Therapeutic Vaccines for Metastatic Melanoma

Standard treatment options for patients with melanoma include surgery, radiation therapy, chemotherapy, biologic therapy, and targeted therapy.1 However, these treatments have not been shown to markedly improve overall survival in patients with metastatic melanoma.2 About 15% of patients with melanoma have stage III (median survival 24 months) or stage IV disease (median survival 7 months) at the time of diagnosis.3 The historically poor prognosis for patients with advanced melanoma has spurred researchers to develop targeted therapies intended to reduce tumor burden, slow disease progression, and extend overall survival. TCVs represent one emerging class of therapies. TCVs are intended for use as either monotherapy or adjunctive therapy (e.g., with surgery and/or cytokine immunotherapy).4

TCVs are designed to stimulate the body's natural defenses against cancer.5 Although most vaccines protect against future infections or disease, TCVs specifically target existing cancer cells or molecules associated with cancer development and growth.6 During treatment, clinicians inoculate a patient with substances known to elicit a strong immune response against key proteins and other molecules associated with cancer.7 These include tumor-associated antigens (TAAs) that are present at higher levels in tumor tissue than normal tissue.8 In many vaccines, chemicals known as adjuvants are combined with tumor antigens. Adjuvants are intended to increase the magnitude and shorten the activation time of the immune response.9 Some TCVs use cells harvested directly from the patient to produce a heightened and/or patient-specific immune response.10 Once activated, the immune system selectively attacks cancer cells that are present as TAAs or as other molecules associated with tumor cell division and growth. TCVs may prove useful in eliminating residual cancer cells after surgery, slowing disease progression, or preventing recurrence.8 TCVs being developed to treat advanced melanoma aim to stimulate a strong and more patient-specific immune response against tumor cells using advanced vaccine technologies.11,12

Several types of TCVs for melanoma are in phase I and II development, including tumor-cell vaccines, antigen vaccines, dendritic-cell vaccines, DNA vaccines, and vector-based vaccines.13 The following vaccines are discussed below:

BioVex Group, Inc. (Woburn, MA, USA; acquired by Amgen in January 2011) has developed T-VEC (talimogene laherparepvec, formerly known as OncoVEXGM-CSF)14, an oncolytic immunotherapy under investigation for treating advanced melanoma. Oncolytic immunotherapy involves using a genetically engineered virus programmed to specifically attack tumor cells or to generate a targeted immune response. T-VEC is a genetically modified variant of herpes simplex virus type 1, from which two genes have been deleted: the neurovirulence factors ICP34.5 and ICP47.15 T-VEC expresses the immunomodulatory cytokine GM-CSF. Upon intratumoral injection, GM-CSF purportedly destroys lesions through viral replication and induction of an immune response against tumor antigens, which can cause a global effect on uninjected lesions.16

Gradalis, Inc. (Carrollton, TX, USA) has produced the autologous tumor cell vaccine FANG, which expresses recombinant human GM-CSF and a bifunctional ribonucleic acid interference effector, bi-short hairpin RNA (shRNA) furin.17 The GM-CSF protein purportedly recruits and activates antigen-presenting cells to elicit the immune response while the furin bifunctional shRNA inhibits tumor growth by blocking furin protein production.17 Besides testing FANG in patients with advanced melanoma,17 researchers are investigating it in clinical trials for treating ovarian cancer18 and colorectal cancer.19

GlaxoSmithKline (Middlesex, UK) has developed GSK2132231A (Astuprotimut-r), an immunotherapy consisting of melanoma antigen A3 (MAGE-A3) antigen-specific cancer immunotherapeutic), which is injected intramuscularly into patients with metastatic melanoma.20 Upon administration, Astuprotimut-r is intended to stimulate a cytotoxic T-lymphocyte response against tumor cells expressing the MAGE A3 antigen that results in cell death.21

NewLink Genetics Corp. (Ames, IA, USA) is developing HyperAcute Melanoma cancer immunotherapy, which consists of human cancer cells that have been modified to express alpha-gal, a carbohydrate to which humans have preexisting immunity. In clinical trials, patients are receiving the vaccine as an intradermal injection.22 The manufacturer is also utilizing HyperAcute technology to develop treatments for pancreas and lung cancers.23

Polynoma LLC (San Diego, CA, USA), a unit of CK Life Sciences International (Holdings), Inc. (Hong Kong, China), is developing POL 103A. It is designed using a three-step process: collection of three melanoma antigens shed by melanoma cell lines during culturing, concentration of the antigens, and purification to prepare doses needed for vaccination.24 Polynoma hopes this injectable, multiple-antigen strategy will provide more targets for immune recognition and be suitable for allogeneic treatment of broad patient populations, which should not require individualized preparation.24

No TCVs for melanoma have yet received FDA marketing approval. FDA has approved one therapeutic vaccine, Provenge, which is...