During the Development of Therapeutic Cancer Vaccines conference held in Los Angeles, April 27-29, 2003, 4 vaccines for the treatment of melanoma were reviewed: Canvaxin™, Melacine®, MAGE-3.A1, and CD34+ dendritic cell vaccine.

Canvaxin™

One of the most studied melanoma vaccines is Canvaxin™ which was developed at the John Wayne Cancer Center and CancerVax Inc. in Carlsbad, California. Dr. Van Epps of CancerVax reviewed the history of this vaccine for the treatment of melanoma. ¹

Canvaxin™ is made from 3 melanoma cell lines originally developed 30 years ago. These 3 cell lines represent a wide range of HLA types (matching 95% of the population) and melanoma antigens. The cells alive, but have been irradiated and cannot reproduce. The vaccine is prepared under GMP conditions and is cryopreserved. After thawing, Canvaxin™ is injected along with BCG. Clinical studies have shown that patients who respond immunologically to this vaccine had clinical responses. Previous studies have shown significant activity in both stage III and IV patients with melanoma. The current trial is a randomized trial which has enrolled 1,118 stage III and 670 stage IV patients with melanoma.

Melacine®

Dr. Martin A Cheever, of the Corixa corporation, presented the current status of their melanoma vaccine Melacine®. ² Melacine® appears to have significant activity in patients with melanoma who have HLA types A2 and/or C3. However, the FDA will require a new study which will take 8-10 years to complete before they approve the commercial use of Melacine® in the US. Melacine® is already approved in Canada. Corixa has not yet decided whether or not to perform this study.

Melacine® is a vaccine made from tumor lysates from two melanoma cell lines and has defined antigens, CHER-2/neu and L523S. For immunization, the lysates are combined with Detox, an adjuvant. The original clinical testing of Melacine® began in 1985. In 1988, a phase II trial in patients with metastatic melanoma showed a 6% response rate with 4 patients in complete remission for 7 to 10 years. On the basis of this trial, the vaccine was approved by the FDA of Canada.

In 1990, a phase III randomized trial with Melacine® vaccination revealed that, when the data was analyzed by HLA type, Melacine® benefited A2 and/or C3 positive patients. This data was not accepted by the FDA because the comparison of outcome by HLA type was retrospective and not prospective. Thus, a new trial randomizing patients with the A2 and/or C3 phenotype will be required before approval.

This trial was performed in patients with stage II melanoma undergoing surgery for tumors 1.5-4 mm with negative lymph nodes. Patients randomized to vaccine received 40 doses of Melacine® over 2 years. They found that the 5-year relapse-free survival was similar between groups, with 66% for the Melacine® group and 62% for the control group. However, when the data was analyzed by HLA type they found that patients who were A2 and/or C3 positive benefited from Melacine®. The 5-year relapse-free survival was 80% for the Melacine® group who were HLA A2 and/or C3 positive compared to 40% in the control group. The overall survival at 5 years was 89% for the Melacine® group and 76% for the control group which was also statistically significant.

MAGE-3.A1

Dr. Thierry Boon from the Ludwig Institute in Brussels presented data on a peptide melanoma vaccine called MAGE-3.A1 and a recombinant vaccine of the same antigen called ALVAC. ³ Both vaccines have produced significant regressions in approximately 10% of patients with stage IV melanoma. The responses to these two vaccines were correlated with CTL responses with 9/16 with CTL responses having clinical responses compared to 2/18 clinical responses in patients without CTL responses. It wasn’t clear where this vaccine was going but attempts to improve it by using a recombinant form did not apparently improve results. 

Dendritic Cell Vaccine For Melanoma

Dendritic cells are antigen presenting cells that have been incorporated into several vaccine strategies over the past decade. Dendritic cells are CD34+ cells collected from the peripheral blood, usually after the administration of Neupogen®. Dr. Jacques Banchereau from the Baylor Institute for Immunology Research presented data on CD34+ dendritic cells as a melanoma vaccine. ⁴

In an ongoing study, 18 patients with melanoma had PBSC mobilized with Neupogen®, which were then cultured in the presence of alfa interferon. These cultured dendritic cells were then pulsed with 4 peptide melanoma antigens. The vaccine was then administered to patients with stage IV melanoma. These peptide loaded CD34+ dendritic cells induced melanoma specific immune responses. This study began in 1999 and of 17 evaluable patients treated, 7 are surviving. Four of these patients had consolidation vaccination and surgery or IL-2 as further therapy. These studies will continue although the exact strategy to develop a commercial vaccine was not clear.

Dr. Joseph Fay, from the Baylor Institute for Immunology Research in Dallas, outlined the results of a dendritic cell vaccine in patients with melanoma. ⁵ This vaccine was derived from CD34+ peripheral blood cells that were pulsed with tyrosinase, MAGE-3, MART-1, and gp 100 peptides that are melanoma specific or melanoma associated antigens. The adjuvant was KLH. They immunized 17 evaluable patients. Six of 7 patients who did not have specific immunity to 2 or less antigens had progression of melanoma. “In contrast, 9 out of 10 patients with immunity to greater than 2 melanoma antigens had measurable tumor regression or stable disease”. Five of the 18 patients in this study had a complete response to vaccine treatment alone. Two additional patients achieved a CR after additional vaccinations and surgery. Seven patients are alive at a median of 39 months from the start of the study. Interestingly, responses were seen in patients with liver and brain metastasis.

References

1. Van Epps D, Characterization of Polyvalent Allogeneic Cancer Vaccines. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

2. Cheever M, Defined antigens and Allogeneic Tumor Lysates as Cancer Vaccines. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

3. Boon T, Development of Peptides as Tumor Vaccines. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

4. Banchereau J, Dendritic Cells as Melanoma Vaccines. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.