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Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8+ T cells.

ABSTRACT: Numerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy. Furthermore, dual CTLA-4/PD-1 checkpoint blockade recently received FDA-approval for patients with metastatic melanoma, becoming the first combination immunotherapy to garner this designation in a rapidly evolving field. Despite this progress, the majority of patients do not respond to treatment, underscoring the critical need for more effective therapies. We have been investigating the mechanisms by which combination immunotherapy with an OX40 agonist plus CTLA-4 checkpoint blockade augments effector T cell responses to elicit anti-tumor immunity. Surprisingly, this approach failed to eradicate well-established tumors, in part due to the induction of anergy in cytotoxic CD8+ T cells. Further work revealed that anergic CD8+ T cells could be rescued by combining a dendritic cell-targeted vaccine with combination immunotherapy. Taken together, these data suggest that novel combinatorial immunotherapeutic strategies incorporating a vaccination strategy may be needed to generate effective anti-tumor responses in the majority of patients with metastatic disease.

SUBMITTER: Redmond WL

PROVIDER: S-EPMC5084978 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8<sup>+</sup> T cells.

Redmond William L WL Linch Stefanie N SN

Human vaccines & immunotherapeutics 20160726 10

Numerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy. Furthermore, dual CTLA-4/PD-1 checkpoint blockade recently received FDA-approval for patients with metastatic melanoma, becoming the first combination immunotherapy to garner this designation in a rapidly evolving field. Despite this progress, the majority of patients do not respond to treatment, underscoring the critical nee ...[more]

PMID: 27459422

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Project description:Liver cancer, the most common form of which is hepatocellular carcinoma (HCC), is one of the most deadly cancers worldwide. As of 2008, in men, HCC was the fifth most common cancer (approximately 450,000 new cases per year) and the second most frequent cause of death from cancer (around 416,000 deaths per year), whereas in women, it was the seventh most frequently diagnosed cancer (150,000 new cases per year) and the sixth most frequent cause of cancer deaths (140,000 deaths per year) [1]. Overall, HCC is the third leading cause of death from cancer globally [2, 3]. Worldwide, the incidence of HCC in males is more than twice that in females. The etiology of HCC is diverse; however, approximately 80% of HCCs occur secondary to chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) [4]. The geographic distribution of HCC is such that the high-incidence regions of Eastern Asia and sub-Saharan Africa bear a disproportionate HCC burden, amounting to more than 80% of the global burden [4]. However, even in areas considered low-incidence regions-North America and Europe-the incidence of HCC is on the rise [4]. In the US, HCC incidence has risen more than threefold in the past 30 years, and it is now the ninth most frequent cause of death from cancer. The major reasons for the increased incidence of HCC in the US are the increasing prevalence of chronic HCV infection, increased immigration from high-incidence countries in Asia and Africa, and the increase in the number of individuals with cirrhosis due to obesity-related fatty liver disease. Most HCCs are diagnosed at an advanced stage for which there is no curative option. Sorafenib, the only agent specifically approved for HCC treatment, is of limited efficacy in this setting. Therefore, an urgent need for improved HCC therapy exists. In this review, we discuss the available data on the development and use of immunotherapy for HCC, with a particular focus on recent results and novel approaches.

Dataset Information

Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8+ T cells.

Publications

Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8<sup>+</sup> T cells.

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