Haematologica 2003 - Supplements

5T33 murine myeloma model. The validation of this DNA fusion
vaccine design led to a phase I/II clinical trial which is in
progress, and underscores the value of pre-clinical models.
As MM cells are MHC class I +ve, activation of cytotoxic CD8+
T cells may also be important. For this, a new DNA vaccine
design has been engineered, incorporating the first domain of FrC
(pDOM) fused to a defined CTL epitope. Here, potentially
competitive MHC class I-binding epitopes from FrC have been
removed, improving presentation of the TAA-derived epitope.
This vaccine design facilitates the induction of immune responses
to intracellular antigens, which are likely to be presented by the
class I pathway. For myeloma, the cancer testis antigen (CTAs)
have emerged as potential intracellular targets in early or late
stage disease. As CTA expression is restricted in normal cells to
the testis and placenta, which lack class I molecules, they provide
an additional advantage of being tumor specific. Several
potential CTA-derived CD8+ T cell epitopes, recognized by
various HLA haplotypes have been described.
We have explored the potential of CTAs as targets for cytotoxic
CD8+ T cells when delivered as DNA fusion vaccines in MM.
To test vaccine design, we used the murine P815 mastocytoma
tumor model, which expresses the P1A gene. This gene is silent
in normal murine tissues excepting the testis and placenta, and
therefore mirrors human CTA expression. P1A encodes a welldefined
MHC class I H2-L(d) CTL motif. A pDOM.epitope
vaccine incorporating this motif was constructed. A single
vaccination led to detection of epitope specific, IFN- positive
CTLs ex vivo, which could be expanded on re-stimulation in
vitro. These CTLs were able to kill P815 tumor cells in an
epitope specific manner. Importantly, in protection experiments
approximately 50% of vaccinated mice were protected from
tumor challenge using this vaccine. Our data therefore suggest
that effective immunotherapeutic intervention in myeloma may
be possible using DNA fusion vaccines encoding CTA epitopes.
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Vaccine Therapy of Advanced Refractory Multiple
Myeloma with Idiotype-Pulsed Dendritic Cells
(Mylovenge) Final Report.
M.R. MacKenzie , M.V. Peshwa, T. Wun, G. Strang, J.
Wolf. C. Redfern, J Mason, V. Caggiano and F.Valone
Sacramento Medical Foundation Blood Center Sacramento CA,
University of California Davis, Sacramento CA. Alta Bates Hospital
Berkeley CCA. Sidney Kimmel Cancer Center, San Diego CA.
Scripps Clinic, La Jolla CA. Sutter Cancer Center Sacramento CA.
and Dendreon Corp. Seattle WA.
Introduction. Dendritic cells are potent antigen presenting cells
that elicit antigen-specific immune responses in vitro and in vivo.
This report presents a phase I/II trial of idiotype-pulsed
autologous dendritic cells (Mylovenge) for treatment of multiple
myeloma. Forty-two patients with advanced refractory myeloma
were treated. The median number of prior chemotherapy
regimens was three, and 36% of patients had progressive disease
after stem cell transplantation. Median M protein was 3.0 g/dl.
Treatment Regimen: Patients underwent a leukapheresis and the
product shipped to Dendreon Corporation where it was processed
to enrich dendritic precursor cells, incubated with unmodified
autologous serum containing idiotype for 40 hours. The cells
harvested were returned to the clinical site. Mylovenge was
infused in either weeks 0, 4, 8, and 24 or weeks 0, 2, 4, and 24.
The mean dose was 350 ± 328 x 106 dendritic cells per infusion.
Results: Treatment related adverse events occurred in 10 of 134
infusions (7.5%)and two (1%), episodes of dyspnea were grade 3-
4 in severity. Mylovenge treatment induced idiotype-specific T
cell immune responses in 43.3% of evaluable patients without
pre-existing immunity. Development of immunity correlated with
improved time to disease progression. No complete or partial
remissions were observed. However nine of these heavily pretreated
patients had disease stabilization or minor responses for
more than 36 weeks. The overall median time to progression was
32 weeks.
Conclusion: The data indicate that Mylovenge induces idiotype
specific immunity and disease stabilization in patients with
refractory myeloma. Further testing in patients with lower tumor
burden is warranted.
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DENDRITIC CELLS VACCINATION POST-PBSCT IN
MULTIPLE MYELOMA: PRELIMINARY CLINICAL
EXPERIENCE.
J.Gayoso, C.Regidor, R.Yañez*, F.J.Peñalver**, R.Forés,
M.Briz, E.Ruiz, J.A.García-Marco, S.Gil, I.Sanjuan,
L.Barbolla**, F.Díaz-Espada*, M.N.Fernández y
J.R.Cabrera
Servicios de Hematología e Inmunología*. Clínica Puerta de
Hierro. UAM. Servicio Hematología** H. de Móstoles. Madrid.
INTRODUCTION: The curability of multiple myeloma is only
possible by means of allogeneic transplant, which is a procedure
available just for a few patients and criticized because of its high
mortality. After our group preliminary experience in follicular
lymphoma (Haematologica 2002; 87:400-407), we have started a
program of idiotypic vaccination after autologous peripheral
blood stem cell transplantation (PBSCT) with dendritic cells
pulsed with the purified paraprotein from patients with myeloma.
Here we communicate our initial experience in the selection and
vaccination of patients.
PATIENTS AND METHODS: We choose patients who were
diagnosed of myeloma and who were suitable for PBSCT. We
isolate the paraprotein from a sample at diagnosis and after
treatment with VAD courses, we perform the mobilization and
collection of PBSC, obtaining a purified fraction of CD34+ in
order to generate dendritic cells. After reevaluation at +3 months
post-PBSCT, the patients in minimal residual disease state began
the vaccination program: 3 subcutaneous doses of dendritic cells
pulsed with the purified paraprotein every two weeks, 5 sc doses
of paraprotein + KLH + GM-CSF monthly, 1 boost dose of
pulsed dendritic cells six months after the beginning of
vaccination and a final boost x 2 doses of paraprotein + KLH +
GM-CSF.
RESULTS: We have evaluated 15 patients suitable for the
vaccination program. PBSCT could not be performed in three
cases due to previous complications, and three are still receiving
chemotherapy treatment. PBSCT was performed in 9 patients: 1
died of refractory disease, two are waiting for reevaluation, 2
have not reached enough response and 4 cases have begun the
vaccination program (3 in CR and 1 in a very good PR). So far,
we have generated enough dendritic cells in all of them; 1 has
finished the vaccination and 3 are still receiving it without local
or systemic adverse effects.
CONCLUSION: The vaccination treatment seems to be feasible
and it does not seems to cause toxicity. One of the problems for
the development of the project is the loss of patients before
vaccination. (Supported by grant FIS 01/0913).
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