Ipilimumab (trade name Yervoy ) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that lowers immune system regulation.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, the inhibitory mechanism interferes with this destruction. Ipilimumab disables this inhibiting mechanism and allows CTL to work.
Ipilimumab was approved by the US FDA in 2011 for the treatment of melanoma, a type of skin cancer. It is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer and metastatic prostate-refractory hormone.
The concept of using anti-CTLA4 antibodies to treat cancer was first developed by James P. Allison when he was director of the Cancer Research Laboratory at the University of California, Berkeley. The anti-CTLA4 clinical development was initiated by Medarex, which was later acquired by Bristol-Myers Squibb. In 2013, it costs $ 120,000 for maintenance. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015.
Video Ipilimumab
Approvals and indications
Melanoma
Ipilimumab was approved by the US FDA in March 2011 to treat patients with end-stage melanoma that has spread or can not be removed surgically. It was then approved by the US FDA on October 28, 2015 for stage 3 patients as adjuvant therapy. On February 1, 2012, Health Canada approved ipilimumab for "inoperable or metastatic melanoma treatment in patients who had failed or did not tolerate other systemic therapy for advanced disease." Ipilimumab is approved in the European Union (EU), for the second-line treatment of metastatic melanoma in November 2012.
Maps Ipilimumab
Adverse effects
Ipilimumab treatment has been associated with severe and potentially fatal fatal immunological adverse effects due to T cell activation and proliferation; this occurs in 10-20% of people and is a major drawback of this drug. Most serious side effects are associated with the gastro-intestinal tract; they include abdominal pain, bloating, constipation or diarrhea, but also fever, respiratory or urinary problems. "Risk evaluation and mitigation strategies" inform planners of potential risks.
Individual cases of severe neurologic disorders after ipilimumab have been observed, including acute inflammatory demyelin polineuropathy and elevated motor paralysis, and myasthenia gravis.
Interactions
A combination of ipilimumab with leflunomide or vemurafenib may lead to increased hepatotoxicity.
Systemic corticosteroids should be avoided before starting ipilimumab; however, systemic corticosteroids can be used to treat the immune-related adverse reactions that arise from ipilimumab treatment.
Patients taking anticoagulants with ipilimumab should be monitored for increased risk of gastrointestinal bleeding.
Action mechanism
T lymphocytes can recognize and destroy cancer cells. However, the inhibitory mechanism interferes with this destruction. Ipilimumab kills this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.
Cancer cells produce antigens, which the immune system can use to identify them. This antigen is recognized by dendritic cells that present antigens to cytotoxic T lymphocytes (CTL) in the lymph nodes. CTL recognizes cancer cells by these antigens and destroys them. However, together with the antigen, dendritic cells present an inhibitory signal. The signal binds to the receptor, the associated cytotoxic T lymphocyte antigen (CTLA-4), in CTL and kills the cytotoxic reaction. It allows cancer cells to survive.
Ipilimumab binds CTLA-4, blocking the inhibitory signals, allowing CTL to destroy cancer cells. In 2014 a study showed that antibodies work by enabling patient T cells to target antigens with greater variation than by increasing the amounts that attack a single antigen.
Identify patients most likely to respond
During "cancer immunoediting", tumor cells can produce antigens that provoke a reduced immune response and/or build an immunosuppressive tumor microenvironment (TME). The latter can arise as a consequence of repeated and ineffective T-cell stimulation. This triggers the target checkpoint ipilumumab. Many patients do not benefit from treatment, which may be associated with reduced mutation loads and/or neoantigens of mutations originating from the missing point. The tumor antigen may be expressed improperly with normal proteins or abnormal proteins with tumor-specific expression. Somatic mutation mutations may produce tumor-specific (non-neoantigen) mutant antigens.
Sequencing and epitope prediction algorithms identify neoantigens in mice tumors that serve as targeted specific tumor T cells. Neoantigens is recognized by T cells in melanoma patients and is most likely the main contributor to the positive clinical effects of cell transfer transfer. The mouse model determined that the neoantigen was a target of T cells activated by postal blockade therapy and that a synthetic long peptide consisting of neoantigen was effective when administered as a vaccine with CTLA-4 and/or PD-1 mAbs. Cancers with higher mutation loads, and possibly associated neoantigens expressed, appear most likely to respond to checkpoint therapy. In melanomas and some other cancers, the number of mutations and neoantigens is correlated with the patient's response. Increased expression of ligand PD 2 transcript (PD-L2) and the sign of immune "cytolytic" gene are also correlated with neoantigen load and tumor response. Expression of CTLA-4 is an indicator of response, which together with PD-L2 may be expressed in immune cells that infect tumors. The inflamed TME before treatment is also associated with the response.
Almost all neoantigens in one study are patient-specific and most likely reflect mutations that do not directly contribute to tumorigenesis. However, nothing reveals an exclusive feature or motive for the respondent.
Historical clinical trial
In 2000, ipilimumab clinical trials were being conducted in patients with melanoma, renal cell carcinoma, prostate cancer, urothelial carcinoma and ovarian cancer. In 2007, there were two fully human CTLA-4 monoclonal antibodies fully in advanced clinical trials. Ipilimumab, which is an isotype IgG1, and tremelimumab (from Pfizer) which is an isotype of IgG2.
Melanoma
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma. Three studies examined 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors at least 10.0% of 155 study patients. Side effects include rash, diarrhea, and hepatitis.
In 2010, a study was presented which showed a mean survival of 10 months in elderly melanoma patients treated with ipilimumab, compared with 6 months for those treated with gp100, an experimental vaccine (n = 676). The one-year survival rate was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those who received both. Phase III clinical studies on drugs were controversial for the use of unconventional control (compared with placebo or standard treatment). This study tested ipilimumab alone, ipilimumab with gp100, and vaccine alone. Patients have a higher survival rate with ipilimumab alone, but it is not entirely clear whether the vaccine causes toxicity, which will make the drug perform better by comparison. Ipilimumab obtained FDA approval in early 2011.
Prostate cancer
In 2008/09 Medarex performed clinical trials of phase I/II phase escalation of ipilimumab in metastatic prostate-refractory hormone (HRPC). Some patients with advanced-stage prostate cancer have shrunken tumors drastically, prompting further testing.
On June 19, 2009, the Mayo Clinic reported two prostate cancer patients who were involved in phase II studies using MDX-010 therapy who had been told initially that their condition was inoperable but their tumors were shrunk by the drug so that the surgery was possible and now cancer-free. However, this press report was criticized as premature and somewhat inaccurate. Clinical trials are still at an early stage and run with other treatments - which can be a real explanation for tumor shrinkage. It is too early to say whether ipilimumab makes a difference.
In 2016, a phase II study using ipilimumab and nivolumab in metastasis-expressing metastatic express prostate cancer was cleared by AR-V7. AR-V7 is a detectable variant of androgen receptor splice in circulating tumor cells in patients with metastatic prostate cancer.
Lung cancer
Medarex runs a phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cells and non-small cell lung cancer. It is scheduled to run from February 2008 to December 2011.
Bladder cancer
Preliminary results of trials on urothelial carcinoma have been reported.
Trial combination
Advanced melanoma
To improve response rates and reduce adverse reactions, various combinations of drugs are being tested.
In 2013 a running trial comparing ipilimumab alone with ipilimumab combined with nivolumab. The response rate (shrunken tumor at least 30%) was 58% for combination, 44% for nivolumab alone, and 19% for ipilimumab alone. This combination received FDA approval for melanoma in October 2015.
In March 2014, open-label, randomized, two-agent, single-center experiments began to combine ipilimumab with phosphatidylserine-targeting immunotherapy bavituximab for the treatment of advanced melanoma. The number of patients treated in arm A (ipilimumab plus bavituximab) was 16, with 8 in arm B (ipilimumab alone). This trial is expected to be completed by March 2016. Previously, preclinical studies have shown that targeting antibodies (such as bavituximab) have increased anti-tumor antibody activity against anti-CTLA-4 and anti-PD-1. Inhibition of tumor growth is correlated with infiltration of immune cells in tumors and induced adaptive immunity. The combination of these mechanisms promotes a strong, localized anti-tumor response, without the side effects of systemic immune activation.
Development
After 1987 CTLA-4 cloning in mice, conservation in humans and similarities with CD28 were immediately noticed. CD28 at the time was a recently identified "immune cell" T molecule essential for T cell activation. Anti-CTLA-4 blockade, ipilimumab-generating discovery, conceived by Allison and Krummel together with CTLA-4 inhibitory role in cell activation T. They were able to show that CTLA-4 signaling in T cells inhibits T cell responses. They then inject intact antibodies and show that CTLA-4 blockade improves T cell response in mice responding to vaccines and super antigens. Leach, a new postdoctoral fellow, was assigned by Allison by applying this in a tumor model. Mice given antibodies showed much less cancer growth compared to controls.
Bluestone and Linsley separately studied the similarities between CD28 and CTLA-4. The Bluestone Laboratory published the study, one along with Krummel and Allison, for in vitro study of CTLA-4 functions. In collaboration with Mark Jenkins, they can see the effect of anti-CTLA-4 in vivo antibodies in immunization settings, but ineffectively bring this to tumor biology. Linsley and colleagues have made antibodies to CTLA-4 three years before Krummel/Allison or Walunas/Bluestone. They concluded that the molecule works the same as CD28 and is a "positive costimulator". They do not seem to pursue CTLA-4 tumor targets, although BMS licensed Allison/Leach/Krummel patents even though they acquired Medarex and MDX010 fully human antibodies, which later became ipilimumab.
References
External links
- US. National Library of Medicine: Drug Information Portal - Ipilimumab
- US. Prescribing FDA-approved Information - ipilimumab
- Bristol-Myers Squibb Information and Support Site for "Yervoy"
Source of the article : Wikipedia
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