Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model

Abstract

Most cancer immunotherapies include activation of either innate or adaptive immune responses. We hypothesized that the combined activation of both innate and adaptive immunity will result in better antitumor efficacy. We have previously shown the synergy of an agonistic anti-CD40 monoclonal antibody (anti-CD40) and CpG-ODN in activating macrophages to induce tumor cell killing in mice. Separately, we have shown that a direct intratumoral injection of immunocytokine (IC), an anti-GD2 antibody linked to interleukin-2, can activate T and NK cells resulting in antitumor effects. We hypothesized that activation of macrophages with anti-CD40/CpG, and NK cells with IC, would cause innate tumor destruction, leading to increased presentation of tumor antigens and adaptive T cell activation; the latter could be further augmented by anti-CTLA-4 antibody to achieve tumor eradication and immunological memory. Using the mouse GD2+ B78 melanoma model, we show that anti-CD40/CpG treatment led to upregulation of T cell activation markers in draining lymph nodes. Anti-CD40/CpG + IC/anti-CTLA-4 synergistically induced regression of advanced subcutaneous tumors, resulting in cure of some mice and development of immunological memory against B78 and wild type B16 tumors. While the antitumor effect of anti-CD40/CpG did not require T cells, the antitumor effect of IC/anti-CTLA-4 was dependent on T cells. The combined treatment with anti-CD40/CpG + IC/anti-CTLA-4 reduced T regulatory cells in the tumors and was effective against distant solid tumors and lung metastases. We suggest that a combination of anti-CD40/CpG and IC/anti-CTLA-4 should be developed for clinical testing as a potentially effective novel immunotherapy strategy.

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

“…This approach seeks to convert a patient's own tumor into a nidus for presentation of tumor‐specific antigens in a way that will stimulate an antitumor T‐cell response, thus activating both innate and adaptive immunity . The BNP consists of four components—an inner polyplex core composed of PC7A and CpG oligodeoxynucleotide, and an outer layer composed of a bacterial membrane that is modified on its surface with maleimide groups to enhance antigen uptake (Mal) ( Figure ) . Certain bacterial membranes are abundant for pathogen‐associated molecular patterns such as toll‐like receptor (TLR) agonists that can stimulate innate immunity and DC activation .…”

“…MS membranes can capture cancer neoantigens and facilitate their DC uptake after RT treatment . The nanosized polyplex core was made of anionic CpG (TLR9 agonist) and pH‐responsive polymer PC7A (endosome disruption), two adjuvants capable of further strengthening the antigen presentation in DCs . The nanosized polyplex was first formed at a pH of 6.5 and then transformed to a more stable hydrophobic core at a pH of 7.4 for more efficient membrane coating.…”

Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma

“…In a recent study, Rakhmilevich and colleagues assayed the efficacy of combining innate and adaptive immunotherapeutic approaches in mouse models of melanoma ( i.e. , B16-GD2 which was transfected to express GD2 and B78, a slow-growing B16 derivative which expresses GD2) [ 84 ]. The authors demonstrated that the administration of anti-CD40 mAb (costimulatory receptor belonging to the superfamily of tumor necrosis factor receptor, predominantly expressed by antigen-presenting cells) with CpG ODNs was able to suppress tumor growth in the B78 melanoma model; these results were due to tumor cell killing via activation of macrophages.…”

“…Finally, the multicombinatorial approach consisting in the administration of anti-CD40/CpG ODNs and anti-CTL-A4/14.18-IL-2 IC was also assayed. This treatment led to increased antitumor effects with respect to single therapy and can be justified by the cooperation of innate and adaptive immunity [ 84 ].…”

Future perspectives in melanoma research “Melanoma Bridge”, Napoli, November 30th–3rd December 2016

“…There is a growing enthusiasm for testing checkpoint blockade in combination with other approaches to augment immune-mediated antitumor effects. Recently synergistic effect of the combination of anti-CTLA-4 mAb blockage and intratumor (IT) administration of the IC on smaller tumors (day-7 B78, < 50 mm 3 ) was demonstrated although the treatment was less efficacious on larger tumors (day 12, B78 tumors) [ 13 ]. Recent studies of mAb/cytokine-based immunotherapies for solid tumors have shown IT-IC is more effective for measurable mouse tumors [ 13 , 14 ] and that IV treatment (mAb or IC) can be effective in minimal residual disease (MRD) setting (COG studies) [ 15 ].…”