Dendritic cell vaccines were reviewed during the Development of Therapeutic Cancer Vaccines conference held in Los Angeles, April 27-29, 2003. This conference was sponsored by the John Wayne Cancer Institute, the Association of Biologics and the Royal Society of Medicine.

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®.

Provenge™ for Prostate Cancer

Dr. Madhusudan Peshwa, from Dendron Corporation, presented the current status of Provenge™, a dendritic cell based vaccine, for prostate cancer. ¹

Provenge™ is a prototype vaccine that incorporates a specific antigen and a proprietary fusion protein of GM-CSF which are loaded onto autologous expanded antigen presenting cells (dendritic cells). The procedure requires mobilization and collection of PBSC for isolation of dendritic cells. Interestingly, this vaccine is given intravenously. Published phase I and II studies of Provenge™ in patients with prostate cancer show that the vaccine is “safe and of potential benefit”.

Results of a phase III double blind randomized trial suggests that this vaccine might be effective in earlier stage prostate cancer. In this study, 82 patients were randomized to receive Provenge™ and 45 to placebo. The end points were delay in pain and median time to tumor progression. There was no difference found in time to tumor progression between the two arms of this study. However, patients with Gleeson scores less than 7 had a decreased time to tumor progression compared to controls but this was not observed in patients who had Gleeson scores of 8 or more. The time to tumor progression was 9 weeks for the control group and 16 weeks for the vaccine group in those with low Gleeson scores. A similar observation was made on time to pain development. Adverse events included fever and chills.

Dendritic Cell Vaccine For Melanoma

Dr. Jacques Banchereau from the Baylor Institute for Immunology Research presented data on CD34+ dendritic cells as a melanoma vaccine. ²

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. ³ 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.

Tumor Lysates, KLH, and Loaded Dendritic Cells

The University of Michigan has been performing clinical trials on dendritic cell vaccines since the mid-1990s. Dr James Mule reviewed some of the trials which have contributed to an extensive IND.

Researchers have established that dendritic cells incorporate dead tumor cells and present specific antigens. The approach taken by the University of Michigan uses autologous dendritic cells collected from the peripheral blood which were cultured with GM-CSF and IL-4. ⁴ Tumor lysates are used as antigens and KLH as the adjuvant. Researchers have evaluated intra-dermal, intra-lesional, intra-nodal, and intra-venous immunizations.

Intravenous administration of tumor lysates, KLH, and loaded dendritic cells has demonstrated efficacy. This study involved 10 pediatric patients with solid tumors including PNET, fibrosarcoma, and neuroblastoma. There were 6 responses in 8 evaluable patients.

Several other trials are ongoing. One is a bladder cancer trial where patients are given intra-tumor vaccine prior to cystectomy. Another trial combines IL-2 to see if this improves activity of the vaccine. A third involves autologous stem cell transplants in children with sarcoma followed by immunization 14 days after stem cell infusion. Another trial will evaluate. Trials that will be started include a colorectal cancer study and a trial that evaluates intra-lesional vaccine injection in melanoma patients following treatment with fludarabine.

Dendritic-Tumor-Cell Fusion Vaccines

Another institution that has been conducting research on dendritic cell vaccines is the Beth Israel Deaconess Medical Center in Boston. David Avigan, presented their results with dendritic-tumor cell fusion vaccines. ⁵

This strategy involves either specific antigens (peptides) or lysates of tumors and cell fusion. In this approach, tumor cells fuse with the antigen presenting cells. The fused cells are described as unique with dendritic cell markers.One problem highlighted was the potential lack of activity of this vaccine in non-HLA identical patients. Also, single antigens are the easiest to manipulate but they have decreased specificity.

In the phase I trial, peripheral blood cells were collected by apheresis, cultured with GM-CSF and IL-4, incubated with tumor lysates and preparation of single cell suspensions. This study was performed in 16 women with breast cancer who had tumor that could be removed surgically. Ten of these women have been treated and 6 progressed during vaccine preparation and were not treated. One dramatic response (90%) was observed with a 24-month progression-free interval. One patient had a 40% response and another patient was stable for 5 months. Also treated were 17 patients with renal cell cancer. Disease was stabilized in 4 of these. T-cell responses and the generation of gamma interferon were observed. Future plans include adding a potent adjuvant to this vaccine.

References

1. Peshwa MV, APC Vaccines:Product Characterization and Clinical Development. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

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

3. Fay J, Palucka K, and Banchereau J, Dendritic Cells and Induction of Immunity Against Cancer. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

4. Mule J, Clinical Trials with Dendritic Cells:An Update of Product Development and Clinical Trials. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.

5. Avigan D, Dendritic-Tumor Cell Vaccines. Conference on the Development of Therapeutic Cancer Vaccines, Los Angeles CA April 27-29, 2008.