Yale Cancer Center carves new path in immunotherapy

Cancer immunotherapy is showing promise in treating patients with a variety of advanced, metastatic tumours, as evidenced by two newly-unveiled studies from Yale Cancer Center. The research will be formally presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, but abstracts were made public by ASCO in advance of the meeting. Yale was a lead trial site for both studies.

This illustration shows how cancer cells interact with cells of the immune system. (Photo courtesy of Genentech Inc).

Both are Phase 1 clinical trials. The first study involved an investigational antibody drug, known as MPDL3280A and manufactured by Roche Genentech, which was designed to prevent a cancer cell's overexpressed PD-L1 protein from putting the immune system to sleep.

The overexpressed PD-L1 protein turns off the immune system's T-cells by binding to its PD-1 and B7.1 proteins. In doing so, it disguises itself and evades detection and destruction by the body's immune response.

This new drug is the latest advance in the burgeoning field of immunotherapy, which aims to boost the body's immune system to fight cancer. In blocking the cancer tumour's PD-L1 protein, MPDL3280A frees the immune system to do its job. This PD-L1 targeted antibody was specially engineered to increase safety and efficacy over earlier immunotherapy agents.

Yale oncologists report that the efficacy of MPDL3280A was evaluated in 140 patients with locally advanced or metastatic solid tumors who had exhausted other means of therapy.

Tumour shrinkage was observed in patients with non-small cell lung cancer, melanoma, kidney cancer, colorectal cancer and gastric cancer. Yale oncologists say ongoing, durable responses were observed in nearly all patients who responded to the drug.

Overall, 29 out of 140 patients (21 per cent) experienced significant tumour shrinkage, and the highest number of responses were in patients with lung cancer and melanoma. MPDL3280A was generally well tolerated, they say, with few immune-related adverse events. Some patients were continuing to respond more than a year after starting treatment.

''We have been very impressed by the response in seriously ill patients whose cancer had metastasized. So far, almost none of those who showed tumor shrinkage have gotten worse, which is extraordinary,'' said lead investigator Dr Roy Herbst, the Ensign Professor of Medical Oncology and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. ''Immunotherapy treatment is providing new hope for cancer patients,'' he added.

In the second Phase 1 study, researchers from Memorial Sloan-Kettering (lead author), Yale Cancer Center (senior author), and elsewhere, presented data that evaluated the safety and efficacy of combining immunotherapy drugs - nivolumab and ipilimumab - in treating advanced melanoma.

Each drug had been known to prolong survival or produce durable tumor regressions in some patients when administered individually, but combining them produced superior clinical results, researchers report, with rapid and deep tumor regressions in many patients.

Both CTLA-4 and PD-1 are targets for cancer immunotherapy because they shut down the immune system's ability to respond to foreign invaders. Nivolumab targets the PD-1 receptor on the surface of T-cells, and ipilimumab targets the CTLA-4 receptors. Both nivolumab and ipilimumab are manufactured by Bristol Myers Squibb.

Researchers provided data for 86 patients in this Phase 1 trial. They report that responses were generally durable, even in patients whose treatment was terminated early.

According to senior author Dr Mario Sznol, clinical research leader of the melanoma program at Yale Cancer Center, this early success in combining drugs may pave the way for large-scale combination immunotherapy trials.

''After many years, we are finally realizing the promise of immunotherapy in providing real and durable benefit for advanced cancer patients. Although this trial was focused on melanoma, the combination will be studied in other cancer types. This is only one of many combinations of agents that will likely lead to even more significant advances in cancer treatment,'' Sznol said.

The first author on this study was Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center.