Idiotype Vaccination With Dendritic Cells Induces Response in Multiple Myeloma Patients

STANFORD, California—Idiotype (Id) vaccination using dendritic cells induced Id-specific T-cell responses in multiple myeloma and was associated with a decrease in the myeloma protein level, according to Stanford University researchers, who reported their results at the ASH meeting.

Arcangelo Liso, MD, a postdoctoral fellow, explained that the Id determinant on the multiple myeloma immunoglobulin can be regarded as tumor-specific antigen. Tumor immunoglobulin is immunogenic and vaccination is protective in murine myeloma models. Anti-idiotype immune responses have also been described in lymphoma and multiple myeloma in humans. Adjuvant immunotherapy using the idiotype might therefore provide control of residual disease following peripheral blood progenitor cell transplantation (PBPCT).

Dr. Liso reported on 26 patients treated at Stanford with high-dose chemotherapy and PBPCT and later vaccinated with the idiotype. Individual idiotype proteins were isolated from sera collected at the time of diagnosis.

Patients received high-dose cyclophosphamide (Cytoxan, Neosar), followed by G-CSF and collection of peripheral blood progenitor cells. Four weeks later, a second collection was made after administration of high-dose etoposide (VP-16 [VePesid]) and G-CSF. The myeloablative regimen consisted of fractionated total body irradiation (TBI) or carmustine (BCNU [BiCNU]) followed by melphalan (Alkeran) and PBPC infusion.

Monthly Immunizations

Six months after transplant, patients were vaccinated with a series of monthly immunizations. Dendritic cells (DC) were obtained by leukopheresis starting 6 months after transplantation.

DC were then pulsed with either Id or Id coupled to Keyhole Limpet Hemocianin (KLH) as an immunogenic carrier protein and reinfused intravenously. Each patient received two DC infusions, 4 weeks apart. (KLH has been shown to increase immune responses in murine models.) This was followed by five subcutaneous boosts of Id-KLH conjugates. The DC infusions and the administration of Id-KLH boosts were well tolerated, with patients experiencing only minor and transient side effects.

Twenty-six patients were vaccinated. Their median age was 53, with a range of 37 to 68. Seven patients had IgA isotype and 19 had IgG isotype myeloma. Median number of regimens was one, and median number of chemotherapy cycles was six. All 26 patients were in partial remission prior to transplantation. After transplantation and prior to vaccination, 21 were in partial remission and 5 were in complete remission. Complete remission was defined as the absence of monoclonal immunoglobulin by immunofixation and less than 5% plasma cells in the bone marrow.

Immune Responses

The patients were observed for toxicity, immune responses, and tumor status. The infusion of dendritic cells and the Id-KLH boosts were very well tolerated, with no grade 3 or 4 toxicity observed. As for immune responses, among the 21 patients with partial remissions, 19 generated KLH-specific cellular immune responses and 1 developed an idiotype-specific cellular immune response. All five patients in complete remission developed a KLH-specific immune response and three developed an idiotype-specific immune response, Dr. Liso reported.

Twenty-two of the 26 patients completed the entire treatment sequence. Of the four who did not, two developed acute leukemia and two had progressive disease. Among the 17 patients alive at median follow-up of 30 months after transplant, 6 are in complete remission, 7 are in partial remission, and 4 have progressed. Of the nine who died, two had acute leukemia and seven had progressive disease.

Feasible Treatment

Of the patients who developed an anti-idiotype response, two remain in complete remission, one at 28 and the other at 35 months after transplant. One patient is in stable partial remission at 17 months and 1 relapsed 34 months after transplant, according to Dr. Liso.

An analysis of myeloma protein kinetics in the 21 patients in partial remission who were vaccinated showed that 8 had a decrease, 7 are stable, and 6 had an increase in these levels. “It is difficult to evaluate the contribution of the vaccination maneuver here, since decreases can also be seen in patients unvaccinated,” Dr. Liso remarked.

The results led Dr. Liso and colleagues to conclude that idiotype vaccination with autologous dendritic cells is feasible for myeloma patients after PBSCT, without undue toxicity. Immune responses were more likely to occur in patients who achieved complete remission. The clinical significance of these findings remains unclear, he cautioned.