[19] 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.
[23] 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.
[25][26] Nivolumab, in combination with ipilimumab is indicated for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma.
[5][29] 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][30][31] 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.
[32] 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.
[33] Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems.
[35] Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.
[49] Sequencing and epitope prediction algorithms identified neoantigens in mouse tumors that functioned as tumor-specific T cell targets.
Increased PD ligand 2 (PD-L2) transcript expression and an immune "cytolytic" gene signature also correlated with neoantigen load and tumor response.
[55] 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).
[11][20] In 2008/09 Medarex performed a phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC).
[56] 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.
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.
[60][61] AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.
The data were presented in an abstract format and as a lecture during the American Society of Clinical Oncology (ASCO) 2020 annual meeting.
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.
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 combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
[74] Anti-CTLA-4 blockade, the invention that gave rise to ipilimumab, was conceived by Allison and Krummel along with CTLA-4's inhibitory role in T cell activation.
[76] They then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens.
[81] 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.