Ipilimumab

Ipilimumab is a fully humanized IgG1κ anti-CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4) monoclonal antibody with indirect antitumor activity. CTLA-4 is expressed by CD4/CD8 positive cells and plays a critical role in the regulation of the immune response. Ipilimumab blocks the immunoinhibitory interaction between CTLA-4 and its ligands (CD80/CD86), which is associated with increased activation and proliferation of T cells. Ipilimumab thus enhances the endogenous T-cell-mediated immune response and may act indirectly against immunogenic neoplasms. Ipilimumab belongs to the group of so-called checkpoint inhibitors or checkpoint modifiers (see below Immune checkpoint). This also includes substances that inhibit another key molecule on T lymphocytes, PD-1 (see below Nivolumab).

Bristol Myers Squibb presented results of a 676-patient phase III trial with the monoclonal antibody ipilimumab. According to the results, the overall survival rate can be improved in patients with advanced, metastatic melanoma . In a randomized double-blind study, a statistically significant increase in overall survival was achieved both in monotherapy and in combination with the vaccine "GP100" compared to the administration of GP100 alone. 44-46% of patients treated with ipilimumab but only 25% of the control arm survived after 1 year, after 2 years the survival rate was 22-24% with ipilimumab compared to 14% in the control arm. Side effects occurred in 60% of the pat. The most common side effects were related to the immune system and thus directly linked to the mechanism of action of the antibody.

The side effects were severe or even life-threatening in some cases (14 deaths in the study) and primarily affected the gastrointestinal tract (immune-mediated colitis in about 44% of patients), the skin (47-68% of patients show a maculo-papular exanthema that occurs after 3-4 weeks), the liver (hepatitis), the kidney(lupus nephritis) or the endocrine system (pituitary inflammation). The data were published in the New England Journal of Medicine and presented at the 46th Annual Meeting of the American Society of Clinical Oncology.

In addition, there have been increased recent reports of cases of agranulocytosis and pancytopenia associated with ipilimumab.

Ipilimumab is approved under the name YERVOY® for the treatment of relapsed or refractory as well as newly diagnosed advanced malignant melanoma.

It is important to note that the S3 guideline (Diagnosis, Therapy and Follow-up of Melanoma) adopted in 2013 states: "The immune-mediated response to ipilimumab is usually delayed, at the earliest 12 weeks after the start of therapy. In some cases, the tumors may still enlarge initially and still shrink later".

Comparison to Nivolumab: In a phase III trial, 906 patients were treated with either intravenous nivolumab (3mg/kgKG every 2 weeks) or ipilimumab (10mg/kgKG every 3 weeks for 4 doses and every 2 weeks thereafter) after complete resection of stage IIIB and IIIC or IV melanomas. Patients were treated for 1 year or until recurrence or unacceptable toxicity. The direct comparison showed a significant longer survival in the nivolumab-treated group with better tolerability (Weber J et al 2017).

1. Hodi S et al (2010) Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med 363: 711-723
2. Kähler K et al (2011) Treatment and side effect management of metastatic melanoma with CTLA-4 antibodies. JDDG 9: 277-286
3. Livingstone E et al. (2014) Therapy-refractory melanoma with pulmonary metastases: Long-term survival with ipilimumab after initial pseudoprogression. Thieme Case Report 6:1-24
4. Mohr P (2014) Immunoncological therapy with ipilimumab - innovative approach heralds a new era in cancer therapy Thieme Case Report 4:1-24
5. Weber J et al (2017) Adjuvant nivolumab versus ipilimumab in Resected Stage III or IV melanoma.
   N Engl J Med 377:1824-1835.