Melanoma vaccines: Are we making any progress?

Issue: August 25, 2008

ByWen-Jen Hwu, MD, PhD

No other cancer has been more of a target for vaccination than melanoma. The rationales for using melanoma as a model to develop cancer vaccine therapy include the absence of effective conventional therapies for disseminated and high-risk melanoma; occasional occurrence of spontaneous remission; rare dramatic and long-lasting tumor regression with immunotherapy, such as interferon, interleukin-2, and anti–cytotoxic T-lymphocyte antigen-4 antibody; and isolation of cytotoxic T lymphocytes from melanoma patients that recognize and kill tumor cells.

Wen-Jen Hwu, MD, PhD
Wen-Jen Hwu

For decades, a great deal of effort has been devoted to the preclinical and clinical testing of a variety of melanoma vaccines in patients with a high risk for recurrence and metastasis. The vaccines include, but are not restricted to whole-cell vaccines, ganglioside vaccines, peptide vaccines, dendritic cell vaccines, DNA vaccines and viral vectors. Commonly, these vaccines have shown promising results in early clinical trials (phase 1 or 2) in the adjuvant setting. Although it is possible that melanoma vaccines are more effective in a minimal disease setting, only randomized, controlled trials can convincingly demonstrate the effectiveness of a therapeutic intervention in the absence of measurable disease. However, in the randomized phase-3 trials, where vaccines were put alongside standard therapy for the comparison of efficacy, vaccines almost uniformly failed to confirm their superiority over conventional therapy.

Ganglioside vaccines

Since 1996, the regimen of high-dose interferon-alpha (HDI) has been established as a postsurgical adjuvant therapy in stage IIB and III high-risk melanoma. Because of the toxicity associated with HDI, the researchers of an Intergroup phase-3 trial (ECOG 1694) evaluated the efficacy of the GM2 ganglioside vaccine coupled to keyhole-limpet hemocyanin and administered with adjuvant QS-21 (GMK vaccine) vs. HDI in 880 patients with stage IIB/III melanoma. When the GM2 vaccine was tested in a single-institution randomized phase-2 study of 122 patients with resected stage III melanoma, it was shown that although GM2 antibody production was associated with a prolonged disease-free interval and survival, there was no statistically significant improvement in the disease-free interval or survival for patients treated with GM2/bacilli Calmette-Guérin (BCG) vs. BCG alone.

Moreover, the main disadvantage of ganglioside vaccines is that they do not generate cellular immunity, which is a critical element of antitumor immune response. After an interim analysis indicated inferiority of GMK compared with HDI in terms of relapse-free survival and overall survival, ECOG 1694 was closed in 2000 with a median duration of follow-up of 16 months.

The largest study in which the effectiveness of GMK was evaluated was the EORTC 18961 phase-3 trial. The researchers compared adjuvant GMK vaccine vs. observation in 1,314 patients with stage II melanoma. The preliminary data were presented by Alexander Eggermont, MD, at the 2008 ASCO Annual Meeting. Criteria needed for ending the trial were met after an interim analysis revealed GMK vaccine failed to show effectiveness of relapse-free survival over observation. The Independent Data Monitoring Committee decided not only to stop the trial but also to halt the additional vaccinations that were scheduled for patients in the vaccination-treatment arm. The GMK vaccine’s impact on survival remains unknown in both of these large randomized trials.

Allogeneic whole-cell vaccines

Allogeneic whole-cell vaccines, prepared from multiple tumor cell lines, have the advantages of induction of an immune response against a wide range of tumor antigens without the need of patient’s tumor tissue, availability for patients in all stages of disease, the potential for generating cellular and humoral immune responses, the ability of multiple vaccinations during a period of time, relatively simple preparation and wide applicability. The most extensively investigated allogeneic whole-cell vaccine to date is Canvaxin, a polyvalent vaccine developed by Donald Morton, MD.

Canvaxin is prepared from three irradiated allogeneic melanoma cell lines containing more than 20 melanoma-associated antigens. Data from two phase-2 studies showed a survival benefit of Canvaxin compared with matched-pair controls in patients with resected stage III and IV melanoma. Canvaxin has been investigated in the postsurgical adjuvant setting in two of the largest multicenter phase-3 trials involving patients with resected stage III (n=1,160) and IV (n=496) melanoma. Patients were randomly assigned into two treatment arms: Canvaxin plus BCG or placebo plus BCG. However, based on the recommendation of the independent Data Safety Monitory Board, both studies were terminated after an interim analysis in November 2005. The preliminary results were presented at the 2007 ASCO Annual Meeting; Canvaxin therapy failed to show additional benefit over BCG.

The second most studied allogeneic vaccine is Melacine (Corixa Corp.), developed by Malcolm Mitchell, MD. Melacine is registered as a combination of a mechanical tumor lysate comprising two melanoma cell lines and an immunological adjuvant DETOX. Contrary to many other melanoma vaccines, the efficacy of Melacine was evaluated initially in patients with non-resectable metastatic melanoma. Researchers from a phase-1 trial reported clinical tumor regression in 29% of 22 patients with metastatic melanoma. Subsequently, in an analysis of the data from seven phase-2 trials involving 139 patients, researchers found two complete responses and five partial responses in 106 patients with measurable stage IV melanoma. Data from a multicenter phase-3 clinical trial, in which the researchers compared Melacine with the Dartmouth regimen (dacarbazine, cisplatin, carmustine and tamoxifen) in 140 patients with stage IV melanoma, showed similar objective responses in patients treated with the vaccine (7.1%) vs. patients treated with combination chemotherapy (10.0%), as well as median survival (11 months vs. 12.4 months; P=.16).

The Southwest Oncology Group conducted a phase-3 trial to evaluate the efficacy of Melacine as adjuvant therapy in 689 node-negative patients with intermediate thickness melanoma (stage II) and found no benefit from the vaccine therapy. However, the data from this trial revealed a subgroup of vaccine-treated patients with expression of two or more HLA class I antigens (HLA-A2, A28, B44, B45, C3) had significantly improved five-year relapse-free survival compared with patients with the same antigen expression but not treated with the vaccine (83% vs. 59%; P=.0005). Most recently, data from a multicenter phase-3 trial in which the researchers compared Melacine and low-dose IFN-alpha with standard HDI adjuvant therapy in 600 stage III melanoma patients was reported. The data showed Melacine plus low-dose IFN-alpha had an effect comparable to standard HDI therapy, with no significant differences in relapse-free survival or overall survival, but exhibiting less toxicity. This study represents, for the first time, a randomized, large-scale trial of a vaccine regimen demonstrating such activity.

Despite the many disheartening results from clinical trials, data from studies of Melacine finally did shed some light on the potential prospects of creating a viable melanoma vaccine. What the data tell us is not only how to develop a melanoma vaccine (therapeutic vaccine with clinical response), but also the feasibility and potential of engineering a cancer vaccine in general. Although we are making encouraging progress in the creation of melanoma vaccines, further research is needed for the development of more efficacious melanoma vaccines. In addition, the use of multimodality approaches and combination regimens holds a great potential to enhance the effectiveness of melanoma vaccines.

Wen Jen Hwu, MD, PhD, is a Professor in the Department of Melanoma Medical Oncology at The University of Texas M.D. Anderson Cancer Center and is a member of the HemOnc Today Editorial Board.

For more information:

Elliott GT, McLeod RA, Perez J, von Eschen KB. Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine in the treatment of disseminated malignant melanoma. Semin Surg Oncol. 1993;2:41-53.

Mitchell MS, Kan-Mitchell J, Kempf RA, et al. Active specific immunotherapy for melanoma: phase OI trial of allogeneic lysates and a novel adjuvant. Cancer Res. 1988:48:5883-5893.

Michell MS, von Eschen KB. Phase III trial of Melacine melanoma theraccine versus combination chemotherapy in the treatment of stage IV melanoma. Proc Am Soc Clin Oncol. 1997;16:494a.

Sondak VK, Liu P-Y, Tuthill RJ, et al. Adjuvant immunotherapy of resected, intermediate-thickness node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol. 2002;20:2058-2066.

Sosman JA, Unger JM, Liu PY, et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome. J Clin Oncol. 2002;20:2067-2075.

Michell MS, Abrahms J, Thompson JA, et al. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon alpha-2b compared with high-dose interferon alpha-2b for resected stage III cutaneous melanoma. J Clin Oncol. 2007;20:2078-2085.