Haematologica 2003 - Supplements

myeloma. Blood 2001; 98:210-216.
6. Treon SP, Agus DB, Link B, Rodrigues G, Molina A,
Lacy MQ, Fisher DC, Emmanouilides C, Richards AI, Clark B,
Lucas MS, Schlossman R, Schenkein D, Lin B, Kimby E,
Anderson KC, Byrd JC: CD20 directed serotherapy induces
responses and facilitates hematological recovery in patients with
Waldenstrom’s macroglobulinemia. J Immunotherapy 2001;
24:272-279.
7. Treon SP, Mitsiades C, Mitsiades N, Young G, Doss D,
Schlossman R, Anderson KC: Tumor cell expression of CD59 is
associated with resistance to CD20 serotherapy in B-cell
malignancies. J Immunotherapy 2001; 24:263-271.
8. Treon SP, Belch AR, Kelliher A, Shima Y, Mitisiades
CS, Mitisades NS, Szczepek A, Ellman L, Harmon D, Grossbard
ML, Preffer FI, Pilarski LM, and Anderson KC: CD20-directed
serotherapy in multiple myeloma: Biological considerations and
therapeutic applications. J Immunotherapy 2002; 25:72-81.
9. Treon SP, Emmanouilides CA, Kimby E, Branagan
AR, Mitsiades C, Anderson KC, Frankel SR. Pre-therapy serum
levels predict clinical response to extended Rituximab in
Waldenstrom’s macroglobulinemia. Blood 2002; 100:813a.
10. Treon SP, Wasi P, Emmanouilides CA, Kimby E, Lister
A, Morel P, Frankel S, Preffer F, Kelliher A, Branagan A,
Anderson KC. Combination therapy with rituximab and
fludarabine is highly active in Waldenstrom’s
macroglobulinemia. Blood 2002; 100:211a.
11. Treon SP, Fox EA, Hansen M, Verselis S, Branagan
AR, Touroutoglou N, Maloney DG, Frankel SR, Anderson KC.
Polymorphisms in Fc gamma RIIIa (CD16) receptor expression
are associated with clinical response to Rituximab in
Waldenstrom’s macroglobulinemia. Blood 2002; 100:573a.
12. Treon SP, Hayashi T, Anderson KC. Treon SP.
Rituximab induced antibody dependent cell mediated cytotoxicity
(ADCC) is enhanced by thalidomide and its analogue Revimid.
Blood 2002; 100: 314b.
13. Treon SP, Kelliher A, Keele B, Frankel S,
Emmanouilides C, Kimby E, Byrd JC, Schlossman R, Mitsiades
N, Mitsiades C, Preffer F, Anderson KC. Expression of
serotherapy target antigens in Waldenstrom’s
macroglobulinemia: Therapeutic considerations and
conmsiderations. Sem Oncology 2003 (manuscript in press).
14. Hayashi T, Treon SP, Hideshima T, Tai YT, Akiyama
M, Richardson PG, Chauhan D, Grewal I, and Anderson KC.
Recombinant humanized anti-CD40 monoclonal antibody
triggers autologous antibody-dependent cell-mediated
cytotoxicity against multiple myeloma cells. Br J Haematology
2003 (in press).
13. Vaccination strategies in multiple
myeloma
P13.1
DNA VACCINATION: FROM THE LABORATORY TO
THE CLINIC
FK Stevenson, G di Genova, J Roddick, F McNicholl, H
McCarthy, J Watkins, SS Sahota, A King, J Rice, N Russell,
TJ Hamblin, CH Ottensmeier
Molecular Immunology Group, Tenovus Laboratory, Southampton
University Hospitals Trust, Southampton SO16 6YD, UK. Tel:#44
2380 796923, email: fs@soton.ac.uk
Introduction: DNA vaccines deliver encoded protein to the
immune system and can activate antibody and cellular responses.
Many new DNA vaccines against infectious diseases are in
clinical trial in normal adults. For cancer, the concept of placing
safe tumor-derived gene sequences into a vaccine format, and
inducing specific anti-tumor immunity, has obvious attractions.
However, for myeloma, there are two major problems. The first is
that tumor antigens are only weakly immunogenic, and the
second is that patients tend to be immunosuppressed, due either
to disease or to treatment. Both these problems have been
addressed in our study.
To strengthen immunogenicity, we have fused a sequence from
tetanus toxin to the tumor-derived sequence. This strategy
dramatically amplifies the response to the tumor protein and in
pre-clinical models leads to protective immunity. 1 Our first target
tumor antigen for myeloma is the idiotypic immunoglobulin
secreted by the neoplastic plasma cells. This is coded by the
variable region genes, V H and V L which can be readily identified
and isolated from patients’ tumor cells. We assemble these as
single chain Fv (scFv) a convenient way of making a single gene
able to produce idiotypic protein. The tetanus toxin sequence
codes the non-toxic C-terminal fragment (Fragment C (FrC)),
which is highly immunogenic and includes a “promiscuous”
helper determinant able to activate high levels of T-cell help. The
DNA scFv-FrC fusion gene induces specific immunity against a
model myeloma (5T33) with protection mediated by antiidiotypic
CD4+ T cells. 1 This vaccine design is in a trial for
patients with lymphoma which is almost complete. No
significant side-effects of the vaccine have been observed, and
immune responses against both components of the fusion gene
are evident in most patients.
To circumvent the problem of immunosuppression in patients
with myeloma, we are currently vaccinating donors of allogeneic
stem cell transplants. The safety of the DNA vaccines allows this
procedure, and ensures that a maximal response will be obtained.
Immune cells are being transferred to the recipient patients at the
time of donor lymphocyte infusion (DLI). Clearly, to extend the
approach to more patients, we need information on the capacity
of the immune response following conventional chemotherapy
with or without autologous transplantation.
Idiotypic antigen is a useful and safe tumor target, but we aim
also to vaccinate myeloma patients against other antigens. One
class of antigens which is attractive is the cancer-testis antigens,
known to be expressed only by cells of the testis, and by cells of a
range of cancers, including myeloma. 2 To attack these
intracellular antigens, it is necessary to induce cytotoxic T cells
(CTL) which can recognize processed peptides presented by the
MHC Class I molecules. For this, we have designed a novel
vaccine incorporating a gene encoding an engineered domain of
the FrC sequence (p.DOM) fused to an epitope from a cancer
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