Treatment Options for Patients with Stage III & IV Melanoma: Part II: Experimental treatments for stage III/IV or refractory/recurrent melanoma

Adam I. Riker, MD; Paul M. Howell, BS
Published: Saturday, Mar 12, 2011

Various immunotherapeutic strategies to treat advanced melanoma have been under investigation for more than a decade—primarily vaccines and adoptive cell transfer (ACT) therapy. Most of these novel approaches appear relatively safe, but with differing levels of efficacy. Researchers continue to believe that some form of immunotherapy, either alone or combined with other therapeutics, may prove to be effective in late-stage melanoma. Data are accumulating in support of novel therapeutic immunotherapy regimens and schedules; these data are often incongruent with the dogma of the past few decades on how the host immune response becomes activated to cancer.

Tumor Cell–Based Vaccines

Several early-phase clinical trials have shown that autologous and allogeneic tumor cell–based vaccines can be given safely with few adverse effects. One of the first such vaccines tested extensively in clinical trials was onamelatucel-L, a polyvalent whole–tumor cell vaccine derived from 3 human melanoma cell lines. Although early trials failed to show significant clinical benefit, a few complete and durable responses provided the impetus for two multicenter, phase III randomized trials in 1998.1 As part of the design of the onamelatucel-L trials, patients with stage IV melanoma were required to undergo definitive surgical removal of all metastatic disease prior to enrollment. Both trials closed prematurely, after an interim analysis revealed no probable efficacy over placebo.1 Evidence supports a hypothesis of first removing the bulk of disease, and long-term responses have indeed been observed in patients who had complete surgical resection of regional nodal disease without any adjuvant immunotherapy.2,3

Over the years, several other tumor cell–based trials4-16 have yielded interesting clinical outcomes. Overall, however, the application of strict response criteria finds that response rates remain exceedingly low. The next generation of whole–tumor cell vaccines has incorporated advances in gene transfer technology with the immunobiology of the cancer cell and host immune system. Initial preclinical studies have shown that a melanoma whole–tumor cell vaccine transduced with the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene confers a potent and long-lasting anti-tumor immune response.17 The secretion of GM-CSF by the transduced melanoma cells attract immune cells, such as antigen-presenting cells and T-lymphocytes, to the vaccine site.17,18 Several phase I/II clinical trials using this approach have been completed, with a few objective clinical responses noted.19-21 These early studies, however, involve small numbers of patients. Further clinical trials that enroll more patients are needed before strong conclusions can be made about the efficacy of this vaccine approach.

Peptide- and Dendritic Cell-Based Vaccines

Rosenberg and associates performed one of the first clinical trials to use peptides derived from melanoma cells.22 The researchers used a modified immune-dominant peptide of the gp100 antigen, g209-2M, to vaccinate 11 patients with stage IV melanoma. They found that 10 (91%) of the patients showed a consistently high level of immunization against the native g209-217 peptide, but not against g280-288, the control peptide. Although many patients developed an immunologic response to the peptide vaccine, all patients went on to develop progressive disease. This study, however, provided a central proof-of-principle that patients with advanced melanoma could mount an immune response against their own self-antigens, an exciting concept not appreciated previously. The trial also highlighted that an immunologic response does not necessarily equate with a clinical response.  

Although the vaccines are seemingly effective at enhancing a tumor-antigen–specific immune response, clinical outcomes have been uniformly disappointing. A recent analysis of 28 different peptide-based vaccines in stage IV patients revealed an objective response rate (ORR) of just 2.9%.23 Other studies using a peptide-based vaccination strategy have produced only limited responses.24,25

Another novel approach to melanoma immunotherapy involves using autologous dendritic cells (DCs) as potent antigen-presenting cells that interact with other immune cells and activate an antigen-specific immune response. The first published clinical trial of DC vaccination was in 1995; this has been followed by 98 additional clinical trials in 15 different countries involving >1000 patients.26 Of these 98 trials, 28 focused on patients with advanced stages of melanoma. The trials have shown that DC-based vaccines are safe, producing few severe adverse effects. Yet, their record of effectiveness has been disappointing, with an ORR of <5% in most trials. A recent DC-based vaccination trial by Schadendorf and colleagues from the German Dendritic Cell Study Group produced similar results.27

Plasmid and Recombinant DNA Vaccines

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Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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