Boosting the Abscopal Effect Using Immunogenic Biomaterials With Varying Radiation Therapy Field Sizes.

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.

Optimizing In Situ Vaccination During Radiotherapy.

Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.

Can the Adoption of Hypofractionation Guidelines Expand Global Radiotherapy Access? An Analysis for Breast and Prostate Radiotherapy.

PURPOSE: The limited radiotherapy resources for global cancer control have resulted in increased interest in developing time- and cost-saving innovations to expand access to those resources. Hypofractionated regimens could minimize cost and increase access for limited-resource countries. In this investigation, we estimated the percentage cost-savings per radiotherapy course and increased radiotherapy access in African countries after adopting hypofractionation for breast and prostate radiotherapy. For perspective, results were compared with high-income countries. METHODS: The cost and course of breast and prostate radiotherapy for conventional and hypofractionated regimens in low-resource facilities were calculated using the Radiotherapy Cost Estimator tool developed by the International Atomic Energy Agency (IAEA) and then compared with another activity-based costing model. The potential maximum cost savings in each country over 7 years for breast and prostate radiotherapy were then estimated using cancer incidence data from the Global Cancer Observatory database with use rates applied. The increase in radiotherapy access was estimated by current national capacities from the IAEA directory. RESULTS: The estimated cost per course of conventional and hypofractionated regimens were US$2,232 and $1,339 for breast treatment, and $3,389 and $1,699 for prostate treatment, respectively. The projected potential maximum cost savings with full hypofractionation implementation were $1.1 billion and $606 million for breast and prostate treatment, respectively. The projected increase of radiotherapy access due to implementing hypofractionation varied between +0.3% to 25% and +0.4% to 36.0% for breast and prostate treatments, respectively. CONCLUSION: This investigation demonstrates that adopting hypofractionated regimens as standard treatment of breast and prostate cancers can result in substantial savings and increase radiotherapy access in developing countries. Given reduced delivery cost and treatment times, we anticipate a substantial increase in radiotherapy access with additional innovations that will allow progressive hypofractionation without compromising quality.