免疫检查点抑制剂治疗晚期结直肠癌的疗效观察

目的:观察及评价免疫治疗在转移性结直肠癌中的疗效及不良反应。方法:对23例接受免疫联合化疗治疗的微卫星高度不稳定（MSI-H）的转移性结直肠癌患者进行临床观察。患者每3周接受一次帕博利珠单抗200 mg,持续1年,直至进展、不可接受的毒性或停药,联合化疗方案为FOLFIRI或FOLFOX4。影像学评估每9周进行一次,为期12个月。主要观察终点是客观缓解率,次要终点为无进展生存期（progression-free survival,PFS）、总生存期（overall survival,OS）、安全性和耐受性。结果:本组部分缓解5例,病情稳定13例,疾病进展5例,客观缓解率21.7%,疾病控制率78.3%。Ⅰ/Ⅱ级不良反应事件有7例疲劳,4例ALT升高,3例皮疹,2例内分泌异常,腹泻和肺炎各1例。Ⅲ级不良反应事件仅有内分泌异常1例,无Ⅳ级不良反应事件。结论:免疫检查点抑制剂治疗MSI-H转移性结直肠癌患者有一定的疗效,且安全性良好。     

免疫检查点抑制剂在前列腺癌治疗中的研究进展北大核心

肿瘤诱导的免疫抑制状态在包括前列腺癌(PC)在内的癌症的发病机制中起着至关重要的作用。细胞毒T淋巴细胞相关抗原4(CTLA-4)和程序性死亡受体-1(PD-1)及其配体PD-L1是近年来研究比较透彻的免疫检查点分子。通过阻断免疫检查点(主要针对CTLA-4和PD-1/PD-L1通路)来增强细胞介导的抗肿瘤免疫成为研究热点。本文主要综述了免疫检查点抑制剂及其用于晚期前列腺癌的理论基础和前列腺癌治疗中的进展。     

Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors

Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4⁺ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.     

免疫检查点抑制剂在膀胱癌治疗中的研究现状与展望

近年来,免疫治疗的迅速发展改变了肿瘤治疗的格局,成为继手术和放化疗之后新的抗肿瘤手段。免疫检查点抑制剂作为目前临床研究最广泛、效果最佳的免疫治疗方法,在膀胱癌的治疗中表现出了良好的抗肿瘤活性和安全性。随着临床试验的不断开展,免疫检查点抑制剂在晚期或转移性膀胱癌的二线治疗乃至一线治疗、肌层浸润性膀胱癌的新辅助和辅助治疗、高危非肌层浸润性膀胱的治疗和保留膀胱的综合治疗中都表现出了极大的治疗潜力。本文重点对免疫检查点抑制剂在各期膀胱癌中的研究进展作综述。     

Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.     

肿瘤免疫检查点抑制剂耐药机制的研究进展

免疫疗法改变了癌症治疗的格局,免疫检查点抑制剂(immune checkpoint inhibitors,ICPis)的引入在提高晚期转移性癌症患者的总体生存率方面取得了巨大的成功.然而,只有较小比例的患者最初对这些抑制剂有反应,越来越多的临床证据表明,相当大比例的初始应答者最终在几个月或几年后因致命的抗药性而复发.因...     

放疗联合免疫检查点抑制剂治疗非小细胞肺癌的研究进展

肺癌是世界范围发病率和死亡率最高的恶性肿瘤,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占85％,其中30％～40％的患者确诊时为局部晚期,40％的患者为转移性肺癌.肺癌的治疗需要采用综合治疗手段,放疗作为传统治疗手段之一,在各期肺癌的治疗中发挥着重要作用.免疫检查点抑制剂(imm...     

How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation

Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.     

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。     

免疫检查点抑制剂相关结肠炎的诊疗进展

针对抗细胞毒T淋巴细胞相关抗原-4(cytotoxic T-lymphocyte antigen 4,CTLA-4)及程序性死亡受体-1及其配体(pro-grammed cell death 1/programmed cell death-ligand 1,PD-1/PD-L1)的免疫检查点抑制剂(immune che...     

The regulatory approvals of immune checkpoint inhibitors in China and the United States: A cross-national comparison study

Immune checkpoint inhibitors (ICIs) are currently one of the most popular treatment methods for cancers. Several ICIs have been approved in China and the United States. We created a database of approved ICIs by extracting the information of interest from the drug labels and reviewing documents disclosed on the official websites of the US Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) and compared the difference between the marketed ICIs in China and the United States regarding the number of indications, tumor types, review time, treatment setting, and so forth. Until June 30, 2022, 9 and 15 ICIs had been approved for 86 and 58 indications in the United States and China, involving 20 and 14 types of tumors, respectively. The correlation between indications and disease incidence was higher in China (r = 0.64) than in the United States (r = 0.45). About half of the indications were approved as first-line therapies in combination with chemotherapy, target therapy, or immunotherapy. Over 30% of indications were approved under accelerated or conditional approval in the two countries. A shorter regulatory review time was required by the FDA (median:181 days) compared to the NMPA (median: 279 days) for the new indication approval. Five ICIs marketed in China were approved by the FDA before the NMPA, with the median launch delay for the same indication of 344 days in China. A differentiated clinical development program that focuses on meeting unmet needs may bring new success for subsequent ICI products.     

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.     

免疫检查点抑制剂的联合治疗在胰腺癌中的研究进展

胰腺癌的恶性程度极高,发现时通常已至晚期,中位生存时间极短,严重威胁人类生命健康.并且与其他癌种相比,近些年取得的治疗进展也十分有限.免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)作为近几年的新兴药物已在多个肿瘤中获得了令人振奋的治疗效果,但是在胰腺癌中却遭遇了滑铁卢.胰腺癌对I...     

Current status and future perspectives of immune checkpoint inhibitors in extensive-stage small cell lung cancer

Small-cell lung cancer (SCLC) is a type of neuroendocrine neoplasms with high aggressiveness and poor prognosis. Chemotherapy has been the standard first-line therapy for SCLC over the past several decades. In recent years, results of randomized phase III CASPIAN and IMpower-133 trials indicated that the combination of immune checkpoint inhibitors (ICIs) with platinum-etoposide chemotherapy improved the overall survival (OS) of patients with extensive stage small-cell lung cancer (ES-SCLC), which has transformed the treatment model for ES-SCLC. ICIs combined with chemotherapy has become the new first-line standard treatment of ES-SCLC with the latest research results from CASPIAN and ASTRUM-005 studies. This review summarizes the recent progress of ICIs in the treatment of ES-SCLC and expounds the mode and efficacy of immunotherapy for ES-SCLC. Future research focused on exploring basic SCLC biology and identifying novel predictive biomarkers in response to ICIs in ES-SCLC is essential. Double-ICIs treatment strategies, bispecific antibodies, and ICIs combined with other therapies, such as chemotherapy, radiotherapy, and targeted therapy, represent a new modality and show great promise for the treatment of ES-SCLC, which should achieve greater therapeutic effects through multiple synergistic mechanisms.     

Immune checkpoint inhibitors in hepatocellular carcinoma: A review of current clinical trials

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.     

Importance of immunopharmacogenomics in cancer treatment: Patient selection and monitoring for immune checkpoint antibodies

In the last 5 years, immune checkpoint antibodies have become established as anticancer agents for various types of cancer. These antibody drugs, namely cytotoxic T‐lymphocyte‐associated antigen, programmed death‐1, and programmed death ligand‐1 antibodies, have revealed relatively high response rates, the ability to induce durable responses, and clinical efficacy in malignancies not previously thought to be susceptible to immune‐based strategies. However, because of its unique mechanisms of activating the host immune system against cancer as well as expensive cost, immune checkpoint blockade faces novel challenges in selecting appropriate patient populations, monitoring clinical responses, and predicting immune adverse events. The development of objective criteria for selecting patient populations that are likely to have benefit from these therapies has been vigorously investigated but still remains unclear. In this review, we describe immune checkpoint inhibition‐specific challenges with patient selection and monitoring, and focus on approaches to remedy these challenges. We also discuss applications of the emerging field of immunopharmacogenomics for guiding selection and monitoring for anti‐immune checkpoint treatment.