Clinical Tumor Biology & Immunotherapy Group
Daniel E. SPEISER
Ludwig Center for Cancer Research
of the University of Lausanne
Web site: www.unil.ch/licr
Phone # : +41 (0)21 314 0182
Fax # : +41 (0)21 314 7477
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. In 1997 he joined the Ludwig Institute for Cancer Research in Lausanne, 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.
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.
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. Besides, there 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 cannot 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.
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. Nearly all 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 T-cell responses. 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.
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. Most promising are combination therapies. Future clinical studies require multiple drugs, and depend on productive collaboration between academia and industry.
List of Publications (2006 - 2011)
Publications-Speiser.pdf (136 Kb)
Anaïs Altmeyer, Postdoctoral Fellow
Petra Baumgartner, Research Associate
Natacha Bordry, Ph.D. Student
Laurène Cagnon, Research Associate
Loredana Leyvraz, Research Nurse
Silvia A. Fuertes Marraco, Postdoctoral Fellow
Christiane Meyer, Postdoctoral Fellow
Nicole Montandon, Technical Assistant
Timothy Murray, Ph.D. Student
Natalie Neubert, Ph.D. Student