title: Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death.
abstract: Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non-Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response.
authors.affiliation: C. Gandini Medical Oncology, Bone Marrow Transplantation Unit, Department of Experimental Oncology, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zappasodi
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
authors.forename: Gaia C
authors.initials: GC
authors.lastname: Ghedini
authors.forename: Italia
authors.initials: I
authors.lastname: Bongarzone
authors.forename: Michele
authors.initials: M
authors.lastname: Magni
authors.forename: Antonello D
authors.initials: AD
authors.lastname: Cabras
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Nicola
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology* / Q000528:radiation effects; D015153:Blotting, Western; D037282:Calreticulin / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology / Q000528:radiation effects; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009336:Necrosis / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D037282:Calreticulin; D019496:Cancer Vaccines; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate