STANFORD, CaliforniaIdiotype (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.
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
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.
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.
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.