Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

Abstract

Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4-blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success.

Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination

“…3). It is still controversial whether such adverse events correlate with clinical benefit (15)(16)(17). Some authors hold that the development of an irAE may not be predictive of ipilimumab activity (15 melanoma, who received the treatment, no correlation between toxicity and efficacy was found.…”

Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series

“…3,6,8,16,17 In a study of 95 patients treated with ipilimumab, Simeone et al reported that decreased levels of lactate dehydrogenase (LDH), c-reactive protein (CRP), and circulating regulatory T cells (Treg) were all significantly associated with clinical response to ipilimumab and improved survival. 3,24 Large multicenter studies will be required to validate these tests, and others, so that care for patients with advanced melanoma can be tailored appropriately.…”

Trial Watch: Peptide-based anticancer vaccines

“…In addition, as for many other (immuno)therapeutic interventions, it will be crucial to identify biomarkers that reliably predict the propensity of individual patients to respond to peptide-based anticancer vaccines. [269][270][271][272][273] Time will tell whether these avenues are those that lead to the approval of peptide vaccination by international regulatory agencies for use in cancer patients.…”