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Daniel Speiser
graduated in 1982 at the University of Zürich, Switzerland.
After clinical training in internal medicine, he specialized in
experimental infectious and tumor immunology with R.M. Zinkernagel.
In 1995 he habilitated at the University of Geneva and initiated
research projects at the University of Toronto. Since 1997 he is
Assistant and Associate Member of the Ludwig Institute for Cancer
Research, Lausanne branch, where he is heading the Clinical Immunotherapy
Trial Program. His team optimizes human T-cell vaccine formulations
to enhance immune responses. His research projects are focused on
activation, differentiation and function of antigen specific T-cells,
with special emphasis on ex vivo analyses of immune activatory and
inhibitory pathways and their relation to parameters of cancer biology.
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T-lymphocytes (“T-cells”)
can destroy tumor cells upon antigen specific recognition. Our goal is
to identify and validate tumor antigens and to elucidate pathways of T-cell
activation and differentiation necessary to achieve tumor cell killing
in vivo. Our clinical studies have the aim to identify vaccine strategies
inducing optimal T-cell activation.
| Introduction |
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Malignant melanoma
develops from pigmented cells (in the skin), and occurs with growing
incidence in western populations, due to increased sun exposure
and other factors. Current treatments of metastatic melanoma are
not satisfactory. As for other cancers, novel therapies are urgently
needed, and immunotherapy is a possible option.
There
is increasing evidence that immune cells play a role in the control
of malignant tumors. Cancer immunity has been demonstrated in various
animal models. For instance, mice with defined immunological defects
exhibit greater susceptibility to spontaneous and induced tumors.
Protection from tumor (progression) depends on multiple factors.
CD8 positive cytotoxic T-cells mediate tumor cell destruction and
thus are essential effector cells. They are activated, and develop
effector functions, upon recognition of specific antigen through
their clonally distributed T-cell receptors (TCRs). Many tumor antigens
of various types of tumors have been identified and molecularly
characterized. The so-called Cancer-Testis (CT) antigens are highly
specific tumor antigens, comprising several gene families of which
NY-ESO-1/ LAGE, MAGE, BAGE, and SSX families are the best studied.
A second group are the differentiation antigens (e.g. Melan-A, tyrosinase
and gp100) which are selectively expressed by the vast majority
of melanoma cells. It has been shown that these antigens are frequently
involved in cancer specific immune responses.
Detailed
clinical investigation revealed spontaneous tumor antigen specific
T-cell responses, demonstrating massive interactions between the
immune system and cancer cells. In metastatic tumor tissue of melanoma
patients, T-cells can accumulate in large numbers in absence or
before therapy. Such T-cell responses can also be generated in vitro,
but those are usually much less potent than T-cell responses developing
in vivo. Indeed, T-cells obtained from metastatic tissues have increased
potential to protect from tumor progression than T-cells generated
in vitro. Fact is that many T-cells can not protect from disease
(progression). One of the hallmarks of protective T-cells is their
capacity to productively recognize and interact with tumor cells.
Without this, the powerful cytotoxic function of these “killer”
T-cells is not sufficiently targeted, and tumor cells can more easily
escape. Despite considerable progress, it remains difficult to determine
whether human T-cells from individual patients are indeed capable
to recognize tumor cells. Therefore, extended analysis of T-cell
clones and TCRs are necessary.
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Projects |
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Step-by-step
development of human T-cell vaccination. Besides preclinical testing,
the development of novel treatments requires multiple small scale clinical
phase I trials to elucidate toxicity and biological effects in humans.
The pharmaceutical industry has the aim to rapidly upscale towards phase
II / III clinical trials, in order to proof clinical efficacy. However,
since most phase I trials provide results that represent only partial
progress, the applied experimental treatments require further optimization.
Thus, the majority of phase I studies re-direct research back to further
preclinical studies. Thus, progress relies on an important loop “from
bench to bedside and back to bench”. Our program for the development
of human T-cell vaccination has the aim to optimize vaccine formulations
such that they induce robust T-cell activation in melanoma patients. The
vaccines are based on tumor antigenic peptides, to which we add various
immunological adjuvants. Incomplete Freund's Adjuvant (IFA) was superior
to various other adjuvants including ligands for Toll-like receptor-2
and -4 (TLR2 and TLR4). To optimize IFA based vaccines, we added bacterial-type
CpG oligodeoxynucleotides known to trigger TLR9. All of 20 patients tested
had strong in vivo proliferation of peptide specific T-cells, reaching
~10 fold higher T-cell frequencies than vaccination with peptide in IFA
(without CpG), and 100-1'000 fold higher than with most other synthetic
vaccines (e.g. with proteins, DNA, RNA, or recombinant viruses). The enhanced
T-cell population consisted primarily of effector cells, with cytokine
production and killing that was comparable to T-cells specific for persistent
viruses (e.g. CMV and EBV).
T-cells
primed by vaccination versus endogenous tumor antigen. Our studies revealed
that weakly active T-cell vaccines primarily amplify immune responses
that have been initiated (“primed”) spontaneously by tumor
derived antigen. In contrast, the more powerful T-cell vaccine with CpG
and IFA can also prime de novo responses. But even then, the previously
primed T-cells remain dominant, and only a minority of patients develop
immune responses with dominance of newly primed T-cells. Our results show
that vaccines need to be optimized towards selective activation of T-cells
with highly specific TCRs. Furthermore, vaccine antigens may need to be
targeted to particular anatomical sites, and to dendritic cells, which
may enhance the selectivity of immune cell activation.
Immune
escape and regulation in the tumor microenvironment. Tumor cells can escape
from immune attack, e.g. through downregulation of antigen or MHC expression.
Fortunately, the majority of melanoma patients bear tumors that remain
positive for these critical molecules, even during progressive disease.
However, in the tumor microenvironment there are further mechanisms interfering
with T-cell immunity, for example through proteases, cytokines or immune
regulatory cells. While animal models revealed basic functions, the responsible
mechanisms in humans remain poorly understood. A major challenge is to
establish the clinical settings, and the laboratory methods, allowing
investigation of the human tumor microenvironment in detail, in vivo or
directly ex vivo, avoiding artifacts introduced by in vitro culture systems.
Combination
therapy. Future treatments will rely on drugs that can overcome negative
immune regulatory mechanisms in the tumor microenvironment. However, progress
will also depend on vaccines that induce T-cell responses which are strong
and systemic. Thus, future clinical studies will likely require multiple
drugs, and therefore depend on productive collaboration between academia
and industry.
| Selected
publications |
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Barbey, C., Baumgaertner, P., Devevre, E., Rubio-Godoy, V., Derre, L.,
Bricard, G., Guillaume, P., Lüscher, I., Lienard, D., Cerottini,
J.C., et al. 2007. IL-12 controls cytotoxicity of a novel subset of self
antigen-specific human CD28+ cytolytic T-cells. J Immunol 178:3566-3574.
Lejeune, F.J., Rimoldi, D., and Speiser, D. 2007. New approaches in metastatic
melanoma: biological and molecular targeted therapies. Expert Rev Anticancer
Ther 7:701-713.
Romero, P., Cerottini, J.C., and Speiser, D.E. 2006. The human T cell
response to melanoma antigens. Adv Immunol 92:187-224.
Speiser, D.E., Baumgaertner, P., Barbey, C., Rubio-Godoy, V., Moulin,
A., Corthesy, P., Devevre, E., Dietrich, P.Y., Rimoldi, D., Lienard, D.,
et al. 2006. A novel approach to characterize clonality and differentiation
of human melanoma-specific T cell responses: spontaneous priming and efficient
boosting by vaccination. J Immunol 177:1338-1348.
Baumgaertner, P., Rufer, N., Devevre, E., Derre, L., Rimoldi, D., Geldhof,
C., Voelter, V., Lienard, D., Romero, P., and Speiser, D.E. 2006. Ex vivo
detectable human CD8 T-cell responses to cancer-testis antigens. Cancer
Res 66:1912-1916.
Appay, V., Speiser, D.E., Rufer, N., Reynard, S., Barbey, C., Cerottini,
J.C., Leyvraz, S., Pinilla, C., and Romero, P. 2006. Decreased specific
CD8(+) T cell cross-reactivity of antigen recognition following vaccination
with Melan-A peptide. Eur J Immunol 36:1805-1814.
Appay, V., Jandus, C., Voelter, V., Reynard, S., Coupland, S.E., Rimoldi,
D., Liénard, D., Guillaume, P., Krieg, A., Cerottini, J.C., et
al. 2006. New generation vaccine in humans induces effective melanoma
specific CD8+ T cells in circulation but not in the tumor site. J Immunol
177:1670-1678.
Speiser, D.E. 2005. Immunological techniques: ex vivo characterization
of T cell-mediated immune responses in cancer. Curr Opin Immunol 17:419-422.
Speiser, D.E., Lienard, D., Rufer, N., Rubio-Godoy, V., Rimoldi, D., Lejeune,
F., Krieg, A.M., Cerottini, J.C., and Romero, P. 2005. Rapid and strong
human CD8+ T cell responses to vaccination with peptide, IFA, and CpG
oligodeoxynucleotide 7909. J Clin Invest 115:739-746.
Slingluff, C.L., Jr., and Speiser, D.E. 2005. Progress and controversies
in developing cancer vaccines. J Transl Med 3:18.
van Baren, N., Bonnet, M.C., Dreno, B., Khammari, A., Dorval, T., Piperno-Neumann,
S., Lienard, D., Speiser, D., Marchand, M., Brichard, V.G., et al. 2005.
Tumoral and Immunologic Response After Vaccination of Melanoma Patients
With an ALVAC Virus Encoding MAGE Antigens Recognized by T Cells. J Clin
Oncol.
Rothenfusser, S., Hornung, V., Ayyoub, M., Britsch, S., Towarowski, A.,
Krug, A., Sarris, A., Lubenow, N., Speiser, D., Endres, S., et al. 2004.
CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific
primary and memory CD8+ T-cell responses in vitro. Blood 103:2162-2169.
Ayyoub, M., Hesdorffer, C.S., Montes, M., Merlo, A., Speiser, D., Rimoldi,
D., Cerottini, J.C., Ritter, G., Scanlan, M., Old, L.J., et al. 2004.
An immunodominant SSX-2-derived epitope recognized by CD4+ T cells in
association with HLA-DR. J Clin Invest 113:1225-1233.
Speiser, D.E., Pittet, M., Rimoldi, D., Guillaume, P., Luescher, I., Liénard,
D., Lejeune, F., Cerottini, J.C., and Romero, P. 2003. Evaluation of melanoma
vaccines with molecularly defined antigens by ex vivo monitoring of tumor
specific T cells. Semin Cancer Biol 13:461-472.
Zippelius, A., Batard, P., Rubio-Godoy, V., Bioley, G., Lienard, D., Lejeune,
F., Rimoldi, D., Guillaume, P., Meidenbauer, N., Mackensen, A., et al.
2004. Effector function of human tumor-specific CD8 T cells in melanoma
lesions: a state of local functional tolerance. Cancer Res 64:2865-2873.
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