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Old 02-26-2015, 08:34 PM
gdpawel gdpawel is offline
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Default Impact on Colorectal Cancer Immunotherapy

Alexandra Mulvey
Cancer Research Institute

It’s almost Colorectal Cancer Awareness Month, and we can’t think of a more appropriate time to share what CRI scientists are doing to understand colorectal cancer and change the course of its treatment.

Colorectal cancer is the third most common type of cancer among both men and women in the United States, and is the second most deadly. Overall death and incidence rates among men and women have been declining for the past 20 years, thanks largely to screening tests that help detect early-stage cancer and pre-cancerous polyps. But due to underuse of screening tests, only 40% of colorectal cancers are diagnosed at an early stage, when the 5-year survival rate is 90%. When the cancer has spread to distant sites, only 13% of those diagnosed will reach the five-year survival milestone.

Colorectal cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. The monoclonal antibodies bevacizumab (Avastin), which helps cut off the nutrient supply to the tumor by suppressing blood vessel growth, and cetuximab (Erbitux) and panitumumab (Vectibix), which target the epidermal growth factor receptor (EGFR), have been FDA approved to treat colorectal cancer.

But in clinical trials are a number of cancer immunotherapies, besides monoclonal antibodies, that may expand and improve treatment options for patients. In a phase III clinical study is the therapeutic cancer vaccine Imprime PGG (NCT01309126), which coats the tumor cells and flags them for attack. In a phase I/II clinical trial, Imprime PGG doubled the overall response rates for second- and third-line metastatic colorectal cancer patients. A phase II trial is testing Reolysin, an oncolytic virus that is able to replicate specifically in cancer cells (NCT01622543). Clinical trials have demonstrated that Reolysin may have activity across a variety of cancer types when administered alone and in combination with other cancer therapies. A phase I/II trial is testing rintatolimod, which binds to Toll-like receptor 3 (TLR3), a part of the innate immune system that are “pattern recognition receptors” that detect pathogens immediately, and are a major component of anti-cancer immunosurveillance (NCT01545141).

Immunotherapy as a potentially promising approach for treatment of colorectal cancer is based on evidence from a landmark study in 1998 by Haruo Ohtani, M.D., who demonstrated that the presence of CD8+ killer T cells within the tumor microenvironment (aka “tumor-infiltrating lymphocytes,” or TILs) correlated with better outcomes in colon cancer. This study provided early evidence that immunotherapies that can induce or enhance optimal immunologic conditions within colorectal cancers may hold promise for extending the lives of colorectal cancer patients. CRI bestowed the William B. Coley Award on Dr. Ohtani, along with Jérôme Galon, Ph.D., and Wolf Hervé Fridman, M.D., Ph.D. (left), for their fundamental contributions to our understanding of the prognostic significance of infiltrating T cells in cancer patients.

Studies to characterize immunological parameters that can aid prognosis have recently led to the development of a new tool, the Immunoscore, by Jérôme Galon, Ph.D., which provides a novel way of classifying tumors that works better than the current staging system in predicting rate of relapse and survival in colorectal cancer patients. An international task force, involving investigators in more than 20 countries, is now under way to validate the Immunoscore, the results of which may lead to the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). A recent paper, on which CRI CEO Jill O’Donnell-Tormey, Ph.D., is a co-author, discusses these efforts in more detail.

[url]http://www.translational-medicine.com/content/10/1/205/abstract
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