OVERALL – SUMMARY The US Food and Drug Administration recently approved several immunotherapies for the treatment of metastatic melanoma and lung cancer, based on their robust anti-cancer activities. Intense effort to apply immunotherapies for many other cancers, including breast and pancreatic cancers, have not yet met with similar success. Much of the effort has been focused on the study of the biological aspects of different immunotherapeutics, rather than the physical spatio-temporal peculiarities and aberrations of tumors (e.g., poor lymphocyte infiltration), which we believe are key parameters for improving the efficacy of immunotherapies. Recent evidence emphasizes the importance of processes within the tumor microenvironment over systemic pharmacokinetics for therapeutic efficacy. Thus, the impact of transport phenomena on immunotherapeutic efficacy (and therapeutic resistance) should be considered when developing strategies for new immunotherapies. Within this conceptual framework, the proposed Center for Immunotherapeutic Transport Oncophysics (CITO) focuses on: 1) understanding transport limitations of immune cells and immunotherapeutics; 2) establishing a precision immunotherapeutics framework on the basis of transport oncophysics; and 3) exploiting oncophysical transport-based cues for the development of successful personalized immunotherapeutics strategies based on transport phenotypes. Our overarching strategy comprise many innovations, including transport as a resistance for immunotherapies, nanotherapeutic vaccines, biomimetic constructs, precision immunotherapeutics, biodistribution theory, and oncophysics models for transport, biodistribution and tumor growth. The research projects focus on breast and pancreatic cancers, as those are cancer types with significant clinical challenges. In particular, we will determine the transport of Nano-DC vaccines and immune cells, and how they can be modulated to affect immunogenicity and therapeutic efficacy, with primary focus on breast cancer (Project 1). We will also determine the biophysical transport barrier(s) within the pancreatic cancer tumor microenvironment that can be modulated to affect the efficacy of immunotherapies (Project 2). Both projects focus on immune cell transport across many transport-limiting barriers (e.g., lymphatics, stroma, and vascular leakiness). They also share a set of animal models, therapeutic, and adjuvant agents, and they are also supported by the Transport Oncophysics Core (TOC). The CITO's overall objectives for the proposed funding period are: 1) to determine transport properties of immunotherapeutic agents in breast and pancreatic tumors; 2) to establish a predictive computational transport oncophysics framework for cancer immunotherapeutics; 3) to determine the extent of therapeutic resistance caused by therapeutic transport limitations and their evolution during cancer progression; and 4) to optimize and personalize systemic immunotherapeutic strategies based on the results of the first three objectives.

OVERALL – NARRATIVE Leaders and investigators from three research and medical institutions, Houston Methodist Research Institute, The University of Texas MD Anderson Cancer Center, and The University of Texas Southwestern Medical Center, have joined expertise and resources to design and propose the Center for Immunotherapeutic Transport Oncophysics (CITO), an integrated research program in physical sciences oncology that will implement highly synergistic strategies to: 1) understand transport limitations of immune cells and immunotherapeutics; 2) establish a precision immunotherapeutics framework on the basis of transport oncophysics; and 3) exploit oncophysical transport-based cues for the development of successful personalized immunotherapeutics strategies based on transport phenotypes. The two research projects of the CITO, supported by the Transport Oncophysics Core, Administrative Core, and the Education and Outreach Unit, will determine the transport phenomena that affect immunotherapies in breast and pancreatic cancers, as those are cancer types with significant clinical challenges. In particular, we will determine the transport of Nano-DC vaccines and immune cells, and how they can be modulated to affect immunogenicity and therapeutic efficacy, with primary focus on breast cancer (Project 1). We will also determine the biophysical transport barrier(s) within the pancreatic cancer tumor microenvironment that can be modulated to affect the efficacy of immunotherapies (Project 2).