab><Clinical Trials><Combination immunotherapy><Combined Modality Therapy><Companions><Data><Definitive Radiation Therapy><Disease><Disorder><Disseminated Malignant Neoplasm><Distant><Dogs><Dogs Mammals><Dose><EBRT><Epitope spreading><External Beam RT><External Beam Radiation Therapy><External Radiation><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><HNSCC><Half-Life><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Human><IL-2 Gene><IL2><IL2 gene><Image><Immune><Immune Evasion><Immune Tolerance><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immune response><Immunes><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunologic Tolerance><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Injections><Interleukin 2 Precursor Gene><Interleukin-2 Gene><Intravenous><Isotopes><Length><Location><Low Dose Radiation><Malignant Melanoma><Malignant Neoplasms><Malignant Soft Tissue Neoplasm><Malignant Tumor><Mediating><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular Target><Monoclonal Antibodies><Multi-Institutional Clinical Trial><Multi-center clinical trial><Multi-site clinical trial><Multicenter clinical trial><Multimodal Therapy><Multimodal Treatment><Multisite clinical trial><Murine><Mus><Mutation><Neoplasm Metastasis><Pathway interactions><Patients><Preclinical Testing><Radiation><Radiation therapy><Radioactive Isotopes><Radioisotopes><Radionuclides><Radiotherapeutics><Radiotherapy><Regimen><Regulatory T-Lymphocyte><SCCHN><Safety><Secondary Neoplasm><Secondary Tumor><Sight><Site><Soft tissue sarcoma><Spatial Distribution><Stimulator of Interferon Genes><T cell infiltration><T cell response><T cell tumor trafficking><T memory cell><T-Cell Growth Factor Gene><T-Cells><T-Lymphocyte><TCGF Gene><Targeted Radiotherapy><Testing><Therapeutic><Therapy trial><Translations><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><Tumor-infiltrating immune cells><Ursidae><Ursidae Family><Veins><Vision><Work><Y-90><Yttrium 90><analog><anti-tumor immune response><anti-tumor immunity><antigen spreading><antitumor immune response><antitumor immunity><bear><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer immunity><cancer location><cancer metastasis><cancer microenvironment><cancer site><canine><check point inhibition><checkpoint inhibition><clinical test><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><domestic dog><dosimetry><dual immunotherapy><efficacy testing><external-beam radiation><genome mutation><head and neck squamous cell cancer><host response><imaging><immune cell infiltrate><immune check point inhibition><immune check point inhibitor><immune checkpoint inhibition><immune competent><immune drugs><immune infiltration><immune modulation><immune regulation><immune suppression><immune system response><immune system tolerance><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune unresponsiveness><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunologic preparation><immunologic reactivity control><immunologic therapeutics><immunological paralysis><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><improved><in situ vaccination><in situ vaccine><in vivo><insight><intratumoral immune cell><mAbs><mRNA Expression><malignancy><malignant soft tissue tumor><melanoma><memory T lymphocyte><mouse model><multi-modal therapy><multi-modal treatment><multidisciplinary><murine model><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><neoplastic cell><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><pathway><pre-clinical><pre-clinical testing><preclinical><prevent><preventing><protein expression><radiation delivery><radiation effect><radiation treatment><radio-therapy><regulatory T-cells><research clinical testing><response><sarcoma><synergism><systemic toxicity><thymus derived lymphocyte><treatment effect><treatment with radiation><trial regimen><trial treatment><tumor><tumor cell metastasis><tumor eradication><tumor immune cell><tumor microenvironment><tumor-specific antigen><uptake><virtual><visual function>