Post-irradiation intratumoral heterogeneity modulates response to immune checkpoint inhibition therapy in a murine melanoma model.

PURPOSE: The underlying mechanism for radiation as a potentiator of immune checkpoint inhibition (ICI) is unclear. We developed a novel murine model to investigate the effects of post-irradiation intratumoral heterogeneity (ITH) on response to ICI. EXPERIMENTAL DESIGN: Parental mouse melanoma B16F10 cells were irradiated in vitro (5Gy x 3 fractions), then an a priori determined number of resulting colonies were implanted in C57BL/6J immunocompetent mice creating syngeneic models of unirradiated (parental) and irradiated tumors with low (irradiated-L) and high (irradiated-H) ITH. Mice were treated with placebo, α-PD-L1, α-CTLA-4 or dual ICI. Murine tumors underwent whole exome sequencing (WES). Clinically correlated paired pre- and post-irradiation patient rectal adenocarcinoma samples underwent WES. RESULTS: Irradiated-L tumors showed increased tumor mutational burden (TMB) and a sustained decrease in ITH. Irradiated-L tumors were predicted to express five neoantigens with high variant allele frequency/clonal distribution. Mice with irradiated-L and irradiated-H versus parental B16F10 tumors demonstrated longer overall survival with dual ICI. Only mice with irradiated-L tumors experienced an overall survival benefit with single agent ICI. Clinically correlated rectal adenocarcinoma samples showed similarly increased TMB and decreased ITH following irradiation. CONCLUSIONS: Post-irradiation ITH modulates ICI response in a murine melanoma model. Irradiation may offer a mechanism to widen the therapeutic window of ICI.

Continuous liquid interface production of 3D printed drug-loaded spacers to improve prostate cancer brachytherapy treatment.

Brachytherapy, which is the placement of radioactive seeds directly into tissue such as the prostate, is an important curative treatment for prostate cancer. By delivering a high dose of radiation from within the prostate gland, brachytherapy is an effective method of killing prostate cancer cells while limiting radiation dose to normal tissue. The main shortcomings of this treatment are: less efficacy against high grade tumor cells, acute urinary retention, and sub-acute urinary frequency and urgency. One strategy to improve brachytherapy is to incorporate therapeutics into brachytherapy. Drugs, such as docetaxel, can improve therapeutic efficacy, and dexamethasone is known to decrease urinary side effects. However, both therapeutics have high systemic side effects. To overcome this challenge, we hypothesized that we can incorporate therapeutics into the inert polymer spacers that are used to correctly space brachytherapy seeds during brachytherapy to enable local drug delivery. To accomplish this, we engineered 3D printed drug-loaded brachytherapy spacers using continuous liquid interface production (CLIP) with different surface patterns to control drug release. These devices have the same physical size as existing spacers, allowing them to easily replace commercial spacers. We examined these drug-loaded spacers using docetaxel and dexamethasone as model drugs in a murine model of prostate cancer. We found that drug-loaded spacers led to higher therapeutic efficacy for brachytherapy, and there was no discernable systemic toxicity from the drug-loaded spacers. STATEMENT OF SIGNIFICANCE: There has been high interest in the application of 3D printing to engineer novel medical devices. However, such efforts have been limited by the lack of technologies that can fabricate devices suitable for real world medical applications. In this study, we demonstrate a unique application for 3D printing to enhance brachytherapy for cancer treatment. We engineered drug-loaded brachytherapy spacers that can be fabricated using Continuous Liquid Interface Production (CLIP) 3D printing, allowing tunable printing of drug-loaded devices, and implanted intraoperatively with brachytherapy seeds. In combined chemotherapy and brachytherapy we are able to achieve greater therapeutic efficacy through local drug delivery and without systemic toxicities. We believe our work will facilitate further investigation in medical applications of 3D printing.

3D printed drug-loaded implantable devices for intraoperative treatment of cancer.

Surgery is an important treatment for cancer; however, local recurrence following macroscopically-complete resection is common and a significant cause of morbidity and mortality. Systemic chemotherapy is often employed as an adjuvant therapy to prevent recurrence of residual disease, but has limited efficacy due to poor penetration and dose-limiting off-target toxicities. Selective delivery of chemotherapeutics to the surgical bed may eliminate residual tumor cells while avoiding systemic toxicity. While this is challenging for traditional drug delivery technologies, we utilized advances in 3D printing and drug delivery science to engineer a drug-loaded arrowhead array device (AAD) to overcome these challenges. We demonstrated that such a device can be designed, fabricated, and implanted intraoperatively and provide extended release of chemotherapeutics directly to the resection area. Using paclitaxel and cisplatin as model drugs and murine models of cancer, we showed AADs significantly decreased local recurrence post-surgery and improved survival. We further demonstrated the potential for fabricating personalized AADs for intraoperative application in the clinical setting.