Localized Multi‐Component Delivery Platform Generates Local and Systemic Anti‐Tumor Immunity

Abstract

As tumors employ complementary overlapping and/or independent mechanisms to evade immune surveillance, many emerging cancer immunotherapies attempt to target multiple pathways to eradicate malignant cells. Although modulation of independent pathways by simultaneous administration of multiple immune modulators (e.g., checkpoint inhibitors, cytokines, and growth factors) has shown great promise, the clinical impact remains limited due to severe toxicity associated with high systemic levels of many of these drugs. Therefore, novel platforms for efficient delivery of multi‐component therapies at lower effective doses would be enabling. Here, a drug delivery platform called immunomodulatory molecule delivery system (iMods), which provides sustained extracellular delivery of a checkpoint inhibitor (anti‐PD‐L1) and simultaneously, targeted intracellular delivery of a tumor antigen (OVA) along with adjuvant (poly(I:C)), and the indoleamine deoxygenase inhibitor 1‐MT is described. In melanoma tumor‐bearing mice, combinatorial delivery of these factors with iMods leads to regression of both treated and untreated (contralateral) melanoma tumors and 100% survival. These promising therapeutic outcomes are attributed to significantly enhanced ratios of anti‐tumor CD8 T‐cell/tumor‐protective regulatory T‐cell (Treg) in tumors and tumor draining lymph nodes. Overall, the iMods delivery platform described here represents a promising advance in multi‐factor cancer immunotherapy.

A cancer vaccine-mediated postoperative immunotherapy for recurrent and metastatic tumors

“…The recent innovation in cancer exome sequencing has further promoted the development of patient-specific neoantigens for personalized immunotherapy 13 – 17 . Unfortunately, the objective response rates of peptide-based vaccines have been disappointing in clinical trials due to tumor heterogeneity and their inefficiency to co-deliver multiple antigen peptides and adjuvants to the draining lymph nodes (LNs) 7 , 18 , 19 . Furthermore, the sequencing and preparation of patient-derived neoantigens is costly and time consuming, which is unfavorable for metastatic or late-stage cancer patients 20 .…”

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

“…By loading two or more immunomodulatory drugs targeting different protumoral signaling pathways in TME into these nanodelivery systems, synergistic effects of each therapeutic modality could be obtained. Although the combination approaches have shown enhanced therapeutic efficacy, a lot of side or toxic effects were also observed . Therefore, the precise dose, order of treatment, and the administration routes should be carefully considered in the design of nanoengineered immune niches to maximize therapeutic outcomes, while minimizing cytotoxic effects.…”

“…In addition to systemic delivery, a platform for the local delivery of IDO inhibitors was also designed to enhance the therapeutic outcome and minimize toxicity. An immunomodulatory molecule delivery system (iMods) was developed to provide the localized release of 1‐methyl‐ dl ‐tryptophan (1‐MT), an IDO inhibitor, anti‐PD‐L1, and a cancer vaccine (ovalbumin (OVA) and poly I:C) in melanoma tumor‐bearing mice . The codelivery of these therapeutics via iMods induced the regression of both the treated primary and distant tumors, resulting in 100% survival.…”

Toward Biomaterials for Enhancing Immune Checkpoint Blockade Therapy

“…Moreover, the expression of IDO1 in tumors can arise the infiltration of T regs into tumor sites. Therefore, the application of IDO1 inhibitors to alleviate the immunosuppression of TME could overcome the resistance and increase the benefit of ICB when used in combination . As mentioned above, biodegradable MN system has been proved to be a superior platform to control the release of anti‐PD‐1 .…”

“…Engineered scaffold with remarkable physical and chemical properties has obtained indelible success in the local application of immunology therapy . Cytokines, tumor antigens, and danger signals can be integrated into the design of scaffolds, which functioned as an immunogenic niche to exploit the interaction between immune cells to battle with malignant cells . Scaffold also can build a bridge between immune checkpoint therapy and adoptive T‐cell therapy.…”