meningeal) by the father of monoclonal antibody treatment (Responsible for development of rituxumab) used for lymphomas. I first heard him speak 36 years ago
Contact: Jillian Hurst
press_releases@the-jci.org
Journal of Clinical Investigation
Modulating the immune system to combat metastatic cancer
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ignore cancer cells. Regulatory T cells are immune cells that function to suppress the immune system response. In this issue of the Journal of Clinical Investigation, researchers led by Ronald Levy at Stanford University found that regulatory T cells that infiltrate tumors express proteins that can be targeted with therapeutic antibodies. Mice injected with antibodies targeting the proteins CTLA-4 and OX-40 had smaller tumors and improved survival. Moreover, treatment with these antibodies cleared both tumors at the primary site and distant metastases, including brain metastases that are usually difficult to treat. These findings suggest that therapies targeting regulatory T cells could be a promising approach in cancer treatment. In an accompanying commentary, Cristina Ghirelli and Thorsten Hagemann emphasize that in order for this approach to be clinically relevant, it will be important to show that targeting regulatory T cells in metastatic tumors also blocks growth.
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TITLE:
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
AUTHOR CONTACT:
Ronald Levy
Stanford University Medical Center, Stanford, CA, USA
Phone: 650-725-6452; Fax: 650-736-1454; E-mail:
levy@stanford.edu
View this article at:
http://www.jci.org/articles/view/648...21d3af9fbb75eb
ACCOMPANYING COMMENTARY
TITLE:
Targeting immunosuppression for cancer therapy
AUTHOR CONTACT:
Thorsten Hagemann
Barts Cancer Institute, London, UNK, GBR
Phone: +442078825795; Fax: +442078826110; E-mail:
t.hagemann@qmul.ac.uk
View this article at:
http://www.jci.org/articles/view/699...75947229d0146a
J Clin Invest. doi:10.1172/JCI64859.
Copyright © 2013, The American Society for Clinical Investigation.
Research Article
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
Aurélien Marabelle1,2, Holbrook Kohrt1, Idit Sagiv-Barfi1, Bahareh Ajami3, Robert C. Axtell3,Gang Zhou4, Ranjani Rajapaksa1, Michael R. Green1, James Torchia1, Joshua Brody1, Richard Luong5,Michael D. Rosenblum6, Lawrence Steinman3, Hyam I. Levitsky7, Victor Tse1 and Ronald Levy1
1Department of Medicine, Division of Oncology, Stanford University, Stanford, California, USA.
2Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
4Cancer Center, Georgia Health Sciences University, Augusta, Georgia, USA.
5Department of Comparative Medicine, Stanford University, Stanford, California, USA.
6Departments of Dermatology and Pathology, UCSF, San Francisco, California, USA.
7Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Address correspondence to: Ronald Levy, Division of Oncology, Stanford University, 269 Campus Drive, CCSR 1105, Stanford, California 94305, USA. Phone: 650.725.6452; Fax: 650.725.1420; E-mail:
levy@stanford.edu.
Published May 24, 2013
Received for publication May 17, 2012, and accepted in revised form March 14, 2013.
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
Having demonstrated the systemic efficacy of our in situ immunotherapy on different models of metastatic tumors, we decided to assess the ability of the antitumor immune response to eradicate tumor cells within the CNS. This question is of the utmost importance both for fundamental immunology and for clinical practice. Indeed, the original experiments of Medawar showed that the brain is an immunologically privileged site for skin allografts (45, 46). In clinical practice, a primary or secondary CNS involvement of any cancer indicates poor prognosis, because all of our treatments, including antitumor mAbs, fail to cross the blood-brain barrier (47, 48). Indeed, in our experiments, chemotherapy and a tumor-targeting mAb showed little effect against the implanted CNS disease. By contrast, injection of CpG and low-dose αOX40/CTLA4 into s.c. tumors eradicated tumor in the brain as well as leptomeningeal and spinal cord metastases. Moreover, cured mice had a long-term, CD8+-dependent, intra-CNS immune protection from late contralateral i.c. tumor rechallenge. Recent murine studies have shown that T cells directed against alloantigens (49) or against nonsyngeneic tumors can access the brain (50–53). Moreover, it has been shown in humans that adoptive antitumor T cell therapy can have an effect against brain tumor sites (54). However, such a strategy requires a conditioning regimen prior to the administration of these ex vivo–generated antitumor T cells. Here we show in a syngeneic tumor model that in situ immunomodulation in a peripheral tumor site generates an antitumor immune response within the distant tumor sites, including in the brain, and is able to eradicate established disseminated disease and provide vaccine protection in the CNS.
Taken together, our results support a paradigm shift in cancer therapy, in which, instead of using mAbs to target the tumor, mAbs will be used to target the immune system in order to stimulate the antitumor immune response. Additionally, instead of systemic treatment, all of the therapies will be delivered locally, with resulting systemic eradication of tumor. This strategy of local tumor immunomodulation could be tested soon in patients, since many of the relevant ligands and antibodies are currently in clinical development.
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