Predict radiation-induced shifts in patient-specific tumor immune ecosystem composition to harness immunological consequences of radiotherapy

Tumor-associated antigens, stress proteins, and danger-associated molecular patterns are endogenous immune adjuvants that can both initiate and continually stimulate an immune response against a tumor. In retaliation, tumors can hijack intrinsic immune regulatory programs, thereby facilitating continued growth despite an activated antitumor immune response. Clinically apparent tumors have co-evolved with the patient’s immune system and form a complex Tumor-Immune EcoSystem (TIES). The success of radiotherapy (RT) may be the result of radiation shifting the relative proportions of tumor and immune cells such that surviving cancer cells are subject to elimination by the immune system. However, current RT fractionation has not specifically focused on enhancing immune responses, nor has immune cell infiltration into the tumor as biomarker been considered to predict treatment response. We hypothesize that patients with a TIES such that radiation debulks the tumor and induces a robust immune response may be cured. A TIES with weak antitumor-immunity or strong immune suppression may not be sufficiently perturbed by current RT dose fractionation to fully harness radiation-immune synergy and provide tumor control. The goal of the project is to combine experimental studies and clinical data to calibrate and rigorously validate the in silico framework that simulates the influence of different TIES compositions on the response to different radiation doses and dose fractionations. We will focus on oropharyngeal cancer, one of the few cancer types increasing in incidence.  

Investigator team

Dr. Heiko Enderling is the contact PI of this PS-OP. He is Associate Member of Integrated Mathematical Oncology at Moffitt Cancer Center. He received his Ph.D. in Mathematical Biology from Dundee University, Scotland, in 2006. Dr. Enderling is interested in quantitative personalized oncology, that is to use mathematical modeling to simulate patient-specific tumor growth dynamics and response to therapy. In particular, he works on radiotherapy modeling and how to personalize and adapt radiotherapy for individual patients based on pre-treatment biology and dynamic responses to intervention. His lab has developed novel dynamic biomarkers to prospectively predict optimal radiation protocols for individual patients.

Dr. Shari Pilon-Thomas is the co-PI of this PS-OP. She is Associate Member of Immunology at Moffitt Cancer Center. Dr. Pino-Thomas’ primary research focus is on the enhancement of anti-tumor immune responses through the use of vaccines or adoptive cell therapy with tumor infiltrating lymphocytes for the treatment of solid tumors. The goal of the lab is to improve TIL-based therapies and translate findings into TIL-based clinical trials for the treatment of solid tumors, including melanoma, sarcoma, bladder and HPV+ tumors.  

Dr. Javier Torres-Roca is a Senior Member in the Department of Radiation Oncology at Moffitt Cancer Center. His research interests include the development of genomic strategies to personalize radiation therapy for individual patients. Dr. Torres-Roca’s team was instrumental in developing RSI, a molecular signature of tumor radiosensitivity that has been clinically-validated in eight different disease sites.

Dr. Christine Chung is Senior Member in the Department of Head & Neck-Endocrine Oncology at Moffitt Cancer Center. Dr. Chung's laboratory characterizes the molecular profiles of tumors from Head and Neck cancer patients based on genomic alterations and gene expression patterns. She is conducting clinical trials to develop less toxic but effective molecularly targeted agents which can potentially benefit different subsets of HNC patients.

Dr. Jimmy Caudell is Associate Member in the Department of Radiation Oncology at Moffitt Cancer Center. His clinical interests include treatment of head and neck cancer and cutaneous malignancies with radiotherapy. Dr. Caudell has also earned a Ph.D. in molecular biology, and his research interests include prediction of radiation sensitivity, evaluation of novel radiosensitizers and radioprotectants, as well as the use of technology to improve radiation delivery for head and neck cancer. 

Dr. Steven Eschrich is Senior Member and Department Chair of Head and Neck-Endocrine Oncology at Moffitt Cancer Center. His research is focused on identifying relevant and novel connections within the context of experiments as a crucial component of biomedical research in the high-throughput era.

Dr. Renee Brady is a postdoctoral fellow in Integrated Mathematical Oncology at Moffitt Cancer Center. Her work focusses on simulating the dynamics of tumor biomarkers before and during therapy to make patient-specific predictions for treatment response.

Dr. Mohammad Zahid is a postdoctoral fellow in Integrated Mathematical Oncology at Moffitt Cancer Center. His work focusses on simulating the dynamics of radiotherapy and its role on the tumor microenvironment. 

Preliminary data / publications

  

A molecular assay of tumor radiosensitivity: a roadmap towards biology-based personalized radiation therapy
Torres-Roca JF. Per Med. 9(5), 547-557, 2017

[pubmed] [publisher]

    

Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy
Enderling H, Alfonso JCL, Moros E, Caudell JJ, Harrison LB. Trends Cancer. 5(8):467-474, 2019

[pubmed] [publisher]

    

The future of personalised radiotherapy for head and neck cancer
Caudell JJ, Torres-Roca JF, Gillies RJ, Enderling H, Kim S, Rishi A, Moros EG, Harrison LB. Lancet Oncol. 18(5):e266-e273, 2017

[pubmed] [publisher]