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Principal Investigator: TIMOTHY M FAN
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $484,753
Funding agency: National Cancer Institute
Project Summary
This is a new MPI R01 proposal bringing together protein engineering for immunotherapy
(Wittrup, MIT) with comparative oncology/veterinary medicine (Fan, UIUC) to test clinical
strategies for combining radiotherapy with intratumoral cytokine administration/retention in pet
dogs with melanoma, at the UIUC veterinary clinic. We have developed a strategy for retaining
injected cytokines (IL-2 and IL-12 in particular) in situ by expressing them as fusions to natural
collagen-binding domains. This approach has been found to be safely curative in challenging
murine transplant and GEM tumor models, and will now be advanced into a more faithful model
for human cancer: spontaneous canine melanoma. These tumors arise spontaneously in
outbred populations, and undergo a natural progression of immunoediting prior to clinical
presentation. Canine melanoma exhibits pathophysiology similar to human melanoma, including
the presence of immune infiltrated, excluded, and desert subtypes. In Aim 1, we will exploit the
more-realistic anatomy of these tumors to optimize the micropharmacokinetics of intratumoral
administration, establishing foundational principles with respect to injectable volume fractions,
needle types, and numbers of sites. In Aim 2, we will test the therapeutic hypothesis that
precisely temporally programmed intense localized cytokine stimulation can be optimally
combined with radiation therapy so as to prime a strong T cell vaccinal response with
consequent systemic impact on efficacy. In Aim 3, we will perform a clinical trial in canine
melanoma to rigorously compare alternative dose scheduling for intratumoral cytokine therapy
following irradiation. We hypothesize that the time delay prior to cytokine injection will have a
critical, all-or-nothing effect on outcomes. This intradisciplinary collaboration has commenced,
and exciting preliminary treatment data is presented herein.
The overarching objective of this project is to develop improved human cancer immunotherapy
protocols that combine intratumoral immunotherapy with local radiation. Multiple previous
clinical trials in this area have yet to realize the full promise of this approach, but by performing
rapid design-build-test-learn cycles in spontaneous canine melanoma, we hope to converge
more efficiently to efficacious strategies.
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II><Interleukin-1><Interleukin-12><Interleukin-2><Interleukin-6><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Investigators><Leakage><Learning><Liquid substance><Lymphocyte Mitogenic Factor><Lymphocyte-Stimulating Hormone><MGI-2><Macrophage Cell Factor><Macrophage-Derived TNF><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mechanics><Mediating><Melanoma><Metastasis to the Lung><Metastatic Neoplasm to the Lung><Metastatic Tumor to the Lung><Mice><Mice Mammals><Mitogenic Factor><Modeling><Modern Man><Molecular Interaction><Monitor><Monocyte-Derived TNF><Murine><Mus><Myeloid Differentiation-Inducing Protein><Myeloid-derived suppressor cells><NKSF><Natural Killer Cell Stimulatory Factor><Needles><Neoplasm Transplantation><Oncology><Oncology Cancer><Oral Melanoma><Outcome><PK/PD><Patients><Pharmacodynamics><Physiopathology><Placebos><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Population><Pre-Clinical Model><Preclinical Models><Probability><Process><Progression-Free Survivals><Property><Protein Engineering><Protocol><Protocols documentation><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Recombinant DNA Technology><Regulatory T-Lymphocyte><Reporter><Research Personnel><Researchers><Resected><Reticuloendothelial System, Serum, Plasma><Safety><Sampling><Schedule><Sham Treatment><Site><Solid Neoplasm><Solid Tumor><Spillage><T Helper Factor><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Techniques><Testing><Therapeutic><Therapeutic Effect><Therapeutic Index><Thymocyte Stimulating Factor><Time><Transplantation><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Cell><Tumor Leakage><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor Spillage><Tumor Volume><Tumor-infiltrating immune cells><Veterinary Clinics><Veterinary Hospitals><Veterinary 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tumor><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-mediated adverse events><immune-related adverse effect><immune-related adverse events><immune-related adverse reaction><immuno therapy><immunogen><immunologic therapeutics><immunophenotype><immunosuppressive myeloid cells><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><infiltration of tumors by immune cells><interferon beta 2><intratumoral immune cell><intratumoral immune infiltrate><irradiation><lFN-Gamma><lipophilicity><liquid><lung metastasis><lymphocyte activating factor><malignancy><mechanic><mechanical><metastasize to the lung><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><nano-string><nanostring><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><pathophysiology><pharmacokinetics and pharmacodynamics><pre-clinical evaluation><preclinical evaluation><primary end point><primary endpoint><programs><protein design><pulmonary metastasis><radiation treatment><rational design><recruit><regional lymph node><regulatory T-cells><retention rate><retention strategy><safety assessment><secondary end point><secondary endpoint><sham therapy><sound><standard of care><suppressive myeloid cells><systemic toxicity><therapeutic evaluation><therapeutic testing><thymus derived lymphocyte><translation to humans><translational study><transplant><treatment with radiation><tumor><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor progression><tumor transplant><tumor transplantation><vaccine response><vaccine responsiveness><vaccine-induced response>