Mannan-MUC1–Pulsed Dendritic Cell Immunotherapy: A Phase I Trial in Patients with Adenocarcinoma

Abstract

Purpose: Tumor antigen-loaded dendritic cells show promise for cancer immunotherapy.This phase I study evaluated immunization with autologous dendritic cells pulsed with mannan-MUC1 fusion protein (MFP) to treat patients with advanced malignancy. Experimental Design: Eligible patients had adenocarcinoma expressing MUC1, were of performance status 0 to 1, with no autoimmune disease. Patients underwent leukapheresis to generate dendritic cells by culture ex vivo with granulocyte macrophage colony-stimulating factor and interleukin 4 for 5 days. Dendritic cells were then pulsed overnight with MFP and harvested for reinjection. Patients underwent three cycles of leukapheresis and reinjection at monthly intervals. Patients with clinical benefit were able to continue with dendritic cell-MFP immunotherapy. Results: Ten patients with a range of tumor types were enrolled, with median age of 60 years (range, 33-70 years); eight patients were of performance status 0 and two of performance status 1. Dendritic cell-MFP therapy led to strong T-cell IFNg Elispot responses to the vaccine and delayed-type hypersensitivity responses at injection sites in nine patients who completed treatments. Immune responses were sustained at 1 year in monitored patients. Antibody responses were seen in three patients only and were of low titer. Side effects were grade 1 only. Two patients with clearly progressive disease (ovarian and renal carcinoma) at entry were stable after initial therapy and went on to further leukapheresis and dendritic cell-MFP immunotherapy. These two patients have now each completed over 3 years of treatment. Conclusions: Immunization produced T-cell responses in all patients with evidence of tumor stabilization in 2 of the 10 advanced cancer patients treated. These data support further clinical evaluation of this dendritic cell-MFP immunotherapy.

Potent Dendritic Cell Vaccine Loaded with Latent Membrane Protein 2A (LMP2A)

“…All kinds of modified DC approaches have been investigated to be applied in antitumor responses. It has been shown that protein-loaded DCs contain viral antigens and have antigen presentation capability that makes them become a potentially attractive vector for trigger T-cell antitumor responses (9)(10)(11)(12)40). However, there is no report about immunotherapy with specific CTL in NPC patients induced by DCs loaded with LMP2A protein.…”

“…It has been demonstrated that DCs modification such as protein load can be successfully applied in tumor immunotherapy. DCs loaded with protein can promote cellular immunity both in experimental animal models and humans (8)(9)(10)(11). Optimal antigen loading strategies provide epitopes presented by both MHC class I and class II leading to a diverse immune response in which many clones of cytotoxic T cells (CTLs) and CD4 + T cells are involved (12)(13)(14).…”

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

“…Recent studies of MUC1-targeted therapies in lung, prostate and ovarian malignancies (Loveland et al, 2006;North et al, 2006) show therapeutic promise. As the majority of epithelioid mesotheliomas demonstrate strong MUC1/epithelial membrane antigen (EMA) positivity by immunohistochemistry (Ordonez, 2003) similar anti-MUC1 therapeutic strategies may have potential in mesothelioma.…”

Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease

“…Dendritic cell vaccines have been widely studied and are currently being applied for treatment of cancers. [21][22][23][24][25][26] Most investigations have focused on the major ability of DC based vaccines to stimulate CD8C T cells. 51,52 However, there is evidence as well that DC based vaccines can stimulate antigen specific B cells with the concomitant release of antibody.…”

“…20 Antigen-sensitized DCs have been evaluated as potential vaccines for cancer treatment. [21][22][23][24][25][26] Other clinical trials have also been performed to evaluate their potential utility against other disorders such as infectious diseases. 27,28 In fact, in animal studies, DCs sensitized with mutant Ab peptides were used to vaccinate different mouse models of AD, without eliciting a generalized inflammatory response.…”