Eco-Evolutionary dynamics of NSCLC to immunotherapy: Response and Resistance
- Eco-Evolutionary dynamics of NSCLC to immunotherapy: Response and Resistance
- H. Lee Moffitt Cancer Center
The Moffitt Integrated Mathematical Oncology (IMO) Department, through collaborations with oncologists, cancer biologists, evolutionary biologists, and imaging scientists, has pioneered the integration of evolutionary dynamics into cancer treatment protocols. In pre-clinical experiments and now with ongoing clinical trials, we have demonstrated that therapies incorporating evolutionary dynamics can significantly improve outcomes using currently available treatments. Major “lessons learned” from this experience include 1) Optimal therapy design requires maximal understanding of the multiscale dynamics that provide the “menu” of resistance strategies for cancer cells undergoing treatment; 2) The eco-evolutionary forces that govern response and resistance in cancer therapy are dominated by non-linear dynamics that defy intuitive analysis and can only be predicted through mathematical models and computational simulation; and 3) Clinical data are typically sparse and can be obtained only in periodic “snapshots” from biopsies or imaging studies. Converting static information to evolutionary dynamics requires mathematical tools. In this U01 we will apply these investigational principles to immunotherapy for metastatic non-small cell lung cancer (NSCLC). During the past decade, the Moffitt Thoracic Oncology Department has pioneered new strategies using immunotherapy for NSCLC. In almost 500 patients treated with immunotherapy at Moffitt, the response rate (CR, PR, and SD) is 30 to 45%. Most responses are followed by evolution of resistance and progression but some patients in each category have experienced durable responses maintained for >1 year.
Our underlying hypothesis is that the observed results from immunotherapy can be improved with sufficient understanding of the evolutionary (cellular and molecular) and ecological (tissue) dynamics that govern response and resistance of NSCLC to immunotherapy. There is clear evidence that integration of other agents can enhance NSCLC response to immunotherapy. But, as we have previously demonstrated, administration of cytotoxic drugs in heterogeneous cancers typically elicits complex, often non-intuitive evolutionary dynamics and integration of evolutionary mathematical models into the clinical protocols can significantly improve outcomes.
To develop such models we will analyze a Moffitt NSCLC immunotherapy cohort to investigate the evolutionary (molecular, cellular) as well as ecological (histological and radiological) dynamics that govern response and resistance to immunotherapy. These investigations will be supplemented with ex vivo studies in which tumor and immune cells obtained from resected primary tumors are dispersed in culture allowing the immediate response to immunotherapy agents to be assessed. We will also perform in vitro studies that dissect the wide range of cellular and tissue ecological engineering strategies available to NSCLC cells as well as the timescales of immunotherapy adaptation. Finally, we will test predictive power of our developed mathematical models to prospectively use pre-therapy data to predict outcomes from anti-PD-L1 immunotherapy and calibrate these results from ongoing clinical trials in NSCLC at Moffitt.
Alexander Anderson, PhD
Dr. Anderson is the Founding Richard O. Jacobson Chair of the Integrated Mathematical Oncology (IMO) department and Co-Director of the Physical Sciences in Oncology Center (PSOC) at Moffitt Cancer Center. For the last 20 years he has been developing mathematical models of many different aspects of tumor progression and treatment that require a tight dialogue between theory and experiment. He has over 100 peer-reviewed, scientific publications, is a Principal Investigator of several NIH/NCI grants and has mentored 7 interns, 10 graduate students and 11 postdoctoral students and 7 faculty. Dr. Anderson performed his doctoral work on hybrid mathematical models of nematode movement in heterogeneous environments at the Centre for Nonlinear Systems in Biology, Dundee University, UK. His postdoctoral work was on hybrid models of tumor-induced angiogenesis with Prof. Mark Chaplain at Bath University, UK. He moved back to Dundee in 1996 where he worked for the next 12 years on developing mathematical models of many different aspects of tumor progression and treatment, including anti-angiogenesis, radiotherapy, tumor invasion, intra-tumor heterogeneity, evolution of aggressive phenotypes and the role of the microenvironment. Due to his belief in the crucial role of mathematical models in cancer research he moved his group to the Moffitt Cancer Center in 2008 to establish the IMO department. Since his arrival at Moffitt his focus has shifted to developing organ specific models of tumor initiation and progression that examine the key role of the microenvironment as a regulating force in the growth and evolution of cancer. A common theme of these organ specific models is the importance of understanding normal organ form and function particularly in relation to homeostatic regulation and how cancer disrupts and exploits these mechanisms. Building models that can generate testable hypothesis and utilizing experimental data to parameterize them is a key component of his research. Dr. Anderson has developed a diverse suite of mathematical and computational tools covering the gamut of spatial and temporal scales that cancer encompasses. In recent years, cancer treatment has become a significant driver of his research and using mathematical models that connect our basic science understanding of a given cancer with clinical translation. This has led to the development of eco-evolutionary therapies that seek to control cancer rather than eradicate it. Through smart treatment scheduling, with combination therapies as well microenvironment targeted treatments, he has developed novel treatments for prostate, breast, lung and skin cancer.
Robert Gatenby, MD
Bob received a B.S.E. in Bioengineering and Mechanical Sciences from Princeton University and an M.D. from the University of Pennsylvania. He completed his residency in radiology at the University of Pennsylvania where he also served as chief resident. Bob remains an active clinical radiologist specializing in body imaging. While working at the Fox Chase Cancer Center after residency, Bob perceived that cancer biology and oncology were awash in data but lacked coherent frameworks of understanding to organize this information and integrate new results. Reaching back to his training in engineering and physical sciences, Bob recognized that cancer was a complex dynamic system (similar, for example, to weather) and that understanding the often non-linear interactions that govern such systems requires mathematical models and computer simulations. As a result, most of Bob’s subsequent research has focused on exploring mathematical methods to understand the first principles and key parameters that govern cancer biology and treatment. In 2008, Bob joined Moffitt as chair of radiology and convinced the leadership to add a group of mathematicians to the faculty and form the Integrated Mathematical Oncology (IMO) department. Now numbering 8 faculty mathematicians and over 20 post docs and grad students, the IMO has catalyzed formation of several disease-oriented teams of oncologists, surgeons, pathologists, radiologists, mathematicians, physicists, cancer biologists, imaging scientists and evolutionary biologists. These multidisciplinary groups are investigating virtually every aspect of cancer biology and therapy. In fact, IMO members are co-PIs of two ongoing clinical trials that use evolutionary dynamics and computational models to guide therapy. There is no other cancer center in the world that has so completely integrated mathematical modeling and computer simulations into basic science and clinical research.
Scott Antonia, MD, PhD
Dr. Antonia is currently the Department Chair of the Thoracic Oncology Department at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. He is also a Professor of Oncologic Sciences at the University of South Florida College of Medicine in Tampa. Prior to being named chair of Thoracic Oncology in 2010, he was associate chairman of the Sarcoma Department. He joined the Moffitt Cancer Center in 1994. Dr. Antonia received his M.D. and his Ph.D. in Immunology from the University of Connecticut Health Center in Farmington, Connecticut. In addition, he completed an internal medicine residency at Yale University School of Medicine and pursued additional training at Yale through a medical oncology fellowship and post-doctoral fellowship in Immunobiology. Dr. Antonia’s work focuses on translational research. Using his molecular biology and cellular background in the development of immunotherapeutic strategies for the treatment of cancer patients, he has developed strategies designed to thwart the immunosuppressive mechanisms used by tumors to evade T-cell mediated rejection. His clinical interests focus on immunotherapy and immunobiology, in particular, gene-modified tumor cell vaccine trials at both pre-clinical and clinical stages. He has designed and conducted numerous cutting-edge studies with novel immunotherapeutics and has two patents for technology he has developed. He has been awarded a K24 grant from the National Cancer Institute to support his clinical research and is the principal investigator for a Thoracic SPORE project. Dr. Antonia is also conducting several ongoing investigator-initiated clinical trials testing novel tumor vaccines, and tumor vaccine augmentation strategies for the treatment of various cancers. Dr. Antonia also serves as chairman of Moffitt’s Scientific Review Committee and medical director of the Tumor Vaccine Production Facility at Moffitt. He was named the Moffitt Physician of the Year in 2005 and Mentor of the Year in 2008. Dr. Antonia has published papers in several peer-reviewed journals, including Science, Clinical Cancer Research, Current Opinions in Oncology, and Cancer Research. In 2014, he was recognized as the “Most Cited Faculty” during the Moffitt Faculty Appreciation/Recognition Reception. In 2015, he was inducted into the National Academy of Inventors.