Cytotoxic T-Lymphocyte–Associated Antigen-4

Salama, April K.S.; Hodi, F. Stephen

doi:10.1158/1078-0432.ccr-07-0813

Cited by 61 publications

(53 citation statements)

References 42 publications

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“…In a randomized phase III study, however, tremelimumab alone was not found to be superior to chemotherapy in advanced stage melanoma (11). It is generally accepted that combination therapy will be needed to achieve maximum clinical benefit with anti-CTLA4 mAb (2). Hormonal therapy, particularly for patients with breast cancer, may be well suited for combination with immune therapy, including combination with anti-CTLA4 mAb.…”

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confidence: 99%

Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Vonderheide

LoRusso

Khalil

et al. 2010

Clinical Cancer Research

263

163

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Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.Results: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for ≥12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells.Conclusions: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade. Clin Cancer Res; 16(13); 3485-94. ©2010 AACR.

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confidence: 99%

Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Vonderheide

LoRusso

Khalil

et al. 2010

Clinical Cancer Research

263

163

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“…They are expressed on activated T cells and interact with molecules of the B7 family that are found on APCs, but are also expressed by many tumours (reviewed in Zou and Chen, 2008). CTLA-4 is upregulated during T-cell activation and causes competitive inhibition of B7-CD28 induced T-cell activation, modulates intracellular signalling pathways and leads to decreased IL-2 production, impaired T-cell receptor signalling and cell-cycle arrest, particularly in the early post-activation phase (Hodi, 2007). Anti-CTLA-4 treatment has been trialled in melanoma and other cancers with some evidence of clinical efficacy (Wolchok and Saenger, 2008;Yuan et al, 2008).…”

Section: Activated T Cells May Be Switched Off By Some Tumoursmentioning

confidence: 99%

Harnessing the immune response to treat cancer

et al. 2010

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It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.

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“…36 One way to inhibit immunological evasion by tumour cells is through blockade of the immune checkpoint molecule cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), thus preventing the normal attenuation of antitumour T-cell responses. 37 In murine prostate cancer models, CTLA-4 inhibition has been shown to potentiate T-cell effects and induce tumour rejection.…”

Section: Ipilimumab -Immune Checkpoint Blockadementioning

confidence: 99%

Management of Metastatic Castration-resistant Prostate Cancer

Antonarakis

2011

European Oncology &Amp; Haematology

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The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forwards in the last two years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel and abiraterone acetate) and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive Phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimise delivery of care and long-term outcomes in men with advanced CRPC. KeywordsCastration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumabDisclosure: Emmanuel S Antonarakis has served as an advisor/consultant for Sanofi-Aventis. While much of the recent focus on prostate cancer relates to the over-diagnosis and over-treatment of this disease, each year almost 100,000 men in Europe and more than 30,000 men in the US still die of advanced prostate cancer, making it the second most common cause of cancer-related deaths.1 Androgen deprivation therapy is the most effective systemic treatment for recurrent prostate cancer; however, the vast majority of these patients will eventually develop resistance to hormonal approaches (see Table 2).

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Cytotoxic T-Lymphocyte–Associated Antigen-4

Cited by 61 publications

References 42 publications

Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Harnessing the immune response to treat cancer

Management of Metastatic Castration-resistant Prostate Cancer

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