January 29, 2018, New York — Ludwig Cancer Research scientists have devised and successfully tested in a Phase II clinical trial a novel regimen combining chemotherapy and immunotherapy for patients with the aggressive skin cancer melanoma. Led by Charlotte Ariyan, who is a researcher with the Ludwig Center at Memorial Sloan Kettering (MSK) and a clinical oncologist at MSK, the study finds that localized, high-dose chemotherapy followed by systemic treatment with the checkpoint blockade immunotherapy ipilimumab induces significant and durable anti-cancer responses in patients with relatively advanced melanoma. The responses significantly exceed those obtained with either agent alone.
Published in the current issue of Cancer Immunology Research, the study enrolled 26 patients whose cancers were “in transit”—with tumors spreading through a limb toward the rest of the body—or, in a few cases, had already become systemic (stage IIIB/IIIC, and stage IV, respectively). The researchers found that 85% of patients receiving the combination treatment had significant anti-tumor responses within 3 months, with 62% having no detectable tumors at that point and 23% showing significant regressions. Overall, the cancer had not progressed any further in 58% of the patients a year later.
“These results,” says Ariyan, “are exciting not only because they could provide a new tool for treating patients whose tumors are insufficiently responsive to immunotherapy but also because they are further evidence that combination therapies are the way forward in the treatment of cancer.”
Ipilimumab targets a protein on the immune system’s T cells named CTLA-4 to release the brakes of the T cell response. It can induce significant remissions in patients with advanced melanoma. But fewer than half of all patients respond to anti-CTLA-4 and other checkpoint blockade therapies.
Researchers have long known that tumors that are inflamed—and so heavily infiltrated by immune cells, especially killer T cells that attack sick and infected cells—are the ones most likely to succumb to immunotherapy. Chemotherapy, meanwhile, can induce potent inflammation in tumors if delivered at sufficiently high doses.
Ariyan and her colleagues initially examined in animal studies how combining chemotherapy and checkpoint blockade would affect tumors. They hypothesized that the cell death and inflammation caused by high dose chemotherapy would reveal cancer antigens—telltale molecular signs of disease—to the immune system. Immunotherapy would then boost the resulting killer T cell attack on the tumor.
This is precisely what happened when mouse models of melanoma and prostate cancer were given the combination therapy. Further, the combination treatment left a lasting immunological memory of the cancer in treated mice—as would a cancer vaccine.
To translate their approach to the clinic, the researchers focused on melanoma patients with in-transit disease, who can be given a form of localized chemotherapy. In this therapy, isolated limb infusion (ILI), the cancerous limb is isolated from the blood supply with a tourniquet and then infused with high dose chemotherapy. Following ILI, the patients were given an average of three doses of ipilimumab.
The response rate from this regimen was not only high, it also appeared to be quite durable: Median progression-free survival for all enrolled patients had not been reached 36 months after treatment. Further, two patients with systemic disease displayed a complete response, one of which lasted two years. This suggests the therapy may teach the immune system to attack tumors in other parts of the body as well—as would a vaccine.
Most of the side effects of the treatment were immune-related, but the two deaths recorded in the trial stemmed from pre-existing cardiac disease. Because the procedure is so invasive, the researchers expect its primary clinical potential is as a therapy for patients who have proved resistant to immunotherapy. Further, the immunological findings of the study have implications for the treatment of not only melanoma but other cancers as well.
A number of Ludwig MSK researchers participated in the study. These include Taha Merghoub and Jedd Wolchok, Co-directors of the Ludwig Collaborative Laboratory at MSK, and Alexander Rudensky, Director of Ludwig MSK, in whose lab Ariyan conducts her research. In addition, James Allison, chairman of immunology at The University of Texas MD Anderson Cancer Center, is the last author of the paper.
The study was supported by Ludwig Cancer Research, Ellen and Gary Davis Foundation, Society of Surgical Oncology, Cycle for Survival, the National Institutes of Health, the Conrad N. Hilton Foundation and Bristol Myers Squibb.