The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience

• Published in: Pharmacology & therapeutics (Oxford) 2015-04, Vol.148, p.132-153
• Main Authors: Berman, David, Korman, Alan, Peck, Ronald, Feltquate, David, Lonberg, Nils, Canetta, Renzo
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Humans; Immunologic Factors - adverse effects; Immunologic Factors - therapeutic use; Neoplasms - drug therapy
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/j.pharmthera.2014.11.017

The discovery and increased understanding of the complex interactions regulating the immune system have contributed to the pharmacologic activation of antitumor immunity. The activity of effector cells, such as T and NK cells, is regulated by an array of activating and attenuating receptors and ligands. Agents that target these molecules can modulate immune responses by exerting antagonistic or agonistic effects. Several T- or NK-cell modulators have entered clinical trials, and two have been approved for use. Ipilimumab (Yervoy®, Bristol-Myers Squibb) and nivolumab (OPDIVO, Ono Pharmaceutical Co., Ltd./Bristol-Myers Squibb) were approved for the treatment of metastatic melanoma, in March 2011 in the United States, and in July 2014 in Japan, respectively. The clinical activity of these two antibodies has not been limited to tumor types considered sensitive to immunotherapy, and promising activity has been reported in other solid and hematologic tumors. Clinical development of ipilimumab and nivolumab has presented unique challenges in terms of safety and efficacy, requiring the establishment of new evaluation criteria for adverse events and antitumor effects. Guidelines intended to help oncologists properly manage treatment in view of these non-traditional features have been implemented. The introduction of this new modality of cancer treatment, which is meant to integrate with or replace the current standards of care, requires additional efforts in terms of optimization of treatment administration, identification of biomarkers and application of new clinical trial designs. The availability of immune modulators with different mechanisms of action offers the opportunity to establish immunological combinations as new standards of care.