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DR. ROMERO: The rationale for development of cancer vaccines is based on experimental work in animal models, in which it has been demonstrated that specific CD8+ T-cells are able to eliminate tumors. It has also been shown in humans that the addition of recombinant interleukin-2 (IL-2), a T-cell growth factor, to in vitro culture of irradiated tumor cells with autologous lymphocytes from peripheral blood or tumor-infiltrating lymphocytes results in the expansion of T-cells that are mainly CD8+ cytolytic T-lymphocytes, which exert very potent anti-tumor effects in vitro.1 Moreover, it has been demonstrated that they often recognize tumor-associated antigens.2-5
Two types of cancer vaccines are in development. The first comprises cellular vaccines, which are supposed to present all possible relevant antigens to the immune system and would be expected to be effective in a large patient population. Instead of relying on immunological endpoints, the effects of cellular vaccines generally are determined by clinical endpoints. Accordingly, large numbers of patients over decades are needed for the progression from proof of concept to efficacy studies.
One of the simplest types of subunit vaccines is that based on synthetic peptides.
The second type of vaccine in development is that consisting of subunit vaccines, which are based on identification of a particular target antigen. Subunit vaccines are targeted to patient populations selected on the basis of their expression of the appropriate major histocompatibility complex (MHC) molecules that may present the antigens to the T-cells. Subunit vaccines allow detailed immunological monitoring and provide the possibility of rapidly optimizing vaccination. In this regard, metastatic melanoma has been well studied because of its strong immunogenicity and the lack of effective treatment options. Since 1991, when the first human tumor antigen was identified,6 well over 100 early-phase clinical studies with subunit cancer vaccines have been reported in patients with melanoma, prostate, lung, and hematologic malignancies. Specific T-cell responses were elicited in a large proportion of vaccinated patients (40%-80%). Subunit vaccines also exhibit modest but promising clinical efficacy. Indeed, clinical responses in the range of 20%-25% have been reported. Conservative estimates based solely on objective tumor responses reduce the proportion of responding patients to 3%Ð10%.7 One of the simplest types of subunit vaccines is that based on synthetic peptides. Peptide together with a small amount of a synthetic TLR-9 agonist delivered subcutaneously in an oil-in-water emulsion has been shown to be a very strong vaccine, rapidly inducing ex vivo detectable specific CD8 T-cells in all vaccinated patients.8
Major weaknesses in current therapeutic cancer vaccines that must be overcome are (1) low potency and (2) short-lived response.
Professor, Division of Clinical
Onco-Immunology
Ludwig Institute for Cancer Research,
Lausanne Branch
Lausanne, Switzerland
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Pedro Romero, MD
Håkan Mellstedt, MD, PhD
David Carbone, MD, PhD
David Jablons, MD
Charles A. Butts, MD
Philip Bonomi, MD
Slides presented at the InFocus Roundtable have been incorporated online as uncut audio-slide show presentations.
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Rationale for Targets for Cancer VaccinesPedro Romero, MD |
Cancer Vaccines and the Immune ResponsePedro Romero, MD |
Monitoring Response to Therapeutic Cancer VaccinesPedro Romero, MD |
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