Sayeda Yasmin-Karim1, Bashkim Ziberi2, Johanna Wirtz3, Noella Bih4, Michele Moreau5, Romy Guthier6, Victoria Ainsworth7, Juergen Hesser8, G Mike Makrigiorgos4, Michael D Chuong9, Xiao Wei4, Paul L Nguyen4, Wilfred Ngwa5. 1. Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: sayeda_yasmin-karim@dfci.harvard.edu. 2. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; University of Tetova, Tetova, Republic of North Macedonia. 3. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Medical Faculty of University Ulm, Ulm, Germany. 4. Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 5. Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; University of Massachusetts, Lowell, Massachusetts; Department of Radiation Oncology and Molecular Radiation Sciences, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 6. Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Data Analysis and Modeling in Medicine, Mannheim Institute for Intelligent Systems in Medicine (MIISM), Heidelberg University, Heidelberg, Germany. 7. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; University of Massachusetts, Lowell, Massachusetts. 8. Data Analysis and Modeling in Medicine, Mannheim Institute for Intelligent Systems in Medicine (MIISM), Heidelberg University, Heidelberg, Germany. 9. Miami Cancer Institute, Baptist Health South Florida, Miami, Florida.
Abstract
PURPOSE: Persistent immunosuppression in the tumor microenvironment is a major limitation to boosting the abscopal effect, whereby radiation therapy at 1 site can lead to regression of tumors at distant sites. Here, we investigate the use of radiation and immunogenic biomaterials (IBM) targeting only the gross tumor volume/subvolume for boosting the abscopal effect in immunologically cold tumors. METHODS AND MATERIALS: To evaluate the abscopal effect, 2 syngeneic contralateral tumors were implanted in each mouse, where only 1 tumor was treated. IBM was administered to the treated tumor with 1 fraction of radiation and results were compared, including as a function of different radiation therapy field sizes. The IBM was designed similar to fiducial markers using immunogenic polymer components loaded with anti-CD40 agonist. Tumor volumes of both treated and untreated tumors were measured over time, along with survival and corresponding immune cell responses. RESULTS: Results showed that radiation with IBM administered to the gross tumor subvolume can effectively boost abscopal responses in both pancreatic and prostate cancers, significantly increasing survival (P < .0001 and P < .001, respectively). Results also showed equal or superior abscopal responses when using field sizes smaller than the gross tumor volume compared with irradiating the whole tumor volume. These results were buttressed by observation of higher infiltration of cytotoxic CD8+ T-lymphocytes in the treated tumors (P < .0001) and untreated tumors (P < .0001) for prostate cancer. Significantly higher infiltration was also observed in treated tumors (P < .0001) and untreated tumors P < .01) for pancreatic cancer. Moreover, the immune responses were accompanied by a positive shift of proinflammatory cytokines in both prostate and pancreatic tumors. CONCLUSIONS: The approach targeting gross tumor subvolumes with radiation and IBM offers opportunity for boosting the abscopal effect while significantly minimizing healthy tissue toxicity. This approach proffers a radioimmunotherapy dose-painting strategy that can be developed for overcoming current barriers of immunosuppression especially for immunologically cold tumors.
PURPOSE: Persistent immunosuppression in the tumor microenvironment is a major limitation to boosting the abscopal effect, whereby radiation therapy at 1 site can lead to regression of tumors at distant sites. Here, we investigate the use of radiation and immunogenic biomaterials (IBM) targeting only the gross tumor volume/subvolume for boosting the abscopal effect in immunologically cold tumors. METHODS AND MATERIALS: To evaluate the abscopal effect, 2 syngeneic contralateral tumors were implanted in each mouse, where only 1 tumor was treated. IBM was administered to the treated tumor with 1 fraction of radiation and results were compared, including as a function of different radiation therapy field sizes. The IBM was designed similar to fiducial markers using immunogenic polymer components loaded with anti-CD40 agonist. Tumor volumes of both treated and untreated tumors were measured over time, along with survival and corresponding immune cell responses. RESULTS: Results showed that radiation with IBM administered to the gross tumor subvolume can effectively boost abscopal responses in both pancreatic and prostate cancers, significantly increasing survival (P < .0001 and P < .001, respectively). Results also showed equal or superior abscopal responses when using field sizes smaller than the gross tumor volume compared with irradiating the whole tumor volume. These results were buttressed by observation of higher infiltration of cytotoxic CD8+ T-lymphocytes in the treated tumors (P < .0001) and untreated tumors (P < .0001) for prostate cancer. Significantly higher infiltration was also observed in treated tumors (P < .0001) and untreated tumors P < .01) for pancreatic cancer. Moreover, the immune responses were accompanied by a positive shift of proinflammatory cytokines in both prostate and pancreatic tumors. CONCLUSIONS: The approach targeting gross tumor subvolumes with radiation and IBM offers opportunity for boosting the abscopal effect while significantly minimizing healthy tissue toxicity. This approach proffers a radioimmunotherapy dose-painting strategy that can be developed for overcoming current barriers of immunosuppression especially for immunologically cold tumors.
Authors: Robert A Cormack; Srinivas Sridhar; W Warren Suh; Anthony V D'Amico; G Mike Makrigiorgos Journal: Int J Radiat Oncol Biol Phys Date: 2009-10-30 Impact factor: 7.038
Authors: Paul J Keall; Gig S Mageras; James M Balter; Richard S Emery; Kenneth M Forster; Steve B Jiang; Jeffrey M Kapatoes; Daniel A Low; Martin J Murphy; Brad R Murray; Chester R Ramsey; Marcel B Van Herk; S Sastry Vedam; John W Wong; Ellen Yorke Journal: Med Phys Date: 2006-10 Impact factor: 4.071