Daniel E. SPEISER
Ludwig Cancer Research Center,
Department of Oncology, University of Lausanne
Biopôle 3, 02DB92
Ch. des Boveresses 155
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 Ludwig Cancer Research and the Department of Oncology in Lausanne, where he is heading a Clinical Immunotherapy Development and Trial Program. His team optimizes (combination-) therapies with the aim to enhance immune and clinical responses. His research projects are focused on activation, differentiation and function of antigen specific T-cells, with special emphasis on direct ex vivo characterization 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 develop new therapies that are optimally activating anti-cancer T-cells mediating clinical responses in cancer patients.
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 rapidly improving, but they still require major improvements. As for other cancers, novel therapies are urgently needed, and immunotherapy is a possible option. Moreover, immunotherapy has taken a leader role in the treatment of patients with metastatic melanoma, to the extent that its preclinical and clinical experience is now being used as a central basis for the development of immunotherapies against other malignancies, such as carcinomas of lung, kidney, bladder and head & neck.
There is increasing evidence that T-cells play central roles in the control of malignant 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) that 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. A major reason is that these T-cells are enriched for tumor antigens, including those specific for mutated neo-antigens. Nevertheless, 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. 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 TCRs and T-cell clones are necessary. Besides TCR affinity and T-cell avidity to tumor antigens, several other “correlates of protection” must also be characterized, in order to determine whether a given T-cell response has the chance of providing anti-cancer activity in vivo in patients.
Step-by-step development of cancer therapies promoting optimal activation of anti-cancer T-cells
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. Progress relies on an important loop “from bench to bedside and back to bench”. By this strategy, immunotherapies are being steadily optimized such that they induce robust T-cell activation in patients.
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 appropriate clinical trial strategies and laboratory methods, allowing reliable investigation of human immune and cancer biology in detail, in vivo or directly ex vivo, avoiding artifacts introduced by in vitro systems.
Future treatments will rely on drugs that can overcome negative immune regulatory mechanisms in the tumor microenvironment. However, progress will also depend on therapies that induce T-cell responses that are strong and systemic. Most promising are combination therapies. Future clinical studies require multiple drugs. All this can best be developed by carefully monitoring immune and clinical responses in carefully designed clinical trials, by dedicated disease oriented teams, in close collaboration of academia with industry.
List of Publications (2009 - 2015)