Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors

Abstract

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.

Adrenocortical Carcinoma Steroid Profiles: In Silico Pan-Cancer Analysis of TCGA Data Uncovers Immunotherapy Targets for Potential Improved Outcomes

“…We also demonstrated a positive correlation between CD8B and CD274 (PD-L1) expression (R = 0.61, p = 1 × 10 −11 ) and CD8B and PDCD1LG2 ( PD-L2) (R = 0.77, p = 8.6 × 10 −18 ) ( Figure 8 ). This may indicate that selective pressure induced enhanced immune evasion by tumor cells, which is in agreement with recent studies ( 51 )⁠. PD-1/PD-L1-related and PD-1/PD-L2-related immune escape mechanisms are known to downregulate the CD8+ T-cell activation process.…”

“…CSF2 expression was added based on the study by Wang et al. ( 51 )⁠, which showed its importance for dendritic cell recruitment in poorly immunogenic tumors. Adjusted p-values for the findings from the DE analysis were used for comparison between groups.…”

Peptide-Based Strategies for Targeted Tumor Treatment and Imaging

“…iRGD has been used in a wide array of cancer models for specific targeting in conjugation with chemotherapy and nanoparticles and other active agents. In a recent study, a peritumorally injected pore-forming alginate gel loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) and doxorubicin-iRGD (Dox-iRGD) conjugate significantly improved the antitumor efficacy against poorly immunogenic triple negative breast cancer (4T1) model [ 235 ]. iRGD incorporated into a self-assembling prodrug polymer delivery system consisting of nanosized polymeric micelles, camptothecin, and photosensitizer IR780 (CPT-S-S-PEG-iRGD@IR780) for combination therapy showed anticancer activity after crossing the BBB in in vivo orthotopic glioma model [ 236 ].…”

Emerging technologies provide insights on cancer extracellular matrix biology and therapeutics

“…Another approach is engineered injectable hydrogel systems suitable for chemotherapy and radiotherapy (Cirillo et al, 2019) or immunotherapy delivery (Weiden et al, 2018;Gosselin et al, 2018). A drug-loaded, thermosensitive PLGA-PEG-PLGA gel has been proposed for the treatment of osteosarcoma (Yang & et al, 2018), whereas injectable macroporous alginate gels loaded with chemokines, adjuvants, and chemotherapeutic drugs have been proposed as chemoimmunotherapy cancer vaccines for poorly immunogenic tumors, including triple-negative breast cancers (Wang & et al, 2020). Implantable biomaterial devices for the local delivery of chemotherapy have been studied, such as chemotherapy drug-loaded ethylene-vinyl acetate copolymer disks in in vivo intracranial glioma models (Bota et al, 2007) and paclitaxel-loaded PLGA fibrous meshes that allow sustained, long-term drug release in a glioma in vivo model (Ranganath and Wang, 2008).…”