The Center for Immunotherapeutic Transport Oncophysics
List of Collaborating Institutions
Houston Methodist Research Institute, The University of Texas MD Anderson Cancer Center, UT Southwestern Medical Center
The use of FDA-approved immunotherapies to treat metastatic melanoma and lung cancer has reignited the interest and examination of similar approaches for other cancers, including breast cancer and pancreatic cancer, for which immunotherapies have met with limited success. Most of the focus has been on understanding the biological mechanisms of the different immunotherapeutics, while deciphering the physical spatio-temporal peculiarities and aberrations of tumors (e.g., poor lymphocyte infiltration, biophysical determinants of immunosuppression in tumor microenvironment, spatial distribution of cells and nutrients), and their interplay, remain largely unexplored. Thus, we approach the study and design of cancer immunotherapeutic strategies from the perspective of multiscale transport phenomena. Within this conceptual framework, the Center for Immunotherapeutic Transport Oncophysics (CITO) focuses on the following:
- Understanding transport limitations of immune cells and immunotherapeutics;
- Establishing a precision immunotherapeutics framework on the basis of transport oncophysics; and
- Exploiting oncophysical transport-based cues for the development of successful personalized immunotherapeutic strategies based on transport phenotypes.
Our research projects focus on breast cancer and pancreatic cancer, both of which exhibit significant clinical challenges. Specifically, we will determine the transport of Nano-dendritic cell (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 affect immune suppression, and thus, the efficacy of immunotherapies (Project 2). Both projects focus on transport phenomena of cells, drugs, and other agents across several transport-limiting barriers, including the lymphatic system, tumor vasculature, and stroma, and the projects are supported by the Transport Oncophysics Core (TOC). The overall objectives for the CITO are:
- To determine transport properties of immunotherapeutic agents in breast cancer and pancreatic cancer;
- To establish a predictive computational transport oncophysics framework for cancer immunotherapeutics;
- To determine the extent of therapeutic resistance caused by transport limitations, and their evolution during cancer progression; and
- To optimize and personalize systemic immunotherapeutic strategies.
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Mauro Ferrari, Ph.D.
Dr. Ferrari is President and Chief Executive Officer of Houston Methodist Research Institute and Executive Vice President of Houston Methodist Hospital. He is also Senior Associate Dean and Professor of Medicine at Weill Cornell Medical College. He has authored over 400 peer-reviewed publications, been granted over 40 patents, and been recognized with national and international awards in oncology, engineering, drug delivery, and the pharmaceutical sciences. He has a long record of leadership in research centers and programs funded by the NCI, NIGMS, DARPA, the Department of Defense, NASA, and the States of Texas and Ohio. Dr. Ferrari is the originator of transport oncophysics, which views the challenges of cancer treatment from the perspectives of transport of cells, nutrients, and drugs through a series of biological barriers. He is also considered one of the pioneers in nanomedicine and multiscale mechanics, expertise in semiconductor and nanotechnology materials for medicine, mathematics, biomaterials, biomechanics, and their applications in different clinical indications.
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Elizabeth Mittendorf, M.D., Ph.D.
Dr. Mittendorf is Associate Professor in the Department of Breast Surgical Oncology at The University of Texas MD Anderson Cancer Center. She has focused both her clinical practice and laboratory work on breast cancer, specifically on breast cancer immunotherapy. She is the principal investigator (PI) of several breast cancer vaccine clinical trials including the Phase III PRESENT clinical trial and a multicenter Phase II trial, which investigates the efficacy of two additional HER2-derived peptide vaccines. She is the PI of a Phase I trial that evaluates combination immunotherapy with vaccines and trastuzumab. Her laboratory research is focused on identifying novel tumor antigens that can be used as targets for vaccination. In addition, her research group studies the link between innate immunity and adaptive immune responses in the tumor microenvironment.
Rongfu Wang, Ph.D.
Dr. Wang is a Senior Member at Houston Methodist Research Institute and Director of the Center for Inflammation and Epigenetics. His research interest and expertise are focused in the areas of cancer antigen discovery, cancer immunology and immunotherapy, innate immune signaling and regulation, and epigenetic regulation of stem cells and cancer. His team has identified critical epigenetic regulators in T-cell differentiation and in induced pluripotent stem cell reprogramming. Dr. Wang proposes that further examination and understanding of the mechanisms of cellular reprogramming will lead to the development of novel cancer therapeutics.
Rolf Brekken, Ph.D.
Dr. Brekken is Professor in the Departments of Surgery and Pharmacology and the Effie Marie Cain Research Scholar in Angiogenesis Research at The University of Texas Southwestern Medical Center. He is also a principal investigator in the Hamon Center for Therapeutic Oncology Research. Dr. Brekken’s expertise and research interests are focused on the biology of tumor microenvironments, specifically in pancreatic cancer, and the development of new cancer therapies. His team studies the role of matricellular proteins (e.g., SPARC, Fibulin-5, and Hevin) in angiogenesis and vascular function in tumors. He has published over 100 peer-reviewed scientific papers and serves on the editorial board of the journal Cancer Research.
Jason Fleming, M.D., F.A.C.S.
Dr. Fleming is a surgeon specializing in pancreatic cancer, and he serves as Director of the Tissue Acquisition and Biorepository Core for the Pancreas Cancer Research Program at The University of Texas MD Anderson Cancer Center (MDACC). Dr. Fleming initiated and developed the first direct xenograft program in gastrointestinal cancer at MDACC. The xenografts are derived from human pancreatic adenocarcinomas from his patients, and these xenografts provide a valuable platform to examine pancreatic adenocarcinoma and its tumor microenvironment.
Haifa Shen, M.D., Ph.D.
Dr. Shen is Associate Member at Houston Methodist Research Institute and Associate Professor of Nanomedicine in the Institute for Academic Medicine, Houston Methodist Research Institute. He is also a faculty member in the Department of Cell and Developmental Biology at Weill Cornell Medical College. He is a cancer biologist who specializes in the application of nanotechnology toward the development of cancer therapeutics and immunotherapeutics, as well as delivery systems for various “payloads” (e.g., siRNA, microRNA, chemical compounds) to primary tumors and metastatic lesions. His team has developed a nanotechnology-based dendritic cell (Nano-DC) vaccine for HER2-positive breast cancer, and they have demonstrated the efficacy of Nano-DC in murine models of metastatic breast cancer and melanoma.
Eugene Koay, M.D., Ph.D.
Dr. Koay is Assistant Professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. He has deep knowledge and experience in the areas of physics, biology, bioengineering, computer programming, imaging analysis, clinical research, and statistics, as well as combining these areas to address the challenging pathologies associated with pancreatic cancer. Recently, his work has focused on the premise that biophysical properties of pancreatic cancer correlate with the delivery of, response to, and outcome after cytotoxic therapies.
Arturas Ziemys, Ph.D.
Dr. Ziemys is Assistant Member in the Department of Nanomedicine at Houston Methodist Research Institute. He has extensive expertise in experimental and computational modeling techniques, with particular focus on drug-target interactions (and prediction of drug release kinetics), drug delivery, pharmacokinetics and biodistribution in tumor microenvironments, and new modeling techniques for in vitro and in vivo studies. These comprise the foundation for his studies to understand how drug penetration or transport depends on features including drug size, interactions with surrounding media, and the zone of influence in the tumor microenvironment.
Bernhard Schrefler, Ph.D.
Dr. Schrefler is Secretary General of the International Centre for Mechanical Sciences in Udine (Italy), Professor Emeritus of the University of Padua, and a Senior Affiliate Member in the Department of Nanomedicine at Houston Methodist Research Institute. He is recognized as a world-leading expert in multiphase porous media mechanics, with applications in the field of biomedical engineering. He has developed one of the most advanced and comprehensive multiphysics models for tumor growth and transport of therapeutics within the theory of porous media flow.
Milos Kojic, Ph.D.
Dr. Kojic is a Senior Member of the Department of Nanomedicine at Houston Methodist Research Institute. Dr. Kojic is a renowned leader in computational mechanics, and he has significantly contributed to the development of computational methods in nonlinear finite element analysis in various fields of engineering and bioengineering, with a large number of publications in the world-leading journals and textbooks. He is the founder and principal investigator of a general-purpose Finite Element program (called PAK) used in research and industry for decades. Recently, his research focus has been on the transport multiscale models of molecules and particles within capillary systems and tissue.
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Project 1: Transport of Effector T Cells and Nano-DC Vaccine in Breast Cancer
Dendritic cells (DCs) are professional antigen-presenting cells that can process and present tumor antigen to T cells to initiate immune responses. In order for a DC vaccine to elicit the proper immune responses, a sequence of physical and biological events must occur: 1) The DC vaccine must migrate from the injection site to lymphoid tissues; 2) The DC vaccine must maintain a mature stimulatory status to persistently process and present the immunizing antigen to T cells; and 3) The antigen-specific T cells must travel to the tumor-bearing organ and infiltrate into the tumor microenvironment to exert their anti-tumor activity. These events are often insurmountable hurdles for most DC vaccines. Clinical studies have shown that less than 5% of intradermally injected DCs can reach the lymph nodes. The stimulatory signals of ex vivo matured DCs cannot be maintained in vivo. Furthermore, the tumor microenvironment prevents sufficient infiltration of the cytotoxic T cells. Thus, therapeutic efficacy of a cancer vaccine hinges on efficient physical transport processes, such as DC trafficking and transport of the activated T cells to the tumor microenvironment, through a sequence of biological barriers, that synergistically complement with biological activities of the DCs and antigen-specific T cells. We hypothesize that successful negotiation of sequential physical and biological barriers determines accumulation of the vaccine in lymphatic tissues, and modification of the tumor microenvironment facilitates transport of not only the effector T cells, but also macromolecular drugs that synergize with the DC vaccine for effective cancer therapy. The specific aims of Project 1 are to determine transport properties of the Nano-DC vaccine, study the changes in transport properties of endogenous DCs and effector immune cells in post-vaccination tumors, and to determine and modulate immunotherapeutic response as a function of these transport processes.
Project 2: Microenvironmental Transport for Immunotherapy in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is considered to be a non-T cell inflamed tumor, and current immunotherapy strategies do not work for most patients with PDAC. Biologically, the intense immune suppression of PDAC occurs due to the presence of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2 macrophages in the tumor microenvironment. Immune checkpoints such as phosphatidylserine (PS) function upstream of other immune checkpoints (PD1 and CTLA4) in cells within the tumor microenvironment to induce and maintain immune suppression. While tremendous efforts have focused on the biological pathways regulating these immunosuppressive cells to allow more effector T cell infiltration and cancer cell killing, the contribution of multiscale physical aberrations, including desmoplasia and hypovascularity inherent in PDAC, has been largely ignored. We propose that the spatial distribution of nutrients in the tumor microenvironment limits immunotherapy efficacy, as its disorganization restricts access of effector T cells to the cancer cells. Also, PS may contribute to PDAC immune evasion in concert with the aberrant physics of PDAC and that PS inhibition will normalize the biological and physical immunosuppression of PDAC. The specific aims of Project 2 are to characterize the multiscale transport phenomena of PDAC in relation to the distribution of nutrients and immune cells in morphologically distinct tumors, measure and model transport during immunotherapy, and rationally design immunotherapeutic strategies for biophysical subtypes of PDAC.
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Transport Oncophysics Core
In the Transport Oncophysics Core (TOC), our computational and modeling approach is based on the biophysical properties of tissues, cells, and molecules that control the efficiency of transport processes. The transport process of immune cells, biomolecules, and other drugs encounters many barriers, including systemic and within the tumor microenvironment. An important step of the transport process is the extravasation of cells and molecules from the blood or lymphatic vessels. Moreover, the tropism of immune cells – the ability to accumulate in tissues at high concentrations against concentration gradients – is another critical aspect. In addition, the impact of transport phenomena (physical spatio-temporal parameters and aberrations of tumors) on immunotherapeutic efficacy should be considered for the development of effective immunotherapies. Thus, vascular permeability, tropism, and multiple transport properties within tissues, together, comprise a set of parameters, which are underexplored in immunotherapies. We believe this is where opportunities exist to improve the delivery and efficacy of immunotherapeutics, by optimizing the transport and penetration of drugs and immune cells, systemically and in the tumor microenvironment to improve the immune response against breast and pancreatic cancers. The TOC supports both research projects of the Center for Immunotherapeutic Transport Oncophysics by providing imaging, analysis, quantification, and unique oncophysical computational tools to rationalize the delivery and transport of immunotherapies, based on the oncophysical modeling framework and Transport and Biodistribution Theory (TBT). The TBT moves boundaries from classical tools used to study pharmacokinetic and efficacy relations, and instead creates novel precision immunotherapeutic tools to rationally tailor individual treatments to patients.
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