Immunity and Fibrosis Platform — Team Science Grants

Title: Anti-human CD3 monovalent Fab as a novel immunotherapy against metastatic melanoma

Investigative team: Diana Gil Pages, Ph.D., Svetomir N. Markovic, M.D., Ph.D., John A. Copland III, Ph.D.

Central hypothesis: Recent immunotherapies have demonstrated the promise of harnessing the power of the body's own immune system to fight cancer. However, for each patient who enters remission using immunotherapies, there are many patients for whom current advances have not led to a cure. The investigators hypothesize that using a novel antibody, CD3 monovalent (mono) Fab, to stimulate T cells will provide oncologists with another way to boost the immune system to fight cancer.

Potential outcomes and advances: Preliminary data in mouse models has demonstrated the efficacy of CD3 mono Fabs in melanoma. The investigative team is taking this approach closer to phase I clinical trials by using humanized mouse models, in which human cancer cells are put into mice to test this novel potential therapeutic in fighting metastatic melanoma.

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Title: Distinguishing the TGFβ-mediated inflammatory response from fibrotic reactions in chronic disease: Implications for endometriosis

Investigative team: Gaurang S. Daftary, M.D., Khashayarsha Khazaie, Ph.D., Joseph P. Grande, M.D., Ph.D.

Central hypothesis: Endometriosis is a common, systemic disease that affects 10 percent of women of reproductive age. It is characterized by the growth of endometrial tissue onto various intra-abdominal structures, such as the peritoneum, ovaries, intestines and bladder, resulting in inflammation and prolific fibrosis that eventually obliterates all recognizable tissue.

The investigators hypothesize that transforming growth factor beta (TGFβ) activates proinflammatory versus profibrotic responses via distinct transcription factors within the Kruppel-like factors (KLF) family and that fibrosis is mechanistically linked with the resolution of inflammation.

Potential outcomes and advances: This project will identify targets causally linked to the disease phenotype of endometriosis, which can improve the understanding of various inflammatory and fibroproliferative disorders. Additional studies will test the role of epigenetic mechanisms in mediating the response and the potential to target them therapeutically.

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Title: Thymic stromal lymphopoetin in pulmonary artery remodeling and fibrosis

Investigative team: Y. (Y S) S. Prakash, M.D., Ph.D., Frank V. Brozovich, M.D., Ph.D., Jordan D. Miller, Ph.D., Robert Vassallo, M.D.

Central hypothesis: Pulmonary hypertension is a fatal disease unless treated and affects people across the age spectrum. As the arteries thicken and narrow, the resulting low oxygen environment induces the expression of a protein called thymic stromal lymphopoietin (TSLP), which in turn causes more constriction and more fibrosis. The thymic stromal lymphopoetin in pulmonary artery remodeling and fibrosis study is designed to determine the mechanistic relation between hypoxia, TSLP and the genesis of pulmonary hypertension.

Potential outcomes and advances: The investigative team is defining a novel mechanism mediating pulmonary hypertension and determining whether targeting this pathway is effective in a murine model. This research could readily lead to new therapies to limit or slow progression of pulmonary hypotension.

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Title: Cancer cells inhibit the immune response at its source

Investigative team: Wei Ding, MBBS, Ph.D., Kay L. Medina, Ph.D., Neil E. Kay, M.D.

Central hypothesis: A significant cause of death for patients with chronic lymphocytic leukemia (CLL) is not the cancer itself, but infections due to a damaged immune system, accounting for 30 to 50 percent of all CLL deaths. The investigators hypothesize that CLL cells damage the bone marrow and prevent the production of new immune cells to fight disease.

Potential outcomes and advances: The focus of this grant is to understand changes in the bone marrow that occur during progression of CLL, which could be responsible for the poor function of the immune system that leads to infections in these patients. If damage to the bone marrow environment is found, then bone marrow transplants will not be useful for these patients. However, identification of changes to the bone marrow mediated by the cancer cells could lead to new pathways for intervention to boost immune cell production.

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Title: Inhibition of immune responses by malignant melanoma

Investigative team: Svetomir N. Markovic, M.D., Ph.D., Haidong Dong, M.D., Ph.D.

Central hypothesis: When they drain, lymph nodes sample the fluids from various tissues to monitor for abnormalities that would initiate an immune response. The investigators hypothesize that melanoma cells secrete factors that change the lymph node environment and inhibit the immune response, thereby allowing the cancer to grow.

Potential outcomes and advances: This investigation aims to identify the melanoma-derived factors that inhibit the immune response and to design therapeutic interventions to counteract these factors. The goal is enhance the immune response against melanoma.

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