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Poorly immunogenic tumors, including triple negative breast cancers (TNBCs), remain resistant to current immunotherapies, due in part to the difficulty of reprogramming the highly immunosuppressive tumor microenvironment (TME). Here we show that peritumorally injected, macroporous alginate gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) for concentrating dendritic cells (DCs), CpG oligonucleotides, and a doxorubicin-iRGD conjugate enhance the immunogenic death of tumor cells, increase systemic tumor-specific CD8 + T cells, repolarize tumor-associated macrophages towards an inflammatory M1-like phenotype, and significantly improve antitumor efficacy against poorly immunogenic TNBCs. This system also prevents tumor recurrence after surgical resection and results in 100% metastasis-free survival upon re-challenge. This chemo-immunotherapy that concentrates DCs to present endogenous tumor antigens generated in situ may broadly serve as a facile platform to modulate the suppressive TME, and enable in situ personalized cancer vaccination., The immunosuppressive tumour microenvironment impairs immunotherapy in poorly immunogenic cancer. Here, the authors load an alginate gel with GM-CSF, CpG oligonucleotides and doxorubicin-iRGD to promote immunogenic death of tumour cells and improve immunotherapy efficacy in triple negative breast cancer models.

Transarterial embolization (TAE) is a standard-of-care treatment for tumors in which embolic particles are locally injected via a catheter to occlude blood flow and induce ischemia in the target tissue. Physicians currently rely on subjective visual cues from fluoroscopy in order to determine the procedural endpoint relative to the injection site. This contributes to highly variable treatment outcomes, including the accumulation of embolic particles in healthy tissue, called off-target embolization. To address this concern, we describe a novel, multilumen catheter that 1) measures real-time pressure upstream of the tumor site during TAE injection; and 2) associates that measurement with the volume of embolic particles injected. Using an in vitro silicon vascular model, we characterize the relationship between blood flow, intravascular pressure, and injection pressure. Furthermore, we identify a predictive pressure curve based on the volume of embolic particles injected. This approach has the potential to standardize and optimize TAE, reducing the likelihood of incomplete or off-target embolization, and improving patient outcomes.

Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR–PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR–PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumours in about 80% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR–PEI vaccine eradicated established lung metastases, controlled tumour growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumour models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination. A strategy to enhance antigen immunogenicity is shown using polyethyleneimine adsorbed on mesoporous silica microrod vaccine as a platform for neoantigens, supporting potent humoral immune response and inhibition of tumour growth following vaccination.

Allotransplantation offers the potential to restore the anatomy and function of injured tissues and organs, but typically requires life-long, systemic administration of immunosuppressive drugs to prevent rejection, which can result in serious complications. Targeting the immunosuppressive drug to the graft favors local tissue concentration versus systemic drug exposure and end-organ toxicity. This could reduce the overall dose and dosing frequency of immunosuppressive drugs, and improve the safety and efficacy of treatment. Here, we developed dibenzocyclooctyne (DBCO)-modified prodrugs of the immunosuppressive drugs tacrolimus, rapamycin and mycophenolic acid, and demonstrated their targeted conjugation both in vitro and in vivo to azido-modified hydrogels via Click chemistry. Such azido-modified hydrogels placed in transplanted tissues enable sustained local release of drugs, and could be repeatedly refilled with systemically administered acid-labile prodrugs after drug exhaustion. Thus, clickable prodrugs with degradable linkers provide new possibilities for graft targeted immunosuppression in the context of allotransplantation.

Biomaterials have shown substantial potential to integrate synergistically with current cancer vaccine strategies and enhance their effectiveness. We recently developed an injectable biomaterial vaccine via spontaneous assembly of mesoporous silica (MPS) microparticles into a 3D scaffold in vivo. When formulated with GM-CSF and the TLR-9 agonist CpG, the MPS vaccine modulates host dendritic cell (DC) activation and trafficking. Here we demonstrate that a single injection of the MPS vaccine induced persistent germinal center B cell activity for over 30 days. Consequently, when immunized with a small linear Her2/neu peptide within the Trastuzumab binding domain, the MPS vaccine elicited over 2 orders of magnitude higher IgG1 and IgG2a antibody titer compared to a traditional bolus vaccine, and the antibody exhibited immunoreactivity on the native Her2 structure on breast cancer cells. To further enhance CTL responses against tumor antigens, we co-presented the antigen with polyethylenimine (PEI) in the MPS vaccine. PEI increased antigen cross-presentation in murine DCs, and TNF-a and IL-6 production in both murine and human DCs in vitro. Compared to the MPS vaccine, the MPS-PEI vaccine enhanced activated and antigen+ DCs in the vaccine and the vaccine draining lymph node by ~2 fold. Systemically, using both OVA and a HPV-E7 peptide as antigens, the MPS-PEI vaccine induced ~2.5 fold higher IFN-y producing antigen specific circulating CD8+ T-cells compared to the MPS vaccine. Impressively, using a HPV-E7 expressing tumor model, we demonstrated that a single injection of the MPS-PEI vaccine completely eradicated large established tumors in over 80% of mice. Finally, when immunized with a pool of recently sequenced B16 melanoma neoantigen peptides, the MPS-PEI vaccine induced potent therapeutic tumor growth control and synergy with anti-CTLA4 checkpoint blockade therapy. These findings suggest that the MPS vaccine may serve as a facile multifunctional and multi-epitope platform to modulate host immune cell function and augment personalized antitumor immunity. Citation Format: Aileen W. Li, Maxence O. Dellacherie, Miguel Sobral, Omr O. Ali, Jaeyun Kim, David J. Mooney. DC-recruiting biomaterial vaccine to enhance antitumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B119.

Certain chemotherapeutic drugs can elicit immunogenic death of tumor cells and enhance antitumor immune responses. Here we explore whether immunogenic chemotherapy can be utilized for the development of antigen-free cancer vaccines, by combining it with peritumorally injected biomaterial scaffolds that recruit dendritic cells (DCs) for subsequent antigen presentation and T-cell priming. Pore-forming alginate gels containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and a doxorubicin-iRGD conjugate were found to efficiently induce the apoptosis of 4T1 triple-negative breast cancer cells in vivo, while recruiting large numbers of DCs. The co-encapsulation of CpG oligodeoxynucleotides in the gel significantly enhanced the immunogenic death of 4T1 cells, increased systemic tumor-specific CD8+ T-cells and tumoral infiltration of CD8+ T-cells, repolarized tumor-associated macrophages towards an inflammatory M1-like phenotype, and resulted in significantly improved antitumor efficacy. This in situ antigen-free gel vaccine shows promise for the treatment of poorly immunogenic tumors, and more broadly, may serve as a facile platform to enable in situ personalized cancer vaccination without requiring identification of tumor-specific antigens and manufacturing of personalized vaccines. Citation Format: Miguel C. Sobral, Hua Wang, Alexander J. Najibi, Aileen Li, Catia S. Verbeke, David J. Mooney. Antigen-free cancer vaccine to treat poorly immunogenic tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B045.