Immunotherapy is a rapidly expanding approach to the treatment of melanoma, employing a number of strategies evident in the pipeline for immunotherapeutics.
The success of ipilumumab,1as well as that of anti-programmed death 1 (PD-1) checkpoint inhibitors pembrolizumab2and nivolumab,3both now approved for metastatic melanoma, has demonstrated the potential for the use of antagonistic antibodies as immunotherapy.
Omid Hamid, MD, director, melanoma program, and chief, translational research and immuno-oncology at the Los Angeles Clinic and Research Institute in California, recently spoke about melanoma immunotherapies in the pipeline at the 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®.
“While the targeted agents may have higher response rates, we have not seen responses as durable as those seen with immunotherapy,”5Hamid said. “We have just begun to touch on the promise of immunotherapy. The future will elucidate optimal combinations of checkpoint inhibition and other immune-oncologic modalities and targeted agents.”
Expected Completion Date
GM-CSF with ipilimumab
Another anti PD-1 antibody in development for melanoma, pidilizumab (CT-011), recently reported its phase II results4(NCT01435369) and an antibody to programmed death ligand 1 (PD-L1), MSB0010718 (NCT01772004), is in an ongoing trial for solid tumors, including melanoma, and due to report in October 2016. These developments have opened the door to combination therapies. A phase III trial of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in patients with previously untreated advanced melanoma is scheduled for completion in November 2017 (NCT01844505).
Yet more targets for antagonistic antibodies are being researched. Preclinical research has suggested that T-cell immunoglobulin and mucin protein 3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and PD-1 define the autologous tumor reactive repertoire6and that anti-TIM-3 or anti-LAG-3 agents, when combined with anti PD-1 agents, lead to increased efficacy. It is expected that these agents will move into clinical trials.7Another possible antagonistic antibody in a phase I trial (NCT01918930) is MGA 271, which targets the receptor B7-H3, present on antigen presenting cells.8The study aims to gain a better understanding of the mechanism of action of the drug in patients with melanoma, and will be completed in February 2016. The drug will not be administered to patients, but used in pharmacodynamic studies on tumor biopsies.Agonistic antibodies may also hold promise in the immunotherapy arena. Varlimumab (CDX 1127) targets the CD27 costimulatory receptor on T cells, promoting their survival and activation. CD27 activation also influences the proliferation and cytotoxic activity of natural killer cells.9-11Varlimumab is in a phase I safety trial in solid tumors, including metastatic melanoma (NCT01460134), and in a phase I/II trial (NCT02335918) in combination with nivolumab in solid tumors, including melanoma and metastatic melanoma of the head and neck.
The monoclonal agonistic antibody TRX528 activates the glucocorticoid-induced tumor necrosis factor receptor (GITR).12The downstream consequences of this include increases in the proliferation of T effector cells and attenuation of the suppressive effects of T regulatory cells. TRX528 was evaluated in a phase I trial for patients with stage III or IV malignant melanoma (NCT01239134). The trial completion date was December 2014, and the results are pending.The established efficacy of cytokines in melanoma has paved the way for clinical research on other cytokines, such as interleukin 12 (IL-12), IL-21, and IL-15 (for examples of ongoing/completed cytokine trials in melanoma seeTable 1). A trial of IL-21 in melanoma was completed in June 2014 and results are awaited (NCT01489059).
Expected Completion Date
Anti-NY-ESO-1 TCR CD62L+ cells, aldesleukin, cyclophosphamide, fludarabine
ACT with TIL infusion, high-dose IL-2, vemurafenib, lymphodepletion
CD8+ T cells, IL-2, ipilimumab, cyclophosphamide
TCR indicates T cell receptor
The impact of BRAF inhibition on the expression rates of melanoma differentiation antigens and other aspects of the immune response has led to an increased interest in this technique, and currently there are 16 phase I or II trials registered.8This approach is best prescribed in patients with slowly growing melanoma because of the time associated with the technique of preparing autologous tumor infiltrating lymphocytes.8,13Table 2provides examples of current phase II trials of ACT in melanoma.Several types of cancer vaccines are in the pipeline undergoing clinical trials for melanoma, using:8
Vaccine, Therapy Details
Expected Completion Date
M-Vax, autologous, hapten-modified melanoma vaccine, BCG, cyclophosphamide, IL-2
AdCD40L therapy. Adenoviral serotype 5 vector, E1/E3 deleted. Human CD40L gene insert driven by RSV promotor.
Autologous dendritic cells and irradiated autologous tumor cells in GM-CSF
BCG indicates Bacille Calmette-Guerin; RSV, respiratory syncytial virus.
Table 3gives examples of vaccines in the most advanced stages of clinical development for melanoma.Oncolytic immunotherapy is a major focus of clinical interest and research. The most clinically advanced is talimogene laherparepvec (T-VEC).
“T-VEC uses an attenuated herpes virus that can only replicate in malignant cells. Unfettered viral replication leads to focal cancer cell lysis while secreting GM-CSF, more virus capable of infecting other malignant cells, and tumor antigens creating an immune stimulatory environment,” said Hamid,5adding, “Today, T-VEC therapy has shown local and distant tumor response, improved response rates and tumor control, and a trend toward improved survival.”
The US Food and Drug Administration has scheduled an advisory hearing on April 29, 2015, to discuss a biologics license application for T-VEC,14which is undergoing phase I/II studies in melanoma, in combination with or without pembrolizumab (NCT02263508), completion date February 2019, and ipilimumab (NCT01740297), completion date November 2017.“Oncologists today have the mandate to reconfigure their preconceived notions of immunotherapy. The toolbox has expanded,” said Hamid, pointing out that “the need to familiarize oneself with these options is tantamount.”
Reflecting on the expected outcome of further approvals for specific immune therapies, and combination therapies adding considerably to treatment choices, Hamid concluded, “With the multitude of targeted therapies, immune modulators, and checkpoint inhibitors/agonists, extensive options exist.”5