Neoadjuvant checkpoint blockade for cancer immunotherapy.
Neoadjuvant checkpoint blockade for cancer immunotherapy.
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DOI：
10.1126/science.aax0182
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发表时间：
2020-01-31
期刊：
影响因子：
--
通讯作者：
Pardoll DM
中科院分区：
文献类型：
--
作者：
Topalian SL;Taube JM;Pardoll DM
针对程序性细胞死亡 1 (PD-1):程序性死亡配体 1 (PD-L1) 免疫检查点通路的癌症免疫疗法开创了现代肿瘤学时代。阻断 PD-1 或 PD-L1 的药物可促进内源性抗肿瘤免疫，并且由于其广泛的活性谱，已被视为癌症治疗的共同点。然而，许多晚期肿瘤表现出新的或获得性治疗耐药性，并且正在进行的研究工作集中于改善患者的治疗结果。使用抗 PD-1 或抗 PD-L1 治疗癌症早期阶段被认为是这样的解决方案之一。本综述重点关注 PD-1 通路阻断时代新辅助（术前）免疫疗法的发展，强调了对生物学机制、临床试验设计和病理反应评估的特殊考虑。新辅助免疫治疗研究的结果可能揭示新治疗组合中可共同靶向的途径、机制和分子，以提高抗 PD-1 和抗 PD-L1 疗效。针对程序性死亡 1 (PD-1) 与其配体 PD-L1 和 PD-L2 相互作用的免疫疗法开创了现代肿瘤学时代。 PD-1 通路是肿瘤微环境 (TME) 中局部免疫抑制的关键介质，但也可以调节次级淋巴组织中针对肿瘤抗原的 T 细胞启动。在其他治疗难以治愈的无法手术的晚期癌症中，阻断淋巴细胞上的 PD-1 受体或肿瘤和/或免疫细胞上的 PD-L1 配体 [抗 PD-(L)1] 的药物可以介导肿瘤消退。尽管抗 PD-(L)1 治疗广泛有效，并被视为癌症治疗的“共同点”，但许多肿瘤表现出新的或获得性耐药性。当肿瘤有可能“可切除治愈”时，在新辅助（术前）环境中使用抗 PD-(L)1 疗法提供了一种潜在的解决方案。这种方法在乳腺癌和肺癌的术前化疗中有丰富的肿瘤学先例，将病理反应与改善的长期临床结果联系起来。我们的综述重点关注 PD-1 通路阻断时代新辅助免疫疗法的发展，强调了对免疫机制、临床开发和病理反应评估的特殊考虑。 PD-1 通路对 T 细胞启动、效应器功能和耗竭的免疫学作用表明，新辅助免疫治疗与化疗之间存在不同的机制。新辅助化疗可以在术前“缩小”肿瘤，而新辅助免疫疗法的目的是增强针对肿瘤抗原的全身免疫力，消除微转移肿瘤沉积物，否则可能成为术后复发的根源。此外，与仅针对切除后微转移性疾病的辅助治疗相反，在原发肿瘤存在时进行新辅助 PD-(L)1 阻断，利用原发肿瘤中存在的较高水平的内源性肿瘤抗原来增强 T 细胞启动。我们讨论了支持两种不同但不相互排斥的模型的科学证据，通过这些模型，新辅助 PD-(L)1 阻断可以促进全身抗肿瘤免疫。首先，抗 PD-(L)1 使已经驻留在 TME 中的肿瘤特异性细胞毒性 T 细胞恢复活力，导致其激活、增殖并转运至微转移沉积物。其次，肿瘤引流淋巴结 (TDLN) 似乎是抗 PD-(L) 1 活性的焦点，其中树突状细胞向 T 细胞呈递肿瘤抗原得到增强；然后这些肿瘤特异性 T 细胞进入血流并迁移到肿瘤部位。微转移的破坏是新辅助 PD-1 阻断应提高可手术患者的无复发生存率和总生存率的核心，否则这些患者仅在手术后就会复发。评估跨肿瘤类型的新辅助免疫疗法有充分的理由。术前给药为深入的机制和生物标志物研究提供了丰富的治疗组织。我们讨论了最近的新辅助抗 PD-(L)1 临床试验的数据，这些数据表明病理性肿瘤消退可以超过放射学消退，并证明了不同细胞亚群参与这一过程。目前，已有超过 100 项新辅助抗 PD-(L)1 阻断剂作为单一疗法或联合疗法的临床试验正在进行或计划中。将抗 PD-1 与抗 CTLA-4（细胞毒性 T 淋巴细胞相关蛋白 4）相结合，或与三阴性乳腺癌和肺癌的多药化疗相结合，已经取得了令人鼓舞的显着病理缓解率，但需要更长时间的随访。下一代试验可能有助于根据病理反应的程度对患者进行术后观察或干预，类似于乳腺癌非免疫新辅助治疗的先例。新辅助免疫治疗后切除的肿瘤为深入的科学探究提供了足够的材料，这些材料有望进一步阐明反应和耐药机制，揭示可在新治疗组合中共同靶向的途径和分子，以提高抗 PD-(L)1 疗法的疗效。新辅助 PD-(L)1 阻断后增强全身抗肿瘤 T 细胞免疫的两种潜在机制。 PD-(L)1 阻断可能导致肿瘤微环境中肿瘤特异性 T 细胞克隆的“原位”扩增。这种扩张和激活很大程度上是由肿瘤中表达 PD-L1 和 PD-L2 的树突状细胞驱动的。肿瘤特异性肿瘤浸润淋巴细胞可能代表幼稚 T 细胞或在 PD-1 通路阻断之前已经“引发”肿瘤抗原的 T 细胞。此外，源自肿瘤的含有肿瘤抗原的树突状细胞拾取肿瘤抗原并运输到肿瘤引流淋巴结，在那里它们无效地或以耐受性方式将抗原呈递给肿瘤特异性T细胞。 PD-(L)1 阻断可以在此时发挥作用，增强肿瘤特异性 T 细胞的生产性刺激或部分逆转耐受诱导。活化的 T 细胞通过传出淋巴管进入循环系统，然后进入组织。
Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti–PD-1 or anti–PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti–PD-1 and anti–PD-L1 efficacy. Immunotherapies that target the interaction of programmed death 1 (PD-1) with its ligands, PD-L1 and PD-L2, have ushered in the modern oncology era. The PD-1 pathway is a key mediator of local immunosuppression in the tumor microenvironment (TME) but can also modulate T cell priming against tumor antigens in secondary lymphoid tissues. In advanced inoperable cancers refractory to other treatments, drugs that block the PD-1 receptor on lymphocytes or the PD-L1 ligand on tumor and/or immune cells [anti–PD-(L)1] can mediate tumor regression. Although anti–PD-(L)1 treatment is broadly active and is regarded as a “common denominator” for cancer therapy, many tumors demonstrate de novo or acquired resistance. Using anti–PD-(L)1 therapies in the neoadjuvant (presurgical) setting, when the tumor is potentially “resectable for cure,” presents a potential solution. There is ample oncologic precedent for this approach with presurgical chemotherapies in breast and lung cancer, associating pathologic response with improved long-term clinical outcomes. Our Review focuses on the development of neoadjuvant immunotherapies in the era of PD-1 pathway blockade, highlighting particular considerations for immunological mechanisms, clinical development, and pathologic response assessments. The immunologic effects of the PD-1 pathway on T cell priming, effector function, and exhaustion suggest distinct mechanisms underlying neoadjuvant immunotherapy versus chemotherapy. Whereas neoadjuvant chemotherapy can “debulk” tumors preoperatively, neoadjuvant immunotherapy aims to enhance systemic immunity against tumor antigens, eliminating micrometastatic tumor deposits that would otherwise be the source of postsurgical relapse. Furthermore, neoadjuvant PD-(L)1 blockade while the primary tumor is in place, as opposed to adjuvant therapy directed only against micrometastatic disease after resection, leverages higher levels of endogenous tumor antigen present in the primary tumor to enhance T cell priming. We discuss scientific evidence that supports two different but not mutually exclusive models by which neoadjuvant PD-(L)1 blockade may promote systemic antitumor immunity. First, anti–PD-(L)1 rejuvenates tumor-specific cytotoxic T cells that already reside in the TME, causing their activation, proliferation, and trafficking to micrometastatic deposits. Second, tumor-draining lymph nodes (TDLN) appear to be the focal point for anti–PD-(L) 1 activity, where dendritic cell presentation of tumor antigens to T cells is enhanced; these tumor-specific T cells then enter the bloodstream and migrate to tumor sites. The destruction of micrometastases is central to the notion that neoadjuvant PD-1 blockade should result in enhanced relapse-free and overall survival in operable patients who would otherwise relapse after surgery alone. There is a strong rationale for evaluating neoadjuvant immunotherapy across tumor types. Presurgical drug administration provides abundant on-therapy tissue for in-depth mechanistic and biomarker studies. We discuss data from recent clinical trials of neoadjuvant anti–PD-(L)1 that show that pathologic tumor regression can outpace radiographic regression and demonstrate the involvement of diverse cellular subsets in this process. At present, more than 100 clinical trials of neoadjuvant anti–PD-(L)1 blockade, as monotherapy or combination therapy, are ongoing or planned. Combining anti–PD-1 with anti–CTLA-4 (cytotoxic T lymphocyte–associated protein 4), or with multidrug chemotherapies for triple-negative breast and lung cancer, has yielded substantial pathologic response rates that are encouraging but require longer follow-up. Next-generation trials may help assign patients to postsurgical observation or intervention depending on the degree of pathologic response, similar to the precedent established with non-immunologic neoadjuvant therapies in breast cancer. Tumors resected after neoadjuvant immunotherapy provide sufficient materials for in-depth scientific interrogations that are expected to further illuminate mechanisms of response and resistance, revealing pathways and molecules that can be cotargeted in new treatment combinations to increase the efficacy of anti–PD-(L)1 therapy. Two potential mechanisms for the enhancement of systemic antitumor T cell immunity after neoadjuvant PD-(L)1 blockade. PD-(L)1 blockade could result in the “in situ” expansion of tumor-specific T cell clones already within the tumor microenvironment. This expansion and activation is largely driven by PD-L1– and PD-L2–expressing dendritic cells in the tumor. Tumor-specific tumor-infiltrating lymphocytes may represent naïve T cells or T cells that have already been “primed” to tumor antigen before PD-1 pathway blockade. In addition, tumor antigen–containing dendritic cells that originate in the tumor pick up tumor antigens and traffic to the tumor-draining lymph nodes, where they present antigens either ineffectively or in a tolerogenic fashion to tumor-specific T cells. PD-(L)1 blockade could act at this point, enhancing productive stimulation of tumor-specific T cells or partially reversing tolerance induction. Activated T cells enter the circulation by way of efferent lymphatics and then egress into tissues.
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影响因子：
32.4
作者：
Dong, HD;Zhu, GF;Chen, LP
通讯作者：
Chen, LP
DOI：
10.1016/s1470-2045(13)70334-6
发表时间：
2014-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Hellmann MD;Chaft JE;William WN Jr;Rusch V;Pisters KM;Kalhor N;Pataer A;Travis WD;Swisher SG;Kris MG;University of Texas MD Anderson Lung Cancer Collaborative Group
通讯作者：
University of Texas MD Anderson Lung Cancer Collaborative Group
影响因子：
3.7
作者：
Keung EZ;Ukponmwan EU;Cogdill AP;Wargo JA
通讯作者：
Wargo JA
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
8
作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry