Immunity and metastasis: in situ activation of protective T cells by virus modified cancer vaccines.
Data from animal models and clinical observations from immunotherapy trials suggest that tumour reactive host T cells can have an important role in the control of metastasis and tumour rejection. If tumour cells express tumour associated antigens recognizable by T cells, their antigenicity/immunogenicity is usually weak, and accessory molecules are required to stabilize the T cell/tumour cell interaction and to deliver the antigen/T cell receptor (TCR) mediated signal (signal 1) together with costimulatory signals (signal 2). The sum of these intracellular signals received by the corresponding T cells with the fitting TCR may determine the intensity of the anti-tumour response. A deficiency of anti-tumour T cell responsiveness in cancer patients could thus be due to a lack of signal 1 and/or signal 2 or to inappropriate timing between the two signals. A further point to consider is the distinction between primary and secondary T cell responses: between priming of virgin T cells and activation of primed memory T cells. Our experience with a metastasizing animal tumour suggests that the microenvironmental requirements for these two steps differ. This means that the site of a primary (or secondary) tumour may be good for one type of response (eg priming) but not for the other (eg memory response). One purpose of active immunotherapy could therefore consist of exposing the cancer patient's immune system to its own tumour cells in the context of a new microenvironment that may be well suited for activating memory type responses. On the basis of these considerations, we discuss the possibilities of immunological intervention and propose the use of a two-component cancer vaccine for active immunization and two signal stimulation of endogenous memory T cells in tumour bearing animals or cancer patients. As a specific component, we favour the use of intact, viable, radiation inactivated autologous tumour cells, which should represent the closest match to the patient's own cancer. If this is not possible, cells from allogeneic corresponding tumours or tumour cell lines could be used. On a longer time scale of treatment, one may consider an induction therapy with autologous vaccine followed by maintenance therapy (when autologous material has run out) with allogeneic material. As a second non-specific component, we favour and have good experience with a virus, NDV, which can easily attach to the cells of the vaccine and facilitate the delivery of costimulatory signals to tumour reactive T cells following postoperative vaccination of tumour bearing hosts.(ABSTRACT TRUNCATED AT 400 WORDS)
Schirrmacher
V
V
Institut für Immunologie und Genetik, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
D000818:Animals; D004195:Disease Models, Animal; D007157:Immunologic Surveillance / Q000276:immunology; D007167:Immunotherapy; D009362:Neoplasm Metastasis / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D014612:Vaccines / Q000276:immunology*
D014612:Vaccines