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Follow‑Up Analysis of a Randomized Phase III Immunotherapeutic Clinical Trial on Melanoma

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Follow‑Up Analysis of a Randomized Phase III Immunotherapeutic Clinical Trial on Melanoma 466 MOLECULAR AND CLINICAL ONCOLOGY 1: 466-472, 2013 Follow‑up analysis of a randomized phase III immunotherapeutic clinical trial on melanoma ROBERT SURIANO1, SHILPI RAJORIA1, ANDREA L. GEORGE1, JAN GELIEBTER1, RAJ K. TIWARI1 and MARC WALLACK1,2 1Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595; 2Department of Surgery, Metropolitan Hospital Center GNS, New York, NY 10029, USA Received November 27, 2012; Accepted February 2, 2013 DOI: 10.3892/mco.2013.97 Abstract. Development of a melanoma‑specific vaccine is over 70,000 individuals would be diagnosed with melanoma of clinical necessity. Therefore, a phase III, randomized, and approximately 9,000 individuals would succumb to the double-blind trial was performed (June 1988-June 1991) to disease in the USA (3). Surgery remains the standard treatment assess the clinical effectiveness of our vaccinia melanoma for localized melanoma skin lesions, whereas the standard of oncolysate (VMO) vaccine in stage III melanoma patients. care for metastatic melanoma remains a single chemothera- Patient data were collected from 11 institutions, as well as peutic agent, known as dacarbazine, which has a response rate from the Social Security Death Index and were analyzed from of 10-15% in patients and is not associated with long-lasting April through August 2008 for disease-free interval (DFI) and responses, since the median survival rate is approximately overall survival (OS). The median OS for patients who were nine months (4,5). This lack of effective chemotherapeutic administered the VMO vaccine was 7.71 years, compared compounds has led researchers to focus on the development of to 7.95 years for patients administered the vaccinia virus immunotherapeutic methods to treat melanoma. vaccine (V) (p=0.70). The median DFI for the VMO group Immunotherapeutic melanoma-treatment strategies have was six years, while the median DFI for the V group has been investigated over the past 30 years and resulted in not yet been reached. This analysis demonstrated a statisti- various clinical trials (6). Immunotherapy has focused on cally significant difference in OS in females in both groups four major areas: immuno-activating cytokines, immuno- (VMO, 79%; V, 92%), as compared to males (VMO, 57%; modulating antibodies, adoptive T-cell therapy and vaccines. V, 68%) (p=0.0473). This follow-up analysis demonstrated that The immuno-activating cytokine, interleukin-2 (IL-2), is one females had a survival advantage over males, thus warranting of three FDA-approved compounds used to treat melanoma; further investigation. This significant observation may facili- it is, however, associated with high toxicity (7). The FDA tate the recruitment of patients for future clinical trials, as well has recently approved an immunotherapeutic compound that as determine which patients are more likely to benefit from targets melanoma, known as ipilimumab (anti-CTLA-4 anti- receiving the VMO vaccine. body) (8), which has shown promising results in clinical trials. In addition, although it is not an immunotherapeutic compound, Introduction it should be noted that the FDA has approved a small molecule inhibitor, known as vemurafenib (BRAF inhibitor) (9), which Melanoma arises from the transformation of the pigment- has also shown promising results in clinical trials. Although producing melanocytes of the skin and is often initiated by there are ongoing clinical trials aimed at assessing the effec- deregulation of the MAPK pathway, which is known to modu- tiveness of various immunotherapeutic compounds, further late melanoma cell survival (1,2). According to the National research on melanoma vaccines is required, since melanoma Cancer Institute (NCI), melanoma remains the most fatal type is one of the most immunogenic types of cancer and several of skin cancer and is the fifth most commonly occurring cancer clinically relevant melanoma-associated antigens (MAAs) in men and the seventh in women. In 2011, it was estimated that have already been identified (10‑13). The possibilities for developing antigen-based vaccines against melanoma are numerous, as multiple MAAs have been identified since the 1970s, cloned (14,15) and well‑character- Correspondence to: Dr Marc Wallack, Department of Surgery, ized, in vivo and in vitro, with respect to their antigenicity. Metropolitan Hospital Center, 1901 1st Avenue, New York, NY Despite their characterization, not all antigens elicit an optimal 10029, USA immune response, which may be attributed to the fact that the E-mail: [email protected] selected antigens were not HLA-typed to match the vaccinated individuals or that an adjuvant is required to help initiate an Key words: melanoma, vaccine, vaccinia virus, immunotherapy antigen‑specific immune response. Examples of antigens used in vaccines against melanoma are MAAs such as gp100, tyros- inase, MAGE-3 and MART-1 (16-18); however, phase I and II SURIANO et al: VACCINIA-BASED MELANOMA IMMUNOTHERAPY 467 studies have not shown promising results when administered difference in either DFI or OS in patients treated with VMO, as a single antigen̸protein‑containing vaccine (19,20). Other compared to those treated with V; however, the same subset of clinical trials have focused on the generation of vaccines males, aged 44‑57 years, with one to five positive nodes, treated that incorporate one or more antigens, combined with the with VMO, showed a statistically significant improvement in administration of an immuno-activating cytokine, such as survival at two‑, three‑ and five‑year intervals (p=0.046). IL-2 or granulocyte-macrophage colony-stimulating factor Based on the results and trends observed in our clinical (GM-CSF) (19,21,22). One such clinical trial recently showed trial, we report on a 10-year follow-up analysis on the patients a high response rate and progression-free survival in patients originally involved in the phase III trial. We have now compiled with advanced melanoma who were vaccinated with gp100 follow-up data on the surviving patients originally enrolled in and IL-2 (23). Melanoma vaccines using a multivalent antigen the phase III trial and present data that reflect upon the validity approach appear promising, although further studies should be and efficacy of the trial design originally envisioned. performed to determine the conditions that are likely to foster a productive immune response, such as selecting an adjuvant Materials and methods with optimal immuno-stimulatory properties. Previously, we developed a melanoma multivalent vaccine Patients. As previously described (31-33), 250 patients were using live vaccinia virus-augmented melanoma cell lysates, in accrued from 11 participating institutions, from June 1988 order to generate the vaccinia melanoma oncolysate (VMO), to January 1991. These institutions are listed as follows: MD or first generation melanoma vaccine. The VMO is composed Anderson Cancer Center, Houston, TX; University of Alabama, of four established allogeneic melanoma cell lines, providing a Birmingham, AL; Emory University, Atlanta, GA; University variety of MAAs that help generate a robust immune response, of Pennsylvania, Philadelphia, PA; Wayne State University, using vaccinia virus as an adjuvant (24,25). Vaccinia virus was Detroit, MI; University of Florida, Gainesville, FL; University incorporated as an adjuvant in VMO since i) it modifies and of Chicago, Chicago, IL; University of Colorado, Denver, CO; re-expresses host membrane-associated melanoma antigens, Duke University, Durham, NC; Brown University, Providence, thus making these antigens more recognizable to the immune RI; and Mount Sinai Medical Center, Miami Beach, FL, USA. system of the host (26) and ii) it non-specifically induces Patients were selected according to strict eligibility criteria, tumor‑specific cytotoxic T lymphocytes (CTLs), thus initiating which included histologically-positive nodes, age range the host immune response (27). 15-70 years, Karnofsky performance status <70% and no The efficacy of VMO in the treatment of melanoma was concomitant malignancy, apart from basal and squamous cell studied in several preliminary trials (24,28), followed by the carcinoma of the skin. Originally, patients with any number Southeastern Cancer Study Group-sponsored phase I and II of positive nodes were eligible for the trial during the first trials (29,30). Given the favorable results of these trials, we year (June 1988-June 1989). Subsequently, only patients with proceeded with the first randomized, prospective, double- one to five positive nodes were accepted, since the protocol blind, multi-institutional, pharma-produced, FDA-approved, advisory panel (including Dr Charles Balch, statistician; NCI-funded melanoma vaccine phase III trial (1988-1991), in Dr Al Bartolucci, medical advisor; and Dr Marc Wallack, order to evaluate the effects of VMO on disease-free interval principal investigator) considered more than five positive (DFI) and overall survival (OS) in patients with stage II nodes to represent excessive tumor burden. Further criteria for melanoma (based on the International Union Against Cancer ineligibility included patients with: lentigo maligna melanoma; criteria). Although the results of the first interim analysis satellite lesions at a distance >2 cm from the primary lesion; (performed in May 1994) showed no statistical difference in previous chemotherapy, radiotherapy, or immunotherapy; OS between patients receiving VMO and those receiving the matted nodes (except during the
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