Engineering Proteins to Overcome Cell Therapy Barriers

Advancing T cell immunotherapy with fusion proteins that improve antitumor function in suppressive tumor microenvironments

Technology Overview

Dr. Shannon Oda

Adoptive immunotherapy, including chimeric antigen receptor (CAR) T cell therapy, is a promising cancer treatment. However, elements of the tumor microenvironment such as signals from suppressing cells, cytokines, and chemokines dampen the efficacy of T cell immunotherapy. Mechanisms such as these limit the costimulation that T cells require for activation, leading to their inhibition and cell death.

Dr. Shannon Oda’s research focuses on improving cancer immunotherapy by identifying obstacles that prevent immune cells from effectively eradicating tumors. Dr. Oda developed new engineered transmembrane proteins for T cells called immunomodulatory fusion proteins (IFPs). In place of domains that send inhibitory signals, IFPs have domains with costimulatory functions. In a groundbreaking example, her team generated IFPs that swap the intracellular death-promoting section of the Fas cell-surface receptor with the costimulatory 4-1BB domain. T cells with this IFP show reduced exhaustion and Fas-mediated cell death. They have a heightened response to stimulation and activity against acute myeloid leukemia (AML) cells. IFPs replace the brakes on T cells with accelerators, rewiring signals for inhibition or death to instead promote proliferation, antitumor activity, and persistence.

Dr. Oda led work testing the ability of IFPs to improve immunotherapy against solid tumors. She used a mouse model with an intact immune system that is genetically engineered to recapitulate human pancreatic cancer. She is also optimizing this approach to improve therapeutic outcomes in brain, ovarian, lung, and sarcoma cancers. This technology can be applied to treatment that is tailored to specific cancers or to the development of more universal, off-the-shelf immunotherapies.

The Oda lab is now working on supercharging T cells with novel engineering strategies. This work has the potential to overcome multiple barriers to T cell immunotherapy by boosting T cell metabolism, activation, proliferation, cytokine production, and concentration in tumors, and to promote anti-tumor function of the endogenous immune system.

Dr. Oda has expertise with in vitro assays with human primary cells including tumor cells and in vivo studies with animal models. Her experience includes collaborating on human clinical trials and industry consulting for an immunotherapy company. She is interested in partnerships to develop engineering strategies to advance adoptive immunotherapy.

Stage of Development

• Pre-clinical in vitro
• Pre-clinical in vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement
• Licensing agreement

Publications

1. Oda SK, Anderson KG, Ravikumar P, Bonson P, Garcia NM, Jenkins CM, Zhuang S, Daman AW, Chiu EY, Bates BM, Greenberg PD. A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy. J Exp Med. 2020;217(12):e20191166.
2. Oda SK, Daman AW, Garcia NM, Wagener F, Schmitt TM, Tan X, Chapuis AG, Greenberg PD. A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia. Blood 2017;130(22)2410-2419.
3. Anderson KG, Voillet V, Bates BM, Chiu EY, Burnett MG, Garcia NM, Oda SK, Morse CB, Stromnes IM, Drescher CW, Gottardo R, Greenberg PD. Engineered adoptive T-cell therapy prolongs survival in a preclinical model of advanced-stage ovarian cancer. Cancer Immunol Res. 2019;7(9):1412-1425.
4. Hu J, Oda SK, Shotts K, Donovan EE, Strauch P, Pujanauski LM, Victorino F, Al-Shami A, Fujiwara Y, Tigyi G, Oravecz T, Pelanda R, Torres RM. Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response. J Immunol. 2014;193(1)85-95.
5. Oda SK, Strauch P, Fujiwara Y, Al-Shami A, Oravecz T, Tigyi G, Pelanda R, Torres RM. Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression. Cancer Immunol Res 2013;1(4):245-55.

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