anti-PD-1/anti-PD-L1 藥物 美國快速審查 (Breakthrough Therapy)

治癌藥雙結合 意外成為趨勢2014年06月19日 15:03中央社專家指出，結合抗CTLA-4抗體及抗PD-1抗體組合藥物治療難治癌症已證實可延長患者生命，「這是未來的趨勢、也非常具有潛力」。第一屆唐獎「生技醫藥獎」得主，由美國學者詹姆斯．艾利森（James P. Allison）和日本學者本庶佑（Tasuku Honjo）共同獲得，兩人分別發現CTLA-4及PD-1為控制免疫系統重要關鍵，讓治療癌症曙光乍現。台北醫學大學校長閻雲表示，艾利森證明受體CTLA-4的抗體可阻斷T細胞抑制性訊息，這樣便可活化T細胞殺死癌細胞活性，已被研發成藥物「Ipilimumab」，用於治療末期轉移性黑色素瘤。閻雲指出，2011年美國食品藥物管理局（FDA）核准上市，台灣2013年健保局也核准給付末期轉移性黑色素瘤患者使用藥物，不過，這個藥物也是有副作用，包括嚴重腹痛、腹瀉及皮膚皮疹出現。針對藥物副作用，讓國際研究單位思考如何降低副作用反應，閻雲說，學者應用本庶佑發現PD-1是T細胞上的抑制受體進行研究，並證實這個蛋白質在腫瘤逃避機制上扮演關鍵角色，目前已投入在臨床試驗及藥物研究。閻雲說，PD-1的出現是彌補CTLA-4的不足，在第一期臨床試驗結果證實有好的反應，且在2週後就看到效果，前述副作用情況都有減緩，將這兩個受體組合的藥物是未來趨勢。閻雲表示，未來這方面的治療以更客製化導向，治療前需測試PD-1是否存在，臨床結果顯示，若PD-1不存在或表現低的患者，治療效果是不好的，反之，若PD-1存在及表現高患者，則治療效果比較好。閻雲指出，腫瘤細胞是非常聰明的，也具有永續經營的觀念，治療時對於抗藥性則要非常注意，因此結合抗CTLA-4抗體及抗PD-1抗體組合藥物運用藥物的互補功能治療難治癌症是「非常難得的潛力」。唐獎教育基金會表示，現在正逢癌症治療史上最令人興奮時期，艾利森及本庶佑的發現，促使國際間在免疫治療法上尋求新的契機，同時也讓許多難以治療癌症曙光乍現。

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."