A paper published on 31 January 2018 in Science Translational Medicine indicate that combined intratumoural delivery of a Toll-like receptor 9 (TLR9) ligand with OX40 activation led to shrinkage of distant, previously untreated tumour sites and long-term survival even in a stringent spontaneous mouse cancer model. Both of these stimuli are in clinical trials as single agents and according to the researchers from Stanford University School of Medicine, Stanford, CA, US could likely be combined at great benefit for cancer patients.
Mobilizing endogenous T cells to fight tumours is the goal of many immunotherapies. Sagiv-Barfi et al. investigated a combination, dual immunotherapy in multiple types of mouse cancer models that could provide sustainable antitumour immunity.
It has recently become apparent that the immune system can cure cancer. In some of these strategies, the antigen targets are preidentified and therapies are custom-made against these targets. In others, antibodies are used to remove the brakes of the immune system, allowing pre-existing T cells to attack cancer cells. The researchers from Stanford have used another approach - in situ vaccination.
Immunoenhancing agents are injected locally into one site of tumour, thereby triggering a T cell immune response locally that then attacks cancer throughout the body. The study team has used a screening strategy in which the same syngeneic tumour is implanted at two separate sites in the body. One tumour is then injected with the test agents, and the resulting immune response is detected by the regression of the distant, untreated tumour.
Using the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG), the TLR9 ligand and anti-OX40 antibody provided the most impressive results in this study. TLRs are components of the innate immune system that recognise molecular patterns on pathogens. Low doses of CpG injected into a tumour induce the expression of OX40 on CD4-positive T cells in the microenvironment in mouse or human tumours. An agonistic anti-OX40 antibody can then trigger a T cell immune response, which is specific to the antigens of the injected tumour.
The approach worked well in laboratory mice with transplanted mouse lymphoma tumours in two sites on their bodies. Injecting one tumour site with the two agents caused the regression not just of the treated tumour, but also of the second, untreated tumour. In this way, 87 of 90 mice were cured. Although the disease recurred in three of the mice, the tumours again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumours.
Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumour that arose often prevented the occurrence of future tumours and significantly increased the animals’ life span.
Finally, Sagiv-Barfi and team explored the specificity of the T cells by transplanting two types of tumours into the mice. They transplanted the same lymphoma cells in two locations, and a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumours but did not affect the growth of the colon cancer cells. According to the researchers, it is about a very targeted approach as only the tumour that shares the protein targets displayed by the treated site was affected.
The researchers hope that this combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers. They believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects.
A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma. It is expected to recruit about 15 patients with low-grade lymphoma.
Ronald Levy, a senior author of the study is a pioneer in the field of cancer immunotherapy. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anticancer treatment in humans.
Sagiv-Barfi I, Czerwinski DK, Levy S, et al. Eradication of spontaneous malignancy by local immunotherapy. Science Translational Medicine 2018; 10(426). pii: eaan4488. DOI: 10.1126/scitranslmed.aan4488.