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Two Immunotherapies Clear Important Regulatory Hurdles

July 08, 2014 | Matthew Tontonoz

The promising immunotherapy drug nivolumab received its first regulatory approval for use, in Japan, making it the first anti-PD-1 cancer therapy to clear this hurdle. Yesterday, the Japanese health ministry approved the drug for the treatment of inoperable melanoma.

Nivolumab will be marketed and sold in Japan under the name Opdivo by Ono Pharmaceutical. Ono obtained rights to the drug from the pharmaceutical company Medarex, which developed it in the early 2000s. Bristol-Myers Squibb (BMS) bought Medarex in 2009, but Ono retains rights to its sale in Japan, Korea, and Taiwan.

Nivolumab is one of the most highly regarded cancer drugs to have emerged in years. It belongs to a class of drugs called checkpoint inhibitors, which “take the brakes off” the immune system, allowing a more potent anti-cancer response. The first checkpoint inhibitor molecule to be approved was ipilimumab (owned by BMS), which blocks a molecule called CTLA-4. It was approved by the FDA in 2011 for metastatic melanoma. Nivolumab targets a different molecule, known as PD-1. What sets nivolumab (and other PD-1 inhibitors) apart from ipilimumab is the fact that it operates “closer” to the site of cancer, and therefore seems to have fewer side effects than CTLA-4 inhibitors. Many cancer types have “learned” how to escape immune destruction by making a molecule, called PD-L1, which binds to and activates PD-1 on T cells, shutting them down. With T cells disarmed in this way, the cancer can proceed unchecked.


“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy.”


Prior to yesterday’s regulatory approval, the only drug available in Japan for the treatment of advanced melanoma is a chemotherapy drug called dacarbazine; ipilimumab is not approved for use there, making nivolumab (Opdivo) the first checkpoint inhibitor to be approved for use in Japan. Ono will make the drug available to eligible patients free of charge until the drug has been listed on Japan’s national insurance price list.

In the U.S., several anti-PD-1/anti-PD-L1 inhibitors, made by several different companies, are in clinical development. These include nivolumab (anti-PD-1, BMS), pembrolizumab (anti-PD-1, Merck), MPDL3280A (anti-PD-L1, Genentech), and MEDI4736 (anti-PD-L1, MedImmune/AstraZeneca). Several of these have received “Breakthrough Therapy” status from the FDA.

The FDA’s “Breakthrough Therapy” designation was implemented in 2012, with the goal of expediting the development of promising new medical treatments. Only a handful of drugs have been given the coveted designation.

The latest addition to this rarefied list is an immunotherapy being developed by researchers at the University of Pennsylvania, under the direction of CRI Scientific Advisory Council member Carl June, M.D., in partnership with the pharmaceutical company Novartis. The approach, called CAR-T cell therapy, uses genetically modified T cells from a patient’s own body to attack and kill cancer cells. To date, the approach has been used successfully to treat patients with a variety of childhood and adult leukemias and lymphomas. The specific CAR-T cell approach given Breakthrough Therapy status is one that targets a molecule on leukemia cells called CD19, found on cancers of B cell origin (including ALL, CLL, and non-Hodgkin lymphoma). The Breakthrough designation only applies to the treatment for childhood and adult refractory or relapsed ALL.  

In one study, 89 percent of ALL patients (22 children and 5 adults) treated with the CD19-targeting therapy had a complete response to the therapy. Among this group of lucky patients is 8-year-old Emily Whitehead, who celebrated 2 years of being cancer free this past May.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Dr. June. “Receiving the FDA’s Breakthrough Designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

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