Nils Lonberg

Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma

The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune‐related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long‐term follow‐up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

Development of ipilimumab

The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune‐related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long‐term follow‐up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

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

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.

De-Risking Immunotherapy: Report of a Consensus Workshop of the Cancer Immunotherapy Consortium of the Cancer Research Institute

With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials. Cancer Immunol Res; 4(4); 279–88. ©2016 AACR.

To Market, To Market—2011

Abstract This years To-Market-To-Market chapter provides summaries for 26 new molecular entities (NMEs) that received first time approval world-wide in 2011. •Anticancer agents topped the list with seven first-time NMEs, of which five are small molecules and two are biologic agents. In the infectious disease area, three antiviral agents and one antibacterial agent were approved. There were three first-time NME drug approvals each for central nervous system, cardiovascular, and endocrine diseases. There were also three approvals in the immunology therapeutic area, with one small molecule two biologic agents. The remaining NMEs include a biologic agent for macular degeneration, a small molecule for the rare disease transthyretin familial amyloidosis, and a small molecule for urinary incontinence. The summaries include indication, information about the disease treated, mechanism of action, selected preclinical data, key steps in the synthesis, pharmacokinetic metabolism profile, clinical efficacy and safety data, and other key information about the approval.

To Market, To Market—2010

Publisher Summary This chapter provides summaries of 24 new molecular entities (NMEs) that have been approved for the first time worldwide, of which 19 are small molecules. Twelve of the summaries presented in the chapter were first approved in the United States and seven were first approved in the European Union. The remaining NMEs are from Canada, Japan, and Russia. Treatments for cancer dominate the list of the NMEs, with five drug approvals for small molecules and approval of the first vaccine for hormone-refractory prostate cancer. The infectious and cardiovascular disease areas are next in the number of new drug approvals, with three each. Two new drugs were approved for the treatment of multiple sclerosis and associated symptoms. In the anticancer area, five new small molecules were approved along with a novel therapeutic vaccine for the treatment of hormone-refractory prostate cancer. Four of the small molecules are related to natural products and one is a cyclic peptide.

Masterful Antibodies: Checkpoint Blockade

Cancer therapeutics that target the immune system rather than the cancer cell itself are becoming standard of care in a growing number of different malignancies. Although cancer immunotherapy is not a new concept, the potential importance of this class of drugs was probably not fully appreciated as recently as a decade ago when much of the focus of cancer drug discovery was on cancer cell–targeted medicines. The authors were lucky enough to be able to witness and participate in the discovery and development of ipilimumab and nivolumab, two relatively early examples of immune system–targeted drugs. The challenges associated with discovering and developing these molecules may be of historical interest and instructive for moving cancer immunotherapy forward for greater numbers of patients. Cancer Immunol Res; 5(4); 275–81. ©2017 AACR.