OVERALL - SUMMARY This is a joint application for a program project grant by Massachusetts General Hospital and MD Anderson Cancer Center. The progress we made in our most recent program projects (a P01 and a U19) has been criti- cal to the clinical, physical, and biological aspects of proton therapy and its significance as an important cancer treatment modality. The main achievements of the recently completed U19 (end date 8/31/20) were (1) the de- velopment and activation of definitive esophagus, liver and glioma randomized proton vs. photon therapy trials in cooperation with NRG, NCI and NCTN; (2) understanding and modeling the differences in response of nor- mal tissues to highly disparate proton and photon dose distribution patterns; (3) understanding the complexities of the biological effects of protons relative to photons; and (4) the development of advanced intensity modu- lated proton therapy incorporating physical uncertainties and the variable biological effectiveness of protons. Our research also revealed major gaps in the knowledge of the biological effects of protons, significant limita- tions of the current population-based models of normal tissue and tumor response to protons vs. photons, and uncertainty in the appropriateness of proton therapy in the face of heterogeneities in patient characteristics and treatment techniques in unselected groups of patients. On the bright side, our research also discovered the strong potential of proton therapy to reduce suppression of the immune system, which is commonly associated with photon therapy and has been shown to lead to adverse outcomes. The overall goals of the proposed P01 are (a) understanding relative clinical, biological and immunosuppressive effects of proton therapy vs. photon therapy; (b) enhancing outcomes based on the physical, biological and immunological properties of protons and photons; and (c) applying individualized (as opposed to population-based) approaches for the se- lection of the optimum radiation modality for each patient and to enhance the potential for outcomes with the use of radiation dose distributions tailored to the individual patient’s baseline and tumor characteristics. The achievement of these goals will be carried out in three projects. Project 1: Understanding Normal Tissue Tox- icity to Identify Patients Most Likely to Benefit from Proton vs. Photon Therapy; Project 2: Radiation-Induced Lymphopenia (RIL): Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies; and Project 3: Investigating Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers. The projects are highly integrated in that decisions regarding treatment modality selection, treatment technique and optimization to maximally enhance the therapeutic ratio cannot be accomplished by any one project alone. Such decisions must consider and balance normal tissue complications, tumor re- sponse based on genotypic factors, and radia...