Dissonant signaling, which can deafen the immune system to cancer, can be replaced by something more harmonious—and therapeutic—if immunotherapies silence a note, sound another, or play an especially resonant chord. This last approach was taken by researchers based at Tel Aviv University (TAU) when they decided to score a requiem for melanoma, the most aggressive type of skin cancer.

Performing in vitro and animal studies, the TAU scientists combined several forms of immunotherapy, reaching a most effective crescendo when they added a nanovaccine—a particle made of biodegradable polymer, sized at 160–190 nanometers, and packed with tumor-associated antigens. Actually, two nanovaccines were evaluated. One was studded with mannose receptors and capable of ligand-mediated (active) targeting of dendritic cells. The other was mannose free and capable only of phagocytosis-dependent (passive) targeting.

When the mannosylated nanovaccines were combined with an anti-PD-1 antibody (αPD-1) for immunosuppression blockade and an anti-OX40 antibody (αOX40) for effector T-cell stimulation, expansion, and survival, robust and widespread complementary outcomes against melanoma were achieved. Details of this work appeared August 5 in the journal Nature Nanotechnology, in an article titled, “Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators.

“Prophylactic and therapeutic combination regimens of dendritic cell-targeted mannosylated nanovaccines with αPD-1/αOX40 demonstrate a synergism that stimulates T-cell infiltration into tumors at early treatment stages,” the article’s authors wrote. “However, this treatment at the therapeutic regimen does not result in an enhanced inhibition of tumor growth compared to αPD-1/αOX40 alone and is accompanied by an increased infiltration of myeloid-derived suppressor cells (MDSCs) in tumors.”

The MDSCs hit a sour note, to be sure. To restore a sweet sound, the TUA scientists administered ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2-inducible T-cell kinase. Doing so, the scientists reported, succeeded in modulating MDSC generation and function.

“Combining the double therapy with ibrutinib leads to a remarkable tumor remission and prolonged survival in melanoma-bearing mice,” the authors of the Nature Nanotechnology article emphasized. “The synergy between the mannosylated nanovaccines, ibrutinib and αPD-1/αOX40 provides essential insights to devise alternative regimens to improve the efficacy of immune checkpoint modulators in solid tumors by regulating the endogenous immune response.”

Notably, the strong therapeutic synergism was only obtained when mannose was grafted on the surface of the nanovaccines. From this, the TAU scientists concluded that the mannosylation of the nanovaccine was crucial for the dendritic-cell-mediated antigen presentation and the activation of tumor-antigen-specific T cells.

The antigens delivered by the nanovaccine particles were Melan-A/MART-1(26-35(A27L)) major histocompatibility complex class I (MHCI)-restricted peptide (MHCI-ag) and the Melan-A/MART-1(51-73) MHCII-restricted peptide (MHCII-ag) aimed at the MHC class I and class II antigen presentation pathways, respectively. In combination with other forms of immunotherapy, the antigen delivery system proved to be effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

“The nanoparticles acted just like known vaccines for viral-borne diseases,” explained Ronit Satchi-Fainaro, PhD, principal investigator at TAU and a corresponding author of the current study. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides—that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

“The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy, and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” noted Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nanovaccine against melanoma and to sensitize the immune system to immunotherapies.”

Satchi-Fainaro and colleagues indicated that they are optimistic that their platform may also be effective against types of cancer other than melanoma.

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