Ipilimumab

Source: Wikipedia, the free encyclopedia.
Ipilimumab
CTLA-4
Clinical data
Pronunciationi pi lim′ ue mab
Trade namesYervoy
Other namesBMS-734016,[1] MDX-010,[2] MDX-101
AHFS/Drugs.comMonograph
MedlinePlusa611023
License data
Pregnancy
category
  • AU: C
Routes of
administration		Intravenous (IV)
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6742H9972N1732O2004S40
Molar mass148634.46 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Ipilimumab, sold under the brand name Yervoy, is a

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.[7] Ipilimumab turns off this inhibitory mechanism and boosts the body's immune response against cancer cells.[7][8]

Ipilimumab was approved by the US Food and Drug Administration (FDA) 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, esophageal cancer.[9][10][11][12] It is undergoing[when?] clinical trials for the treatment of bladder cancer[13] and metastatic hormone-refractory prostate cancer.[14]

The concept of using anti-CTLA4 antibodies to treat cancer was first developed by

Bristol-Myers Squibb. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015.[17] Allison later was the co-winner of the 2018 Nobel Prize in Physiology or Medicine.[18]

Medical uses

Ipilimumab was approved by the U.S. Food and Drug Administration (FDA) in March 2011, to treat people with late-stage melanoma that has spread or cannot be removed by surgery.[7][10][19][20][21] It was later approved by the US FDA on October 28, 2015, for stage 3 patients as adjuvant therapy.[22] 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."[23] Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma in November 2012.[24][25]

Nivolumab, in combination with ipilimumab is indicated for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma.[5][26]

Ipilimumab, in combination with nivolumab, is indicated for the treatment of adults and adolescents twelve years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.[5][27]

Ipilimumab, in combination with nivolumab, is indicated for the treatment of people with hepatocellular carcinoma who have been previously treated with sorafenib.[5][28]

Ipilimumab, in combination with nivolumab, is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test.[5][29][30]

In October 2020, the U.S. 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.[31] This is the first drug regimen approved for mesothelioma in sixteen years and the second FDA-approved systemic therapy for mesothelioma.[31]

Adverse effects

A major drawback of ipilimumab therapy is its association with severe and potentially fatal immunological adverse effects due to

T cell activation and proliferation, occurring in ten to twenty percent of patients.[32] Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems. A "risk evaluation and mitigation strategy" informs prescribers of the potential risks.[21][33]

Between 5.7 and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis.[34]

Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory

motor paralysis, and myasthenia gravis.[35]

Interactions

The combination of ipilimumab with either leflunomide or vemurafenib may lead to increased hepatotoxicity.[36][37][38][39]

Systemic

adverse reaction that arises from ipilimumab treatment.[40]

Patients taking

anticoagulants with ipilimumab should be monitored due to an increased risk of gastrointestinal bleeding.[40]

Mechanism of action

T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.[8]

Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by

CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.[8]

Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells.[8][41][42][43][44][45][46] 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.[47]

Identifying patients most likely to respond

During "cancer immunoediting", tumor cells can produce antigens that provoke a reduced immune response and/or establish an immunosuppressive tumor microenvironment (TME). The latter can arise as a consequence of repeated, ineffective T cell stimulation. This triggers the checkpoint that ipilumumab targets. Many patients do not benefit from treatment, which may be related to reduced mutation load and/or missense point mutation-derived neoantigens.[7] Tumor antigens can either be improperly expressed normal proteins or abnormal proteins with tumor-specific expression. Somatic cancer mutations can produce "nonself" tumor-specific mutant antigens (neoantigens).[48]

Sequencing and

tumor-infiltrating immune cells. An inflamed TME prior to treatment is also associated with response.[48]

Nearly all neoantigens in one study were patient-specific and most likely reflected mutations that do not directly contribute to tumorigenesis. However, none revealed features or motifs exclusive to responders.[48]

Clinical trial history

In the 2000s, ipilimumab clinical trials were under way on patients with melanoma,

urothelial carcinoma and ovarian cancer.[49] By 2007, there were two fully human anti CTLA-4[50] monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.[51][52]

Melanoma

On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma.[53] 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 ten months in advanced melanoma patients treated with ipilimumab, compared with 6.4 months for those treated with gp100, an experimental vaccine (n=676), and 10.1 months for those treated with both the vaccine and ipilimumab.[54] 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.[10][19]

Prostate cancer

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.[55]

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.[56] This press report however was criticized as premature and somewhat inaccurate. The clinical trials were still at an early stage and were run alongside other treatments – which could have been the real explanation for the tumor shrinkage.[57] It was too early to say whether ipilimumab made any difference.[58]

In 2016, a phase II study using ipilimumab and

splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.[60][61]

Lung cancer

CHECKMATE-227 [62] tested the combination of nivolumab and ipilimumab in patients with stage IV or recurrent NSCLC without previous treatment.[63][62] Patients with a PD-L1 expression level of 1% or more were randomized in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy.[63][62] The chemotherapy used was cisplatin or carboplatin, combined with gemcitabine for patient with squamous cell NSCLC, or pemetrexed for patients with nonsquamous disease.[63][62] The overall survival was 17.1, 15.7 and 14.9 months, respectively.[63][62] The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy.[63][62] The OS was 17.2, 15.2 and 12.2 months, respectively.[63][62]

CHECKMATE-9LA [64] 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.[63] 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.[64] Median OS was 15.6 and 10.9 months, in the immunotherapy-chemotherapy and the chemotherapy only groups, respectively.[64][63]

Urothelial cancer, including cancer of the bladder, urethra, ureters and renal pelvis

A Phase 2 clinical trial entitled First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma was first reported in 2015 [65] Thirty-six patients were treated with chemotherapy, adding ipilimumab after the second 21-day cycle. Though the study did not meet its primary endpoint, a significant expansion of circulating CD4 cells was noted upon addition of ipilimumab, which correlated with improved survival, especially in patients with deleterious somatic DNA damage response mutations.[66]

Combination trials

Advanced melanoma

To increase response rate and reduce adverse reactions, various drug combinations are being tested.

In 2013, a trial was running that compared ipilimumab alone against ipilimumab in combination with nivolumab. The response rate (tumours shrinking by at least 30%) was 58% for the combination, 44% for nivolumab alone, and 19% for ipilimumab alone.[67] This combination gained FDA approval for melanoma in October 2015.

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).[68] The trial was terminated in April 2016 due to low enrollment.[69] 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.[70]

Development

Following the 1987 cloning of CTLA-4 in mice,

super antigens.[76] Leach, a new postdoctoral fellow, was tasked by Allison with applying these in tumor models. Antibody-treated mice showed significantly less cancer growth than the controls.[15]

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.[77][78] In collaboration with Mark Jenkins, they were able to see effects of anti-CTLA-4 antibodies in vivo in an immunization setting,[79] 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".[80] 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.

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Ipilimumab&oldid=1216820356"