Melanoma

Here is a link to the full article:http://stm.sciencemag.org/content/10/426/eaan4488.full

and here is the text of the discussion{DISCUSSION

We have developed a practical strategy for immunotherapy of cancer. It takes advantage of the preexisting T cell immune repertoire within the tumor microenvironment. The combination of a TLR agonist and an activating antibody against OX40 amplifies these antitumor T cells and induces their action throughout the body against tumor at nontreated sites. This in situ vaccination does not require knowledge of the tumor antigens. Potential drawbacks include reliance on adequate immune infiltrates and the availability of a suitable injectable site of tumor.

After screening a series of immune activators and checkpoint antibodies, we identified the combination of CpG oligodeoxynucleotide (TLR9 ligand) and anti-OX40 antibody to be the most potent form of in situ vaccination in multiple mouse models. TLR7/8 agonists could substitute for CpG, but checkpoint antibodies against PD1, PDL1, or CTLA4 could not substitute for anti-OX40.

The synergistic therapeutic effect between locally injected CpG and anti-OX40 antibodies is explained by the fact that CpG induced the expression of the OX40 target on CD4+ T cells in the tumor microenvironment. CpG also induced OX40 in CD4+ T cells in the tumor microenvironment of human lymphoma tumors, and therefore, our results are likely to translate to human cancer.

It has been reported that local intratumoral administration of CpG together with systemic antibody against IL-10R leads to rejection of the injected tumor and distant metastases (17, 18). This combination was shown to deflect M2 to M1 macrophages in the tumor microenvironment (19). Therefore, we examined the requirement for induction of OX40 expression on CD4 T cells by CpG in our system. We found that it was dependent on cytokines secreted by myeloid cells, including IL-12, IFN-γ, or TNF-α but not IL-2, IL-4, IL-10, and GM-CSF.

The therapeutic effect at the distant sites was specific for antigens expressed by the tumor at the injected site that were shared with the tumor cells at the distant sites. This result not only established the tumor specificity of the immunization but also proved that it was the local effect of the injected agents in the tumor microenvironment rather than their systemic delivery that triggered the systemic antitumor immune response.

Autoimmune toxicities are a common complication of systemically administered immune checkpoint antibodies (20–24). In contrast, direct injection of the antibodies into the tumor at very low doses can avoid these side effects (25, 26). In our experiments, in situ injection of microgram quantities of immune stimulants and checkpoint antibodies proved to be sufficient to induce the required local immune modulation, resulting in a systemic antitumor immune response.

A major challenge in tumor immunotherapy lies in breaking tumor immune tolerance. In a previous report, we showed that depletion of tumor-specific Tregs by the addition of anti-CTLA4 antibody was associated with enhanced antitumor efficacy (27). However, we find here that activating antibody against OX40 is sufficient. It is known that OX40 is expressed on both Tregs and Teffs in the tumor microenvironment, and as we now realize, OX40 can be further induced on CD4+ T cells in response to CpG. Modulating both Teffs and Tregs is essential to obtain therapeutic effect (28–30). Antibodies to OX40 costimulate Teffs (31–37), and they also inhibit the function of Tregs (12, 27, 38–40).

Having demonstrated the potent therapeutic efficacy of in situ immunotherapy in several different transplanted tumor types, we assessed this form of therapy in a spontaneous arising tumor. The MMTV-PyMT mouse model recapitulates several of the characteristics of virulent human breast cancer, among them showing histology similarity, having loss of estrogen and progesterone receptors, and overexpressing ErbB2/Neu and cyclin D1 (6, 41, 42). Although the tumors within a mouse arise independently in different mammary glands, they all share the expression of the PyMT antigen (43). Injection of CpG and anti-OX40 antibody into the first tumor to occur in each mouse resulted in reduced tumor load in the other mammary fat pads and prevented lung metastases. These results demonstrate the potency of the in situ vaccine maneuver in a situation of spontaneous cancer-driven by a strong oncogene, suggesting the possibility of a direct application to human cancer. By analogy to the genetically prone mice, we can imagine administering an in situ vaccine at the site of the primary tumor before surgery in patients at high risk for the occurrence of metastatic disease and/or in patients genetically prone to develop second primary cancers, such as those with inherited mutation in the BRCA genes.

The CpG used here, SD-101, is currently being tested in patients as a single agent and in combination with other therapeutic modalities (NCT02927964, NCT02266147, NCT01745354, NCT02254772, and NCT02521870). Anti-OX40 antibody is also currently being studied in phase 1 clinical trials (NCT02559024, NCT01644968, NCT02221960, NCT02318394, NCT02274155, NCT01862900, NCT01303705, and NCT02205333). The results from our current preclinical studies provide strong rationale for combining CpG with agonistic anti-OX40 antibodies in a therapeutic format of in situ vaccination in patients with lymphoma and solid tumors. As we have shown, CpG and anti-OX40 antibodies work locally at very low doses that should provide the advantage of avoiding toxicities that occur with their systemic administration.

Good results in mice (a total of 90). Nice proof of concept. A while to go before humans can get it.Maybe a little premature pr work.

Some countries have less stringent protocols for making a drug available and other countries will follow countries who have certified a drug.  But the countries that don't have that type of control are unlikely to have the drug available to them at all.