Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo

Abstract

IntroductionAmong human cancers, B-cell lymphomas appear among the most susceptible to immunotherapeutic strategies, because of their high rate of response to monoclonal antibodies (mAbs) targeting the B-cell differentiation antigen CD20 and encouraging results from early phase clinical trials of tumor-specific therapeutic vaccines. 1 The availability of both passive and active immunotherapeutic agents against B-cell lymphomas has made them an important testing ground for the development of clinically effective immunotherapies in humans. [1][2][3] The best characterized target for active immunotherapy of B-cell lymphoma is tumor-specific immunoglobulin (idiotype, Id). 4 Immunization of patients with Id protein derived from their own tumors can elicit humoral and T cell-mediated immune responses associated with improvements in survival and tumor burden. [5][6][7][8] Traditional Id vaccines consist of Id protein chemically conjugated to the highly immunogenic carrier protein keyhole limpet hemocyanin (KLH) and injected together with an immunologic adjuvant. 1 Because of their potent antigenpresenting properties, 9 dendritic cells (DCs) have been used to augment lymphoma vaccine effectiveness, and durable tumor regressions have been observed after immunization with Id-loaded DCs. 10,11 Granulocytemacrophage colony-stimulating factor (GM-CSF), a DC growth and maturation factor, has also been used as an effective adjuvant in Id-KLH vaccines. 4,7,12 However, despite the elegant nature of the Id vaccine approach, shortcomings of this strategy include the requirement of producing a custom-made protein for each patient and limitation of the antitumor response to a single antigen. In contrast, vaccines using whole tumor cells offer the opportunity to elicit immunity against the entire collection of antigens expressed by the tumor. Pulsed DC vaccination using apoptotic tumor cells or lysates has emerged as a popular strategy for immunization against tumors in a variety of preclinical and human studies. While killed tumor cells in the form of apoptotic bodies or freeze-thaw lysates alone display limited immunogenicity, DCs loaded with these preparations have been found to elicit antitumor immunity in a variety of preclinical models [13][14][15][16] and early clinical trials. [17][18][19][20][21] Other strategies using DCs to present the full repertoire of tumor antigens expressed by tumor cells include fusion with tumor cells 22 or pulsing with tumorderived RNA. 23 The goal of these approaches is to achieve processing and presentation of exogenous cell-derived antigenic peptides by professional antigen-presenting cells (ie, "crosspresentation"), thereby evoking a CD8 ϩ T-cell antitumor response. 24 One attractive strategy for increasing tumor antigen crosspresentation is the targeting of IgG-complexed antigens into DCs via Fc␥ receptors. 25 Antigen-antibody complexes internalized via Fc␥ receptors at the DC surface efficiently enter both the MHC class I 26-28 and class II 29,30 antigen-presentation pathways. Several investi...

Structural and functional characterization of the trifunctional antibody catumaxomab

“…6 In this context, it is noteworthy that the chimeric mouse/rat Fc portion binds not or only marginally to the inhibitory low-affinity receptor FcγRIIb (CD32b), e.g., on B lymphocytes and platelets. 4 As the issue of abrogating the inhibitory FcγRIIb-engagement is central for improving effector mechanisms induced by mAbs such trastuzumab (anti-HER2/neu) or rituximab (anti-CD20), this feature of Triomab…”

Recapitulation of the anti-Idiotype antibodies as vaccine candidate

“…Moreover, anti-idiotypic antibodies can mimic either non-protein or protein antigens. The two possible vaccinating antibodies whether it's Ab1 or Ab2 the end result will be the anti-anti-idiotypic response (Ab3) produced because of the host from the tumors that need antibody-dependent cell mediated cytotoxicity (ADCC), and further cell-mediated cytotoxic pathways including natural killer cells and cytotoxic T cells [36]. Once immunization is performed against TAA with antibodies that provoke internal mage antibodies they resulted in the clonal development of cells that play in the antitumor activity.…”

Localized Low-Dose Radiotherapy for Follicular Lymphoma: History, Clinical Results, Mechanisms of Action, and Future Outlooks

“…As with LDRT, rituximab induces apoptosis (65), and it is currently suspected that this apoptosis contributes to the induction of a specific antilymphoma immune response in mice (66). The ability of rituximab to enhance radiationtriggered apoptosis in lymphoma cells (67,68) has also been described.…”