Exploring the potential of immuno-oncology-based treatment for patients with non-small cell lung cancer

Immune evasion is recognized as a key strategy for cancer survival and progression. With increased understanding of immune escape mechanisms, the development of immunotherapies to restore anti-tumor immune responses has flourished. Immuno-oncology (I-O) agents targeting checkpoints in the immune regulation cascade currently form the mainstay of approaches of cancer immunotherapy. Since initial success in melanoma, evidence for the notable effects of the I-O modality has been expanding, with numerous clinical studies underway or completed in a variety of solid tumors, including non-small cell lung cancer. This review highlights the rationale and potential role of immunotherapy in non-small cell lung cancer management, with a focus on immune checkpoint inhibitors. We also discuss the potential for I-O-based combination therapy.     

放疗联合免疫检查点抑制剂治疗肿瘤的应用基础

免疫检查点抑制剂单药有效率不足30%。放疗可以促进机体的抗肿瘤免疫应答,通过协同效应或互补机制增进免疫检查点抑制剂的疗效。笔者就放疗联合免疫检查点治疗的应用基础及面临的问题进行深入阐述。     

Acquired and intrinsic resistance in cancer immunotherapy

A number of immunotherapies, in particular immune checkpoint targeting antibodies and adoptive T‐cell therapies, are starting to transform the treatment of advanced cancers. The likelihood to respond to these immunotherapies differs strongly across tumor types, with response rates for checkpoint targeting being the highest in advanced melanoma, renal cell cancer and non‐small cell lung cancer. However, also non‐responsiveness is observed, indicating the presence of intrinsic resistance or naturally acquired resistance. In addition, a subgroup of patients that do initially respond to immunotherapy will later recur, thereby also pointing towards a role of therapy‐induced acquired resistance.Here, we review our current understanding of both intrinsic and acquired resistance mechanisms in cancer immunotherapy, and discuss potential strategies to overcome them.     

癌症治疗的新兴免疫靶点及相关研究进展

免疫检查点是在机体自身免疫和抗肿瘤作用之间维持平衡的一系列重要因子，通过配体/受体相互作用可识别和启动多条免疫检查点通路，在维持自身免疫耐受和机体免疫稳态中起关键作用，但肿瘤细胞可以利用该途径逃避免疫监视。因此，免疫检查点阻断（immune checkpoint blockade，ICB）通路能够增强抗肿瘤免疫反应，免疫检查点抑制剂应运而生。随着免疫疗法在肿瘤治疗领域取得的重大突破，免疫检查点抑制剂受到越来越多的关注，许多新兴免疫靶点脱颖而出，极具应用前景和临床价值。本文就部分新兴的免疫治疗靶点的特性及相关研究进展进行综述。      

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.     

非小细胞肺癌肝转移免疫微环境及未来干预策略

肺癌是发病率和死亡率最高的恶性肿瘤，约有75%以上患者在诊断时已是晚期。肝转移是肺癌患者预后差的重要原因，约有20%的非小细胞肺癌（non-small cell lung cancer，NSCLC）患者会发生肝转移。近几年，免疫检查点抑制剂（immune checkpoint inhibitors，ICI）单药和联合治疗在晚期NSCLC患者取得了突破性进展。临床研究提示，肝转移患者亦可从ICI治疗中获益，但相较于整体人群，肝转移仍然是免疫治疗效果差的独立预后因素。因此，深入探索肝转移患者的免疫微环境，对提高这部分人群的生存预后具有重要意义。肿瘤微环境（tumor microenvironment，TME）表型是决定免疫治疗效果的关键因素，不同器官的TME具有特异性，可能是其免疫疗效差异的重要原因所在。肝脏中的多种细胞成分相互作用，构成了复杂的免疫微环境，共同参与肝脏的免疫调节。因此，聚焦于肝脏免疫微环境，并结合免疫治疗最新进展，对NSCLC肝转移的国内外研究进展进行总结，以期为确立肝转移患者治疗新策略提供线索。     

免疫检查点抑制剂在转移性结直肠癌患者治疗中的研究进展

免疫检查点抑制剂的出现,增加了许多实体肿瘤的治疗选择。尽管在黑素瘤和肺癌的治疗中效果良好,但大多数转移性结直肠癌患者无法从免疫治疗中获益。免疫检查点抑制剂在错配修复功能缺失转移性结直肠癌患者中明确有显著和持久的临床反应,即使在既往多线治疗失败的群体中也是如此。然而,这种临床获益仅限于小部分肿瘤患者,约占转移性结直肠癌的4%。事实上抗程序性死亡受体1(programmed cell death protein 1,PD-1)单抗对错配修复功能缺失转移性结直肠癌患者是无效的。迫切需要新颖的治疗策略使这些肿瘤具有免疫应答。破坏肿瘤的疗法(化学疗法,放射疗法和靶向疗法),从而释放肿瘤抗原,是免疫检查点抑制和其他疗法相结合的最直接的策略。这些标准疗法远没有像曾经担心的那样削弱免疫反应,反而还可以增强免疫应答。     

Advances in personalized cancer immunotherapy

There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the “Cancer-Immunity Cycle”) is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the “Cancer-Immunity Cycle”. Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.     

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy

Immune checkpoint inhibitors-based immunotherapy offers a new effective modality in the treatment of advanced malignancies. Considering the remarkable efficacy of immune checkpoint inhibitors in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors. However, only limited patients with certain cancers can benefit from monotherapy of immune checkpoint inhibitors. Interventional therapy for cancer can not only destroy the primary tumors, but also regulate the immune system through different mechanisms, which provides a potential possibility for the combination of immune checkpoint inhibitors and interventional modalities in cancer treatment. This article reviews the possible synergistic mechanisms of interventional therapy combined with immune checkpoint inhibitors and summarizes the research progress of the combined therapy in cancer treatment.     

Immunotherapy for lung cancer: Focusing on chimeric antigen receptor (CAR)-T cell therapy

Besides traditional treatment strategies, including surgery, radiotherapy, and chemotherapy for lung cancer as the leading cause of cancer incidence and death, immunotherapy has also emerged as a new treatment strategy. The goal of immunotherapy is to stimulate the immune system responses against cancer, using various approaches such as therapeutic vaccines, monoclonal antibodies, immune checkpoint inhibitors, and T-cell therapy. Chimeric antigen receptor (CAR)-T cells, one of the most popular cancer immunotherapy approaches in the last decade, are genetically engineered T-cells to redirect patients' immune responses to recognize and eliminate tumor-associated antigens (TAA)-expressing tumor cells. CAR-T cell therapy provides promising benefits in lung tumors. In this review, we summarize different immunotherapy approaches for lung cancer, the structure of CAR-T cells, currently undergoing CARs in clinical trials, and various TAAs are being investigated as potential targets in designing CAR-T cells for lung cancer.     

肺癌脑转移颅内放疗联合免疫检查点抑制剂的研究进展CSCD

近年来,免疫治疗不断发展,免疫检查点抑制剂联合颅内放疗治疗黑色素瘤脑转移的安全性和有效性已得到初步认可,但免疫检查点抑制剂联合颅内放疗治疗肺癌脑转移是否产生类似的协同作用尚未达成共识,免疫检查点抑制剂与颅内放疗联合的最佳时机、联合治疗的获益人群等也需进一步探讨。本文主要就肺癌脑转移患者颅内放疗联合免疫检查点抑制剂的研究进展进行综述。     

A review of immune checkpoint blockade in breast cancer

In the recent years characterized by the cancer immunotherapy revolution, attention has turned to how to potentially boost and/or generate an efficient anti-tumor immune response in breast cancer (BC). Clinical activity of immune checkpoint blockade (ICB) targeting PD-1 or PD-L1 in BC has been more evident in the triple negative subtype and in earlier lines of the treatment. Remarkably, some responders to single agent ICB have achieved durable responses with metastatic disease, possibly as a result of treatment-induced immunological memory. However, most BC are immunologically quiescent and current research efforts developing ICB combinations are attempting to convert “cold” into “hot” tumors by manipulating the tumor microenvironment, expanding anti-tumor T cells improving efficient antigen presentation, and suppressing pro-tumor inhibitory cells. The aim of this review is to summarize existing data on the efficacy of immune checkpoint blockers as single agents and combination strategies in all BC subtypes, highlighting the BC subgroups that benefit most from ICB.     

结直肠癌免疫检查点治疗的研究进展

目前免疫治疗正在非小细胞肺癌、黑色素瘤、膀胱癌等各个瘤种中如火如荼地开展,其治疗方法也多种多样,包括肿瘤疫苗治疗、过继性T细胞疗法、免疫检查点抑制剂治疗等,但目前结直肠癌免疫治疗主要集中于免疫检查点抑制剂（PD-1/PD-L1及CTLA-4抑制剂等）。自从PD-1/PD-L1抑制剂在dMMR/MSI-H晚期结直肠癌患者上表现出较好的疗效以来,免疫检查点抑制剂在结直肠癌领域获得了越来越多的关注,治疗方案也从晚期后线治疗逐渐移至一线治疗或新辅助治疗并获得了成功,本文就近年来国内外结直肠癌免疫检查点治疗的研究进展作一综述。     

原发性肝癌中PD-L1表达的调控机制

免疫疗法的应用是目前肿瘤研究的热点,尤其是免疫检查点抑制剂在晚期不可手术切除原发性肝癌的治疗中发挥了重要的作用。但不同患者免疫检查点抑制剂治疗疗效的差异较大,这引起了行业对PD-L1在肝脏肿瘤免疫逃逸中的调节机制的关注。PD-L1在肝癌中是由多个层次和多个信号通路调控的,包括表观遗传、转录调控、转录后调控和翻译后修饰。有研究发现PD-L1的高表达可能是影响原发性肝癌免疫治疗的主要因素,因此明确原发性肝癌中PD-L1的调控机制,可为原发性肝癌免疫治疗以及免疫联合治疗策略提供更多的依据。     

Immunotherapy: A New (and Old) Approach to Treatment of Soft Tissue and Bone Sarcomas

Soft tissue and bone sarcomas are a rare and heterogeneous form of cancer. With standard of care treatment options including surgery, radiation, and chemotherapy, the long‐term survival is still low for high‐risk soft tissue sarcoma patients. New treatment strategies are needed. Immunotherapy offers a new potential treatment paradigm with great promise. Immunotherapy of soft tissue sarcomas dates back to Dr. Coley's first use of toxins in the late 1800s. A variety of strategies of immunotherapy have been tried in soft tissue and bone sarcomas, including various vaccines and cytokines, with limited success. Results of these early clinical trials with vaccines and cytokines were disappointing, but there are reasons to be optimistic. Recent advances, particularly with the use of adoptive T‐cell therapy and immune checkpoint inhibitors, have led to a resurgence of this field for all cancer patients. Clinical trials utilizing adoptive T‐cell therapy and immune checkpoint inhibitors in soft tissue and bone sarcomas are under way. This paper reviews the current state of evidence for the use of immunotherapy, as well as current immunotherapy strategies (vaccines, adopative T‐cell therapy, and immune checkpoint blockade), in soft tissue and bone sarcomas. By understanding the tumor microenviroment of sarcomas and how it relates to their immunoresponsiveness, better immunotherapy clinical trials can be designed, hopefully with improved outcomes for soft tissue and bone sarcoma patients.

Implications for Practice

Immunotherapy is a promising treatment paradigm that is gaining acceptance for the management of several cancers, including melanoma, renal cell carcinoma, prostate cancer, and lung cancer. There is a long history of immunotherapy in the treatment of soft tissue and bone sarcomas, although with little success. It is important to understand past failures to develop future immunotherapy treatment strategies with an improved possibility of success. This article reviews the history of and current state of immunotherapy research in the treatment of soft tissue and bone sarcomas, with particular regard to vaccine trials, adoptive T‐cell therapy, and immune checkpoint blockade.     

Commensal microbiota contributes to predicting the response to immune checkpoint inhibitors in non-small-cell lung cancer patients

Immunotherapy against cancer, through immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 axis, is particularly successful in tumors by relieving the immune escape. However, interindividual responses to immunotherapy are often heterogeneous. Therefore, it is essential to screen out predictive tumor biomarkers. In this study, we analyzed the commensal microbiota in stool samples and paired sputum samples from 75 metastatic non-small-cell lung cancer (NSCLC) patients at baseline and during treatment with immune checkpoint inhibitors. Results showed distinct microbes’ signatures between the gut microbiota and paired respiratory microbiota. The alpha diversity between the gut and respiratory microbiota was uncorrelated, and only the gut microbiota alpha diversity was associated with anti-programmed cell death-1 response. Higher gut microbiota alpha diversity indicated better response and more prolonged progression-free survival. Comparison of bacterial communities between responders and nonresponders showed some favorable/unfavorable microbes enriched in responders/nonresponders, indicating that commensal microbiota had potential predictive value for the response to immune checkpoint inhibitors. Generally, some rare low abundance gut microbes and high abundance respiratory microbes lead to discrepancies in microbial composition between responders and nonresponders. A significant positive correlation was observed between the abundance of Streptococcus and CD8⁺ T cells. These results highlighted the intimate relationship between commensal microbiota and the response to immunotherapy in NSCLC patients. Gut microbiota and respiratory microbiota are promising biomarkers to screen suitable candidates who are likely to benefit from immune checkpoint inhibitor-based immunotherapy.     

Immunological effect of tyrosine kinase inhibitors on the tumor immune environment in non-small cell lung cancer

Acquired resistance to tyrosine kinase inhibitors (TKIs) limits the duration of antitumor effects and impairs the survival of patients with oncogene-driven non-small cell lung cancer (NSCLC). At present, little is known about the immunomodulatory ability of TKIs during the entire treatment period, including the drug-sensitive and drug-resistant periods. The present review aimed to comprehensively explore the dynamic changes in the tumor microenvironment (TME) during TKI treatment in NSCLC. Previous clinical and preclinical studies from medical and health databases related to NSCLC are reviewed. During the response period, cytotoxic immune cells accumulate in the TME and contribute to the formation of an inflammatory microenvironment. During the resistance period, the number of immunosuppressive cells increases, as does the expression of immune checkpoint proteins, which are critical mechanisms for tumor progression. The combination of targeted therapy and immunotherapy has been explored in multiple studies, and preliminary data showed controversial results. Extensive studies are needed to confirm the criteria of the selected patient subgroups and the toxicity profiles of EGFR TKIs and immune checkpoint inhibitors (ICIs). At present, the reagents targeting other immune cells, cytokines and related pathways remain underexplored compared with the revolutionary effect of ICIs in lung cancer. In the future, the precisely selected regimens for combination treatment should be further investigated in carefully designed xenograft models and clinical trials.     

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.Key words: Non-small cell lung cancer (NSCLC), Immunotherapy, Epidermal growth factor receptor (EGFR)-sensitive mutations     

肿瘤免疫治疗耐药机制与克服策略

免疫治疗已成为肿瘤治疗的主要手段之一,但耐药率高是限制其临床应用的主要因素。尽管大量研究已揭示了免疫治疗耐药发生的众多机制,但面对错综复杂的肿瘤免疫微环境,仍是冰山一角。如何判定不同肿瘤类型免疫治疗耐药的主要机制,并精准制定逆转免疫治疗耐药的高效策略是当前肿瘤免疫治疗领域亟需解决的关键问题。本文系统阐述免疫治疗耐药机制及应对策略的相关研究进展,以期为临床清晰地认识免疫治疗耐药发生过程,以及发掘新型逆转耐药策略提供新的思路。     

基于免疫检查点PD-1的肿瘤免疫耐药机制及耐药后再治疗的策略

免疫治疗被认为是继手术、放疗和化疗后的第四种肿瘤治疗方法。近年来随着对免疫治疗特别是免疫检查点抑制剂研究的深入,PD-1/PD-L1通路抑制剂被批准用于许多癌种的治疗,但由于肿瘤细胞通过多种耐药机制规避免疫应答,免疫检查点阻断存在整体应答率低、原发或继发性耐药等难题。本文阐述了肿瘤免疫耐药的机制,探讨了耐药后再治疗的策略,为提高免疫检查点抑制剂的应答率、降低免疫耐药发生的概率提供理论和临床依据。