安进（Amgen）与默沙东（Merck & Co）达成合作，计划启动一项I期临床试验，评估安进癌症疫苗T-vec（talimogene laherparepvec）与默沙东PD-1免疫疗法Keytruda（pembrolizumab）联合治疗转移性黑色素瘤。目前该I期试验已招募到首例患者，双方计划招募约110例患者，在美国、澳大利亚、欧洲35个临床试验基地评估T-vec/Keytruda抗癌免疫鸡尾酒疗法。
癌症疫苗单用疗效不佳，鸡尾酒是未来方向
早前，癌症疫苗概念一经提出，便获得业界广泛关注，这种新颖疗法旨在利用肿瘤抗原激活人体免疫系统攻击癌细胞，从而改变疾病病程。然而事实证明并非如此，癌细胞能够避机体免疫侦察，这就意味着，如果癌症疫苗在很大程度上错过了靶标，单靠发动更强的免疫冲击是不够的。默克（Merck KGaA）的癌症疫苗Stimuvax和葛兰素史克（GSK）的癌症疫苗MEGA-A3都在大型III期临床惨遭失败，就是2个非常好的例子。今年4月，安进溶瘤免疫疗法T-vec在黑色素瘤关键III期临床中尽管缩小了肿瘤体积也触发了系统性免疫反应，但却未能显著改善总生存期（OS），也是一个很好的例证。
这些确凿的证据表明，癌症疫苗作为一种单药疗法并不能很好地发挥作用，而癌症疫苗联合免疫检查点抑制剂的抗癌免疫鸡尾酒，可能是未来的发展方向。
T-vec/Keytruda鸡尾酒的理论基础
T-vec是一种溶瘤免疫疗法，旨在促进肿瘤抗原的释放和呈递以引发抗肿瘤免疫反应；Keytruda则是一种PD-1/PD-L1免疫检查点抑制剂，能够释放PD-1通路介导的抗肿瘤免疫反应，2者可能具有互补的作用。而抗原的释放和呈递是发动系统性（全身性）抗癌免疫反应的基石，T-vec和Keytruda具有互补性，将2者组成T-vec/Keytruda免疫鸡尾酒具有强有力的理论基础。
PD-1/PD-L1免疫疗法实质改善生存
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力，有望实质性改善患者总生存期（OS）。该领域的佼佼者——默沙东、百时美施贵宝、阿斯利康、罗氏均在火速推进各自的临床项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
此次竞赛中，百时美和默沙东稍微领先。百时美的PD-1抑制剂Opdivo（nivolumab）于今年7月获日本批准，是全球批准的首个PD-1抑制剂；而默沙东的PD-1抑制剂Keytruda（pembrolizumab）于今年9月初获FDA批准，是美国批准的首个PD-1抑制剂；这2种药物获批的首个适应症均为黑色素瘤。阿斯利康和罗氏的PD-L1抑制剂也已处于III期临床。
关于T-vec：
Talimogene laherparepvec(T-Vec)是一种实验性溶瘤免疫疗法（oncolytic immunotherapy），是一种基因工程化的病毒，能够表达GM-CFS。T-Vec直接注射入肿瘤，并能够在肿瘤细胞中复制直至细胞膜破裂及死亡（即细胞裂解），同时能够在肿瘤组织局部释放GM-CSF，这是一种白细胞生长因子，能够激活系统性免疫反应。T-Vec通过2种重要且互补的方式发挥作用：引发肿瘤组织溶解，同时激发一种全身性的抗肿瘤免疫反应。
关于Keytruda：
Keytruda（pembrolizumab）是一种人源化抗程序性死亡因子(PD-1)单克隆抗体，PD-1蛋白是一种肿瘤应答元件，能够使肿瘤逃避免疫系统的攻击。Keytruda于2014年9月获FDA批准，用于黑色素瘤的治疗。目前，默沙东正在大型临床项目中评估Keytruda用于广泛类型肿瘤的治疗潜力。
关于PD-1/PD-L1免疫检查点：
PD-1/PD-L1作为免疫球蛋白超家族协同刺激分子的重要成员，参与自身免疫、移植免疫以及肿瘤免疫等机体免疫调节过程。PD-1是一种主要表达于活化T细胞上的抑制性受体，与其配体PD-L1结合，可显著抑制T细胞的活化和增殖，并调节细胞因子的表达和分泌。PD-L1则广泛表达于多种免疫细胞、上皮细胞以及肿瘤细胞上。目前诸多研究表明，多种人类肿瘤大量表达的PD-L1分子与患者临床病理特征及预后紧密相关，成为肿瘤检出和预后判断的新的生物学指标。肿瘤细胞通过高表达PD-L1分子，与T细胞上的受体PD-1结合，传递负调控信号，导致肿瘤抗原特异性T细胞的诱导凋亡和免疫无能，使肿瘤细胞逃避机体的免疫监控和杀伤。
鉴于PD-1/PD-L1信号转导机制在肿瘤免疫应答中的重要作用，尝试将阻断该信号通路应用于肿瘤免疫治疗，对进-步拓展肿瘤治疗的思路和方法具有重要价值。
英文原文：New Trial Initiated evaluating Amgen's Talimogene Laherparepvec In Combination With Merck's Anti-PD-1 Therapy KEYTRUDA® (Pembrolizumab) For Advanced Melanoma
THOUSAND OAKS, Calif. -- Amgen (NASDAQ: AMGN) today announced the initiation of a trial of talimogene laherparepvec, an investigational oncolytic immunotherapy, in combination with an investigational use of Merck's U.S. Food and Drug Administration (FDA) approved, anti-PD-1 therapy, KEYTRUDA® (pembrolizumab) in patients with regionally or distantly metastatic melanoma. The trial has enrolled its first patient and will evaluate the combination of these two therapies in approximately 110 patients across 35 clinical trial sites in the U.S., Australia and Europe.
"Data from this trial will help us further understand the safety and efficacy that comes from combining two immunotherapeutic agents," said F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-oncology at Dana-Farber Cancer Institute and Steering Committee Chair for this study. "Talimogene laherparepvec is designed to promote tumor antigen release and presentation to initiate an anti-tumor immune response, which may be complementary to KEYTRUDA's role in releasing PD-1 pathway-mediated inhibition of anti-tumor immune responses. Antigen release and presentation is a fundamental step required for mounting a systemic effect against melanoma, and we think there is a strong rationale for combining the oncolytic immunotherapy talimogene laherparepvec with the immune checkpoint inhibitor KEYTRUDA."
"This new trial underscores our commitment to researching different treatment approaches for patients with this aggressive and highly recurrent form of skin cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We are excited to partner with Merck and explore the potential of talimogene laherparepvec and KEYTRUDA. This will also give us insights into talimogene laherparepvec beyond the monotherapy setting, wher a Phase 3 trial has shown encouraging results."
"Merck is advancing the study of immuno-oncology combinations with KEYTRUDA across a broad range of malignancies," said Dr.Eric Rubin, vice president, Clinical Development for Oncology, Merck Research Laboratories. "We are pleased to collaborate with Amgen to evaluate the potential of KEYTRUDA and talimogene laherparepvec as a combination regimen for the treatment of advanced melanoma."
A Biologics License Application has recently been accepted for review by the FDA as has a Marketing Authorization Application in the European unio for talimogene laherparepvec for the treatment of patients with regionally or distantly metastatic melanoma. FDA has set a review goal date under the Prescription Drug User Fee Act (PDUFA) of July 28, 2015.
The regulatory filings included data from more than 400 patients and is based on a global, randomized, open-label Phase 3 trial evaluating the safety and efficacy of intralesional talimogene laherparepvec in patients with stage IIIB, IIIC, or IV melanoma that are not surgically resectable compared to granulocyte-macrophage colony-stimulating factor (GM-CSF). An Amgen-sponsored expanded access protocol (EAP) is currently active for qualified patients with unresected, stage IIIB to IV melanoma who are not eligible for or who cannot access ongoing talimogene laherparepvec trials.
about the Combination Trial
The multicenter, open-label clinical trial is designed to evaluate the safety of talimogene laherparepvec in combination with KEYTRUDA, as well as the efficacy of this combination versus KEYTRUDA alone and following progression after treatment with KEYTRUDA alone.
The study will be conducted in two phases:
Phase 1 will determine the safety and tolerability of talimogene laherparepvec in combination with KEYTRUDA in patients with previously untreated, unresected, stage IIIB to IVM1c melanoma.
The randomized phase will further evaluate the safety and efficacy of talimogene laherparepvec in combination with KEYTRUDA.
about Talimogene Laherparepvec
Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response to target cancer cells that have metastasized. Talimogene laherparepvec was designed to work in two important and complementary ways. First, it is injected directly into tumors wher it replicates inside the tumor's cells causing the cell to rupture and die in a process called lysis. Then, the rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a system-wide immune response wher white blood cells are able to seek out and target cancer that has spread throughout the body.
Amgen has initiated a comprehensive clinical development program for talimogene laherparepvec in metastatic melanoma, which includes combination studies with checkpoint inhibitors in patients with late-stage disease and monotherapy prior to surgery (neoadjuvant) in patients with resectable disease. Additionally, based on its mechanism of action, talimogene laherparepvec has the potential to be studied in a variety of solid tumor types.
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