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Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication 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, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and boosts the body's immune response against cancer cells.
Ipilimumab was approved by the US Food and Drug Administration in March 2011, for the treatment of melanoma, renal cell carcinoma (RCC), colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, and esophageal cancer. It is undergoing for the treatment of bladder cancer (completed) and metastatic hormone-refractory prostate cancer. (completed)
The concept of using anti-CTLA4 antibodies to treat cancer was first developed by James P. Allison while he was director of the Cancer Research Laboratory at the University of California, Berkeley. Clinical development of anti-CTLA4 was initiated by Medarex, which was later acquired by Bristol-Myers Squibb. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015. Allison later was the co-winner of the 2018 Nobel Prize in Physiology or Medicine.
Nivolumab, in combination with ipilimumab is indicated for treating the following:
In October 2020, the FDA approved the combination of nivolumab with ipilimumab for the first-line treatment of adults with malignant pleural mesothelioma that cannot be removed by surgery. This is the first drug regimen approved for mesothelioma in 16 years and the second FDA-approved systemic therapy for mesothelioma.
In April 2025, the FDA approved nivolumab with ipilimumab for people aged 12 years and older with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. The FDA also converted the accelerated approval to regular approval for single agent nivolumab for people aged 12 years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan.
Between 5.7% and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis.
Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.
Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.
Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells. In 2014 a study indicated that the antibody works by allowing the patients' T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen.
Bluestone and Linsley separately studied the similarities between CD28 and CTLA-4. Bluestone's lab published studies, one together with Krummel and Allison, for in vitro studies of CTLA-4 function. In collaboration with Mark Jenkins, they were able to see effects of anti-CTLA-4 antibodies in vivo in an immunization setting, but did not effectively carry this into tumor biology. Linsley and colleagues had made 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 "positive costimulator". They apparently did not pursue CTLA-4 tumor targeting, although BMS licensed the Allison/Leach/Krummel patent through their acquisition of Medarex and the fully humanized antibody MDX010, which later became ipilimumab.
In 2010, a study was presented that showed a median survival of ten months in advanced melanoma patients treated with ipilimumab, compared with 6.4 months for those treated with , an experimental vaccine (n=676), and 10.1 months for those treated with both the vaccine and ipilimumab. 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). Ipilimumab gained FDA approval in March 2011.
In June 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 was criticized as premature and inaccurate, because the clinical trials were still at an early stage and were run alongside other treatments, which could have been the main reason for the tumor shrinkage. Thus, it was too early to say whether ipilimumab made any difference.
In 2016, a phase II study using ipilimumab and nivolumab in AR-V7-expressing metastatic castration-resistant prostate cancer was opened. AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.
CHECKMATE-9LA randomized patients with stage IV NSCLC, to nivolumab 360 mg Q3W + ipilimumab 1 mg/kg Q6W + two cycles of chemotherapy or 4 cycles of chemotherapy alone. The chemotherapy used was Cisplatin or Carboplatin combined with Pemetrexed or Paclitaxel. The data were presented in an abstract format and as a lecture during the American Society of Clinical Oncology (ASCO) 2020 annual meeting. Median OS was 15.6 and 10.9 months, in the immunotherapy-chemotherapy and the chemotherapy only groups, respectively.
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. The number of treated patients in arm A (ipilimumab plus bavituximab) was to be 16, with 8 in arm B (ipilimumab only). The trial was terminated in April 2016 due to low enrollment. Previous, 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.
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