Roxanne Nelson, RN, BSN
February 08, 2018
According to researchers at the Stanford University School of Medicine in California, 87 of 90 mice were cured of cancer, and among the 3 animals that experienced a recurrence, the tumors once again regressed after a second treatment.
The study used an approach called in situ vaccination. With this strategy, immunoenhancing agents are injected locally into one site of tumor, which in turn triggers a local T cell immune response that will then attack the cancer cells in the rest of the body.
The study was published January 31 in Science Translational Medicine.
Lead author, Ronald Levy, MD, professor of oncology at Stanford University School of Medicine, told Medscape Medical News that clinical trials of this vaccine are already planned.
"A phase 1 trial is about to begin in lymphoma, and if there are good results, we will branch out to other tumor types," he said.
Vaccine Injected Directly Into Tumor
Advances in the field of immunotherapy, including clinical success with immune checkpoint modulators, have rekindled interest in the development of a cancer vaccine. Investigations are ongoing in prostate cancer and metastatic colorectal cancer, and investigators are even exploring the idea of a universal cancer vaccine.
"Our product is different from others only in the fact that we found a particular combination of immune stimuli that work the best," Dr Levy commented.
He pointed out that a product already on the market for melanoma uses a similar strategy: talimogene laherparepvec (T-VEC, Amgen) which was approved in the United States in 2015. "It is directly injected into tumors like we did with our product," Dr Levy told Medscape Medical News.
"Targeting the material directly into the tumor means that we are not depending on any other type of delivery method," he pointed out.
Tumors that are transplanted into animal models lack certain aspects of naturally occurring tumors, so the researchers also studied the effects of this combination in a spontaneous mouse model of breast cancer. "What is unique in our result compared to other past results is that we have also eliminated naturally arising tumors rather than just artificially introduced tumors," Dr Levy emphasized.
Two Key Ingredients
The researchers conducted a preclinical screening process in order to identify candidate immunostimulatory agents that could trigger a systemic antitumor T cell immune response when injected locally into one site of tumor. They found that toll-like receptor 9 (TLR9) ligands induced the expression of OX40 on CD4 T cells within the microenvironment of the tumor itself.
Further investigation revealed that adding an agonistic anti-OX40 antibody would provide a synergistic effect and simulate an even a greater antitumor immune response. This combination of a TLR9 ligand and anti-OX40 antibody effectively treated spontaneous breast cancers and distant sites of established tumors.
The selected product used in this study reactivates the cancer-specific T cells by injecting microgram amounts of CpG oligonucleotide, a ligand for TLR9, and an anti-OX40 antibody directly into the tumor.
Dr Levy and his colleagues noted that this combination "worked startlingly well" in mouse models that had transplanted lymphoma tumors in two sites on their bodies. When one tumor site was injected with the product, regression occurred not only in the treated tumor but in the second one as well.
In mice that were genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads, treatment of the first tumor prevented future tumors and significantly increased survival.
The in situ vaccination was also effective against other tumors with a variety of histologic types, including colon cancer and melanoma.
The specificity of the T cells was also explored by transplanting the same lymphoma cancer cells in two locations and a colon cancer cell line in a third location. The lymphoma tumors regressed with treatment, but the growth of the colon cancer cells was unaffected.
The CpG and anti-OX40 antibodies work locally at very low doses, which should provide the advantage of avoiding toxicities that can occur with their systemic administration, the researchers note.
Experts Weigh In
Approached by Medscape Medical News for an independent comment, Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at the Icahn School of Medicine at Mount Sinai in New York City, explained that this is a "very exciting" study and a beautiful illustration of "smart immunotherapy."
"While several immunotherapies, such as PD1/PDL1 [programmed cell death 1/programmed cell death ligand 1]-blocking antibodies, have become standard therapy for several types of cancer, those therapies have limitations," Dr Brody said. "Because they potentially activate many immune cells in the body, there is a real chance of inducing autoimmune responses, which can be quite serious."
He added that the in situ vaccine approach taken in this study "will very likely improve both the efficacy and the safety of newer immunotherapies being developed for numerous types of cancer, including breast cancer, lymphoma, head/neck cancers, and others."
Another expert, Takemasa Tsuji, PhD, assistant professor of oncology with the Center for Immunotherapy and the Department of Immunology at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that the authors present an impressive large set of data demonstrating a therapeutic effect of in situ vaccination in multiple murine tumor models.
"They found that injection of a mixture of immune-stimulating agents, CpG oligonucleotide and anti-OX40 antibody, into a single tumor nodule completely eliminates not only the treated tumor but also other distant tumors," he said. "I am very impressed by their treatment, in which only a small amount of agents completely eliminated multiple established tumors."
Dr Tsuji agreed with the authors that the small dose is a great advantage because it is likely to limit treatment-related toxicity without losing antitumor effects.
"The next step will be to test whether the same treatment is effective against human tumors in model experiments and clinical trials," he said. "Both CpG oligonucleotide and anti–OX-40 antibody have already been tested independently in multiple clinical trials, and therefore, testing a combination of these agents should be relatively straightforward."
However, Dr Tsuji pointed out that, as discussed in the paper, the therapeutic effect may depend on pre-existing antitumor immune responses in the tumor. "Therefore, it may be possible that the treatment is not effective in a fraction of patients whose tumor does not contain sufficient antitumor immune cells. If this is observed, combination with additional immunotherapy treatment that induces and recruits antitumor immune cells into tumors may be required," Dr Tsuji cautioned.
The study was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation, and the Phil N. Allen Foundation. Stanford's Department of Medicine also supported the work. Dr Levy is a member of the Stanford Cancer Institute and Stanford Bio-X. Coauthor Dr Gambhir is the founder and equity holder in CellSight Inc, which develops and translates multimodality strategies to image cell trafficking and transplantation. Drs Brody and Tsuji have disclosed no relevant financial relationships.
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SOURCE: Medscape, February 08, 2018. Sci Transl Med. Published online January 31, 2018.