The aim of T-cell-based immune therapy for cancer has been to generate durable clinical benefit for patients. Following a generation of therapies that largely showed minimal activity, substantial ...toxicity, and no biomarkers to identify which patients benefit from treatment, early studies are showing signs that programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitors are highly active. Preclinical and early data from clinical studies suggest that targeting this pathway can induce durable clinical responses in patients in a variety of tumor types, including lung and colon cancer. Furthermore, correlations with tumor PD-L1 expression may enable selection of patients most likely to benefit from treatment. The emerging data not only offer the hope of better cancer therapy but also provide evidence that changes our understanding of how the host immune system interacts with human cancer.
Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma ...have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.
In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.
Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval CI, 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.
Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).
Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies ...targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy.
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response ...to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.
Cancer immunotherapy using immune-checkpoint inhibitors has emerged as an effective treatment option for a variety of advanced cancers in the past decade. Because of the distinct mechanisms of ...immunotherapy that activate the host immunity to treat cancers, unconventional immune-related phenomena are encountered in terms of tumor response and progression, as well as drug toxicity. Imaging plays an important role in objectively characterizing immune-related tumor responses and progression and in detecting and monitoring immune-related adverse events. Moreover, emerging data suggest a promise for molecular imaging that can visualize the specific target molecules involved in immune-checkpoint pathways. In this article, the background and current status of cancer immunotherapy are summarized, and the current methods for imaging evaluations of immune-related responses and toxicities are reviewed along with their limitations and pitfalls. Emerging approaches with molecular imaging are also discussed as a future direction to address unmet needs.
The treatment for metastatic melanoma has evolved significantly in the past few years. Ipilimumab, an immunotherapy, is now in mainstream oncology practice given that it has shown improved overall ...survival in randomized clinical trials. Other immune modulating agents, such as programmed death receptor‐1 and programmed death receptor ligand‐1 antibodies, are showing promise in early clinical trials. This manuscript will review ipilimumab and its most common side effects. Immune‐related adverse events (irAEs) are important to recognize early, and their presentation, timing of onset, and general recommendations for workup and management will be reviewed. Assembling a multidisciplinary team, as well as thorough education of the patient, is recommended to optimize patient care.
摘要
过去的几年内，转移性黑色素瘤的治疗已出现的重大的进步。作为一种免疫疗法， ipilimumab已在随机临床试验中证实能够改善总生存，因而是目前肿瘤临床实践的主流。其他免疫调节剂，如程序化死亡受体1以及程序化死亡受体配体1抗体，也在早期临床试验中获得很有希望的结果。本文将回顾ipilimumab及其最常见的副反应。免疫相关不良事件（irAE）的早期识别是非常重要的，本文还将讨论irAE的临床表现、发作时间以及对检查和治疗管理的一般性建议。我们推荐建立多学科团队，同时对患者进行全面教育，这样才能获得最优化的患者管理。The Oncologist 2013;18:733‐743
Ipilimumab is now in mainstream oncology practice and it has shown improved overall survival in randomized clinical trials. Other immune modulating agents are showing promise in early clinical trials. This review discusses ipilimumab, its side effects, and their management.
The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T ...cell effector function following initial activation by costimulatory signals. Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and antitumor responses in patients with advanced metastatic melanoma. Responses observed with such immune checkpoint therapy can follow a different pattern from that seen with cytotoxic chemotherapy or targeted therapy and may continue after therapy is discontinued. In addition, the toxicities that are associated with anti-CTLA-4 therapy may differ from those of conventional therapies and consist of inflammatory events in parts of the body that do not contain cancerous cells. Early recognition of these inflammatory events and intervention is important, and the identification of predictive biomarkers continues to be an unfulfilled need in the field of immunotherapy. Combinatorial approaches with targeted therapies, radiation therapy, chemotherapy, or other immune checkpoint agonists/antagonists have the potential to increase the efficacy of CTLA-4 blockade.
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