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Old 02-26-2015, 09:34 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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Old 02-26-2015, 09:36 PM
gdpawel gdpawel is offline
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Default Current CRI Research

CRI scientists are actively pursuing research that is shedding light on the biology of colorectal cancer and improving its treatment. Ten of our postdoctoral fellows are looking at inflammation and its role in colorectal cancer. This includes April Price, Ph.D., a CRI postdoctoral fellow at the University of California, Berkeley, who is working to understand how Toll-like receptors (TLR), a type of receptor that recognizes molecules that are broadly shared by pathogens, contribute to colorectal cancer, and Timothy Eitas, Ph.D., a CRI postdoctoral fellow at the University of North Carolina, Chapel Hill, who is exploring the role of a protein called NLRX1 and its role in mediating the production of inflammatory molecules called cytokines in ulcerative colitis and colitis-associated cancer. Better understanding of the role that inflammation plays in the development of colorectal cancer may lead to effective strategies to interrupt this inflammation and therefore prevent the development of cancer in the first place.

One postdoctoral fellow is working on cancer-testis (CT) antigens, which have been a focus of therapeutic vaccine approaches, but which are only very infrequently expressed in colorectal cancers. Jeffrey Chou, M.D., Ph.D., at Fred Hutchinson Cancer Research Center, is using the chemotherapy decitabine to enhance the expression of the NY-ESO-1 antigen in colorectal cancer cells, with the goal of making vaccines for this cancer more effective.

Research by Dirk Jäger, M.D., a member of the CRI/Ludwig CVC Trials Network at the University of Heidelberg in Germany, is working to elucidate how immune parameters correlate with prognosis in colorectal cancer. He has published several studies demonstrating that T cell infiltrates at the invasive margin of liver metastases from colorectal cancer predict response versus no response to chemotherapy, and represent the strongest independent prognostic factor in metastatic colorectal cancer. Jäger and colleagues are now testing how to make the tumor better accessible to the immune system by modulating the local inflammatory tumor environment.

To learn more about CRI’s contributions to colorectal cancer research, visit [url]http://cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/colorectal-cancer
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Old 03-03-2015, 10:32 PM
gdpawel gdpawel is offline
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Default Avastin (bevacizumab)

Robert A. Nagourney, M.D.

An E-Publication article in the February Journal of Clinical Oncology analyzes the cost efficacy of Bevacizumab for colon cancer. Bevacizumab, sold commercially as Avastin, has become a standard in the treatment of patients with advanced colorectal cancer. Indeed, Bevacizumab plus FOLFOX or FOLFIRI, are supported by NCCN guidelines and patients who receive one of these regimens are usually switched to the other at progression.

A Markov computer model explored the cost and efficacy of Bevacizumab in the first and second line setting using a well-established metric known as a Quality-Adjusted Life Year (QALY). In today’s dollars $100,000 per QALY is considered a threshold for utility of any treatment. To put this bluntly, the medical system values a year of your life at $100,000. The authors confirmed that Bevacizumab prolongs survival but that it does so at significantly increased costs. By their most optimistic projections, Bevacizumab + FOLFOX come in at more than $200,000 per QALY. Similar results were reported for Canadian, British and Japanese costs. Though more favorable, the results with FOLFIRI + Bevacizumab still came in above the $100,000 threshold.

No one doubts that Bevacizumab provides improved outcomes. It’s the incremental costs that remain an issue. Society is now confronting an era where the majority of new cancer agents come in at a cost in excess of $10,000 per month. Where and how will we draw the line that designates some treatments unaffordable? On the one hand, clinical therapies could be made available only to the “highest bidder.” However, this is contrary to the western societal ethic that holds that medical care should be available to all regardless of ability to pay. Alternatively, increasingly narrow definitions could be applied to new drugs making these treatments available to a shrinking minority of those who might actually benefit; a form of “evidence-based” rationing. A much more appealing option would be to apply validated drug predication assays for the intelligent selection of treatment candidates.

In support of the latter, the authors state, “Bevacizumab potentially could be improved with the use of an effective biomarker to select patients most likely to benefit.” This is something that genomic (DNA) profiling has long sought to achieve but, so far, has been unable to do. This conceptual approach however is demonstrably more attractive in that all patients have equal access, futile care is avoided and the costs saved would immediately provide highly favorable QALY’s as the percentage of responders improved.

Similar to the recent reports from the National Health Service of England, the American public now confronts the challenge of meeting the needs of a growing population of cancer patients at ever-higher costs. It is only a matter of time before these same metrics described for colon cancer are applied to lung, ovarian and other cancers for which Avastin is currently approved.

At what point will the American medical system recognize the need for validated predictive platforms, like EVA-PCD analyses, that have the proven capacity to save both money and lives? We can only wonder.

[url]http://jco.ascopubs.org/content/early/2015/02/17/JCO.2014.58.4904.abstract
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