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Ipilimumab (i pi lim′ ue mab; also known as MDX-010 and MDX-101), marketed as Yervoy, is a drug used for the treatment of cancer. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, a type of skin cancer. It is a monoclonal antibody developed by Medarex (acquired by Bristol-Myers Squibb) that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy cancer cells.
In addition to melanoma, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer, and metastatic hormone-refractory prostate cancer.
The cost is $120,000 for a course of treatment.
Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease." Additionally Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma, November 2012.
Ipilimumab treatment has been associated with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation. Most of the serious adverse effects are associated with the gastro-intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also fever, breathing or urinating problems. A "risk evaluation and mitigation strategy" has been set up to inform prescribers of the potential risks.
The combination of ipilimumab with either leflunomide or vemurafenib may lead to increased hepatotoxicity. Systemic corticosteroids should be avoided before starting ipilimumab; however, systemic corticosteroids may be used to treat an immune-related adverse reaction that arises from ipilimumab treatment. Patients taking anticoagulants with ipilimumab should be monitored due to an increased risk of gastrointestinal bleeding.
Mechanism of action
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.
Cancer cells produce antigens, which the immune system can use to identify and destroy them. These antigens are recognized by dendritic cells, which present the antigens to CTLs in the lymph nodes. The CTLs can then recognize the cancer cells by those antigens and destroy them. However, dendritic cells also present the antigens to CTLs along with an inhibitory signal, which binds to a receptor, CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.
Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells.
Clinical trial history
|This section is outdated. (March 2011)|
By 2007 there were two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma. The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea, and hepatitis.
In 2010, a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6 months for those treated with gp100, an experimental vaccine (total n=676). Additionally, one year survival was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those receiving both. The Phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). The study tested ipilimumab alone, ipilimumab with gp100, and the vaccine alone. Patients had a higher survival rate with ipilimumab alone, however it is not fully clear whether the vaccine caused toxicity, which would make the drug perform better by comparison. However, it gained FDA approval in early 2011. In August 2011, it was approved for use in the UK.
In 2008/09 Medarex performed a Phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). Some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.
On June 19, 2009, the Mayo Clinic reported two prostate cancer patients involved in a Phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result. This press report however was criticized as being somewhat inaccurate and entirely premature. The clinical trials were still at an early stage and were being run alongside other treatments – which could be the real explanation for the tumor shrinkage. It was far too early to say whether ipilimumab has made any difference at all.
Medarex ran a Phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cell and non-small cell lung cancer. It was scheduled to run from February 2008 to December 2011.
|This section is outdated. (May 2014)|
In March 2014, an open-label, randomized, two agent, single center trial started combining ipilimumab with phosphatidylserine-targeting immunotherapy bavituximab for the treatment of advanced melanoma, sponsored by University of Texas Southwestern Medical Center. The number of treated patients in arm A (ipilimumab plus bavituximab) will be 16, and in the arm B (ipilimumab only) will be 8. The trial is expected to complete in March 2016. Previously, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
Following the initial cloning of CTLA-4 in the mouse, its conservation in human and similarities with CD28 were soon noticed. CD28 at that time was a recently identified "T cell costimulatory" molecule important for T cell activation. Anti-CTLA-4 blockade, the invention that subsequently gave rise to ipilimumab, was conceived by James P. Allison and Matthew F. Krummel as part of Krummel’s PhD thesis work in Allison's lab that uncovered an inhibitory role for CTLA-4 in T cell activation. Krummel and Allison’s antibodies were first applied to in vitro studies as a means to engage or block CTLA-4 and they were able to demonstrate that CTLA-4 signaling in T cells inhibited T cell responses. Given that antibodies have long half-lives in vivo, they then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens. Using conditions worked out from these studies, Dana Leach, who had just begun as a postdoctoral fellow in Allison’s lab, was tasked by Allison with applying these in tumor models. With remarkable efficacy, antibody-treated but not control-treated mice showed significantly less cancer growth. This work was published in the journal Science.
Jeff Bluestone’s lab, then at University of Chicago, and Peter Linsley’s group at Oncogen and then Bristol-Myers Squibb in Seattle also noted the similarities between CD28 and CTLA-4 and studied them extensively. Bluestone’s lab published studies, one of which was published together with Krummel and Allison, for in vitro studies of CTLA-4 function. In collaboration with Mark Jenkin’s lab at the University of Minnesota, they were also able to see effects of their own anti-CTLA-4 antibodies in vivo in an immunization setting but did not effectively carry this into tumor biology. Linsley and colleagues had also made monoclonal antibodies against CTLA-4 three years prior to those of Krummel/Allison or Walunas/Bluestone. They concluded that the molecule functioned similarly to CD28 and was a "postive costimulator". They also did not apparently pursue targeting of CTLA-4 in tumors, although BMS ultimately came to license the Allison/Leach/Krummel patent though their acquisition of Medarex and the fully humanized antibody MDX010, which later became ipilimumab.
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