Radiation therapy is a highly effective means to kill cancer cells;unfortunately tumors can grow back from small pockets of residual disease. We propose that immune responses initiated by radiation therapy have the potential to control residual disease in the treatment site and distant metastases. Our research thus far has demonstrated three main points: first, that radiation therapy induces tumor antigen-specific T cell responses that are required for the full efficacy of radiation therapy;second, that high dose radiation therapy releases adjuvants that are required to prime adaptive responses to tumor antigens;and third, a negative fact, that the tissue repair response activated by radiation damage limits immune responses at the tumor.
The aim of this proposal is to understand the relationship between radiation dose and the positive and negative immune responses to tumors. We hypothesize that hypofractionated radiation therapy would result in superior adaptive immune responses to tumor antigens. We further examine how radiation interacts with immunotherapies to extend inflammation in the tumor and target residual disease.
The specific aims of this study are to 1: Test the hypothesis that hypofractionated radiation therapy would result in superior adaptive immune responses to tumor antigens;2: Test the hypothesis that vaccine therapies synergize with hypofractionated radiation therapy to boost and target T cell responses, and extend inflammatory destruction in the tumor;3: Test the hypothesis that hypofractionated radiation therapy is a superior partner for clinical vaccine therapies in neoadjuvant chemoradiation for pancreatic cancer. Our study design incorporates preclinical radiation therapy of spontaneous models of pancreatic cancer using an advanced imaging and treatment platform. In addition, we use two matching clinical studies of immunomodulation combined with neoadjuvant chemoradiation therapy for locally advanced and borderline resectable pancreatic cancer to examine the effect of radiation fractionation on T cell immune responses. We and others are designing and conducting clinical studies combination immunotherapy and radiation: these data will be key to the design of an effective combination.

Public Health Relevance

Cancer patients are treated with effective cytotoxic therapies that can reduce the tumor to few viable cancer cells: unfortunately for cancer patients, tumors can recur from small pockets of residual disease. Killing cancer cells using high dose radiation therapy provides an opportunity to prime adaptive immune responses to target this residual disease. This proposal uses an advanced preclinical model and clinical studies to determine whether high dose radiation therapy can more effectively target adaptive immune responses to the tumor than conventionally fractionated radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA182311-01A1
Application #
8760163
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Ahmed, Mansoor M
Project Start
2014-06-15
Project End
2019-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$321,625
Indirect Cost
$114,125
Name
Providence Portland Medical Center
Department
Type
DUNS #
099142093
City
Portland
State
OR
Country
United States
Zip Code
97213
Crittenden, Marka R; Zebertavage, Lauren; Kramer, Gwen et al. (2018) Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Sci Rep 8:7012
Tormoen, Garth W; Crittenden, Marka R; Gough, Michael J (2018) Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol 3:520-526
Alice, Alejandro F; Kramer, Gwen; Bambina, Shelly et al. (2018) Amplifying IFN-? Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity. J Immunol 200:177-185
Baird, Jason R; Monjazeb, Arta M; Shah, Omid et al. (2017) Stimulating Innate Immunity to Enhance Radiation Therapy-Induced Tumor Control. Int J Radiat Oncol Biol Phys 99:362-373
McGinnis, Gwendolyn J; Friedman, David; Young, Kristina H et al. (2017) Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget 8:9155-9173
McGinnis, Gwendolyn J; Raber, Jacob (2017) CNS side effects of immune checkpoint inhibitors: preclinical models, genetics and multimodality therapy. Immunotherapy 9:929-941
Baird, Jason R; Feng, Zipei; Xiao, Hong D et al. (2017) STING expression and response to treatment with STING ligands in premalignant and malignant disease. PLoS One 12:e0187532
Crittenden, Marka R; Baird, Jason; Friedman, David et al. (2016) Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy. Oncotarget 7:78653-78666
Baird, Jason R; Friedman, David; Cottam, Benjamin et al. (2016) Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors. Cancer Res 76:50-61
Crocenzi, Todd; Cottam, Benjamin; Newell, Pippa et al. (2016) A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma. J Immunother Cancer 4:45

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