Research
Engineering Proteins for Next-Generation Immunotherapies
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Despite incredible strides made through the advent of immunotherapies, cancer remains a leading cause of death worldwide due to challenging tumor resistance mechanisms arising after treatment. Thus, there is a great need to develop more potent immunotherapies that are poised to overcome these barriers to efficacy, particularly in solid tumors. Developing a deeper understanding of the complex immune interactions within the tumor microenvironment (TME) will allow for exploitation of these pathways for more potent therapies.
In the Yamada-Hunter Lab, we employ protein engineering and synthetic biology to develop next-generation therapeutics tackling diseases ranging from cancer to autoimmunity and beyond. Our research sits at the intersection of immunology, bioengineering, and cancer biology, performing translational research to create a suite of engineered immunotherapies, with a focus on combination therapy and ultimately clinical development. Our previous work centered on the combination of macrophage activating anti-CD47 antibody (anti-CD47) and adoptive T cell therapy (e.g. CAR T), revealing unexpected insights into antagonistic relationships between macrophages and T cells. As a solution, we engineered CD47 variants to be expressed on adoptive T cells paired with anti-CD47, resulting in a new class of combination immunotherapy with surprising synergy and efficacy against solid tumors (Yamada-Hunter, S.A., et. al., Nature, 2024).
Our lab will advance these discoveries forward through the following research programs:
In Program 1, we will develop a mechanistic understanding of adoptive T cell and macrophage-activating combination therapies in the treatment of solid tumors.
In Program 2, we will use protein engineering to design custom proteins tailored for next-generation T cell combination therapies.
In Program 3, we will establish platforms for integrating protein engineering strategies directly into cellular therapy products, leveraging both directed evolution and machine learning to vastly broaden the scope of “engineerable” protein targets.
In concert, our lab tackles major challenges facing cancer immunotherapy by mechanistically dissecting the antitumor properties of distinct immune populations within the TME, while advancing the limits of cell engineering platforms to engineer tailored and highly effective combination immunotherapies.
We welcome students and postdocs from all backgrounds who are motivated to engineer the next wave of immunotherapies. Initial projects in the lab that are available for students to work on include: screens to understand T cell phagocytosis, interrogation of T cell – macrophage combination therapeutic efficacy and resistance, epitope engineering to design orthogonal protein pairs, development of safer and more effective anti-CD47 therapies, engineering of macrophage activating immunotherapies, in situ CAR engineering, and enhancement of T cell payload delivery for TME modulation, among others.