2014年肿瘤免疫疗法进展回顾

哥伦比亚大学Isabel Cunningham博士

梅奥诊所Axel Grothey 博士

孟菲斯西部诊所博士

毫无异议，2014年肿瘤学领域的热点是肿瘤免疫疗法，作为一个新兴的肿瘤疾病治疗方法，肿瘤免疫疗法是手术、化疗、放射和生物疗法的有力补充。大量基础科学和转化科学的信息都明确了这一颇具历史性的概念，即宿主免疫系统被在与肿瘤细胞的战争中被暂时封存，而肿瘤有多种躲避免疫系统追杀的方法。免疫耐受的主要机制已被阐明，即在一个复杂系统中含有多种不同进程，现已被证明，该系统可激发癌症的免疫清除。

免疫疗法对我们来讲并不陌生，比如干扰素α和白介素2已被应用了数十年，19世纪中期科利毒素可导致疾病症状的显著缓解。然而，这些活性广泛的分子具有多重效性，可激活大量的免疫反应，导致多重严重毒性，但只有为数不多的肿瘤得到根除。随着人们对细胞毒性T细胞作用的认识逐渐深入，新的肿瘤免疫治疗药物（如伊匹单抗）得以被发明。CTLA4作为免疫检查点可抑制肿瘤杀伤性T细胞的响应，而伊匹单抗则可以抑制CTLA4。基于在黑素瘤这一疑难肿瘤中取得的鼓舞人心的数据，伊匹单抗在2011年被批准用于治疗黑素瘤。2014年一项晚期黑素瘤患者的长期疗效报告表明，有相当部分（约是20%）既往服用伊匹单抗患者的肿瘤得到长期根除。更为显著的是，这些患者只接受了几个月的治疗，但患者的免疫反应却维持了数年，甚至在治疗后十年依旧得到维持。

更鼓舞人心的数据来源于作用于PD1的单克隆抗体。PD1是由T细胞表达的程序性死亡受体，当其激活时，可促使T细胞反应的进一步发展。配体PD-L1 和PD-L2可阻断PD1的激活，这两种配体都存在于肿瘤细胞和免疫细胞。这一配体-受体间的相互作用是种保护性事件，可阻止肿瘤对机体的破坏。PD1 抗体 pembrolizumab 和nivolumab则可激活 PD1，从而导致肿瘤细胞死亡。基于大量治疗黑素瘤患者的显著疗效，这两种药物都于今年被批准。和达卡巴嗪相比，在一线治疗黑素瘤过程中，Nivolumab显著提高了药物反应率和患者生存率，其1年生存率竟高达72.9%，这么高的生存率在这种致死性疾病中还是首次出现。

对于抗PD1单抗以及一般的免疫疗法来说，最引人的是免疫治疗机制并不仅仅适用于某种肿瘤或某种组织。因此，在许多种肿瘤中我们都看到了好的报告结果。迄今为止，nivolumab治疗非鳞状细胞非小细胞肺癌可以实现15% 的应答率，中位总生存期是8.2个月。在2014年年底召开的ASH2014大会中，有篇关于抗PD1 单抗治疗复发或难治性霍奇金淋巴瘤的报告，其结果令人惊讶，对于既往接受骨髓移植、化疗和抗体偶联药物都失败的患者，抗PD1 单抗治疗实现了87% 这一惊人的应答率。非霍奇金淋巴瘤也表现出对抗PD1 单抗的高度敏感性，标明该药物并不仅仅是对实体瘤有效。其他研究报告也显示抗PD1 单抗在治疗膀胱癌、非鳞状细胞非小细胞肺癌甚至三阴性乳腺癌时也有非常好的应答率。

关于免疫治疗的应答和耐药性的预测因素还需要更深入的研究，不过迄今为止这种新型疗法的试验结果在临床上具有颠覆性的意义。一些预后较差的患者正是这种新型治疗方法的受益人群。不同免疫治疗药物联合使用正在大力研发之中，有望为更多肿瘤患者提供突破性的治疗选择。

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Indisputably, the oncology story of the year was immunotherapy taking its place as a new pillar of treatment, complementing surgery, chemotherapy, radiotherapy, and biological therapy. An explosion of basic and translational science has confirmed the time-honored concepts that the host immune system is locked in an ongoing tug-of-war with tumors, which have multiple methods of evading immune destruction. The major mechanisms behind immunotolerance have been elucidated, consisting of a number of different processes in a complex system that, now identified, can be targeted to stimulate immune clearance of cancer.

Immunotherapy is not new: Interferon alpha and interleukin 2 have been in use for decades, and Coley’s toxin led to remarkable remissions in the nineteenth century. However, these broadly active molecules with pleotropic effects trigger vast swaths of immune reactions, leading to severe and multiple toxicities and only a small percentage of selected tumors eradicated. More recently, greater appreciation of the role of cytotoxic T cells has led to the development of other drugs like ipilimumab, which inhibits CTLA4, an immune checkpoint–blocking molecule preventing priming of a tumoricidal T-cell response. Ipilimumab was approved in 2011 for melanoma based on encouraging response data in this difficult-to-treat tumor. This year, reports of long-term results for patients with advanced melanoma previously treated with ipilimumab revealed that there is a significant number of patients—approximately 20% of trial participants—who enjoy long-term disease-free survival. What is more remarkable is that these patients received only a few months of therapy, yet the immune response is maintained for years, even a decade after treatment.

Even more impressive were the results of monoclonal antibodies directed against PD1, the programmed death receptor expressed by T cells, which, when activated, cause the T-cell response to go forward. PD1 activation can be blocked by the ligands PD-L1 and PD-L2, which are found on tumor cells and inflammatory cells. This ligand–receptor interaction prevents the destruction of the cancer and is a protective event. The PD1 antibodies pembrolizumab and nivolumab activate PD1 and cause tumor cell death. Both drugs were approved this year based on remarkable responses in previously heavily treated melanoma patients. Nivolumab compared with dacarbazine in the front-line treatment of metastatic melanoma markedly improved response rates and survival, with 1-year survival of 72.9%, a figure previously unheard of in this lethal disease.

What is most interesting about PD1 antibodies specifically, and immunotherapy in general, is that the mechanism is not limited to one tumor or one tissue type. Therefore, good results have been demonstrated in many different types of tumors. To date, heavily pretreated patients with squamous cell non–small cell lung cancer showed a 15% response rate and a median overall survival of 8.2 months to nivolumab. A remarkable result presented at the recent ASH 2014 meeting was obtained with PD1 antibody in relapsed or refractory Hodgkin’s lymphoma, with an astonishing 87% response rate in patients who had failed transplant, chemotherapy, and antibody drug conjugates. Non-Hodgkin’s lymphoma also displays high sensitivity to PD1, showing that the response is not limited to solid tumors. Other studies have shown intriguing response rates in bladder cancer, non-squamous non–small cell lung cancer, and even triple-negative breast cancer.

While much needs to be learned about factors predicting response and resistance to immunotherapy, the results to date are paradigm-shifting. Patients with diseases with terrible prognoses are now the beneficiaries of a new therapeutic approach that creates clinically meaningful improvement. Combination therapy trials of multiple immunotherapy agents are progressing and hold the promise of even greater benefit for patients across a large spectrum of tumor types.

Copyright © 2015 Elsevier Inc. All rights reserved.