Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses

Abstract

Checkpoint blockade with antibodies against CTLA-4 or PD-1 elicits durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients1–3. This suboptimal outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint4–8. Here we demonstrate a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse melanoma model; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended half-life recombinant IL-29, anti-PD-1, and a powerful T-cell vaccine10. Depletion experiments revealed that CD8+ T-cells, cross-presenting DCs, and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable.

Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments

“…Our results using three different murine models, as well as a human tumor model using humanized mice, indicate that Clec9A-AFN may represent such a broad-spectrum, off-the-shelf therapy. Furthermore, in contrast with other proposed therapies, DC-targeted AFN combines DC activation and T-cell recruitment and responses, without relying on tumor-specific surface markers (53).…”

Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

“…In conclusion, our data illustrate the potential for this particular and for other nanoparticle-based lymph-node targeting platforms (19,(44)(45)(46) efficacy of neoantigen-based therapeutic vaccines in patients, most obviously to target HPV + cancers with the well-validated E7LPs, but potentially also other cancers for which stimulatory neoantigens have been identified (50). It is possible that the use of antigenic peptides coupled with such systems will enhance many immunotherapeutic vaccine strategies for solid tumors, whether single or combinatorial, involving SLPs.…”

“…Promising results have also been reported for other distinct vaccine delivery platforms based on larger particles (44,45) and lymph node targeting vaccines, either alone (19) or in complex combinatorial strategies (46). Compared to an impressive but elaborate combinatorial therapeutic regimen (46), we show that a relatively simple approach, solely based on conjugation of an antigenic SLP to a nanoparticle-based delivery system and its administration in a single dose is sufficient to elicit a significant antitumor response not achievable with a traditional unconjugated "liquid" formulation. …”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…One exciting biomaterials example coupled amphiphilic vaccines comprised of antigen and adjuvant with an albumin-binding domain that efficiently shuttled vaccine components to LNs through natural albumin trafficking mechanisms [64]. Another approach demonstrated effective eradication of large tumors through LN targeting and combinatorial activation of both innate and adaptive immune responses using a four-part vaccine: tumor-antigen targeting antibody, recombinant IL-2, anti-PD-1 (a checkpoint inhibitor), and the vaccine antigen [65]. Lastly, artificial APCs composed of PLGA particles functionalized with anti-CD28 and MHC displaying tumor antigen have been designed to activate T cells [66].…”