Synergistic Effect of Dendritic Cell Vaccination and Anti-CD20 Antibody Treatment in the Therapy of Murine Lymphoma

Abstract

Indolent B-cell lymphomas are characterized by repeated remissions and relapses with most patients eventually dying of the disease. Although combination treatments with chemotherapy and the anti-CD20 antibody rituximab improved duration of remissions and overall survival, the disease is essentially incurable. Thus, novel therapeutic approaches are needed. One such approach is active immunization with dendritic cells (DCs). Given that rituximab depletes patients of normal B cells, optimal vaccination strategies for rituximab-treated patients require induction of effector T cells. We have previously demonstrated in a murine model that idiotype (Id)-keyhole limpet hemocyanin-pulsed DCs induced Id-reactive CD8 T cells and protection against tumor challenge in the absence of anti-Id antibodies. On the basis of these results, we investigated vaccination in a therapeutic model, in which mice carrying advanced tumors of the highly aggressive 38C-13 lymphoma were treated with chemotherapy and anti-CD20 antibodies combined with a DC-based vaccine. As a rule, cytoreduction by cyclophosphamide was required in each regimen of combination treatment, and vaccination with tumor cell-loaded DCs was more effective than vaccination with Id-keyhole limpet hemocyanin-loaded DCs. We demonstrated that under conditions of large primary tumors that had already spread to lymph nodes, when anti-CD20 antibody treatment showed minimal effect and DC vaccination had no effect, synergism between anti-CD20 antibodies and DC vaccines resulted in significant long-term survival that did not involve active antitumor antibody production. Combination treatments including tumor cell-loaded DC vaccines may therefore provide a strategy for enhancing the potency of therapy in rituximab-treated patients.

Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect

“…DCs loaded with antibody/tumor antigen immune complexes stimulate potent T cell responses that are capable of eradicating tumors (Kalergis and Ravetch, 2002). In vitro studies have demonstrated that anti-CD20 mAb treatment of lymphoma cells stimulates DC maturation and CD8 T cell activation (Selenko et al, 2002), and a synergistic effect between vaccination with hCD20 + tumor cells and anti-hCD20 mAb treatment has been demonstrated in mice (Gadri et al, 2009). CD8 + DCs are considered to be excellent cross-presenters of cell-associated antigens (Mayer et al, 2014), and soluble immune complexes stimulate cross-presentation by DCs more potently than antigen alone (Berlyn et al, 2001; Rafiq et al, 2002).…”

Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

“…Other proposed strategies involve elimination of tumor cells by radiotherapy, chemotherapy, antibody therapy, or viral oncolytic therapy in combination with DC vaccination as determined in animal models of lymphoma and prostate cancer, among others [178–181]. This aims to decrease the deleterious effect of tumor cell products while generating an inflammatory milieu that can enhance the efficacy of the vaccination.…”

Fc-Receptor Interactions Regulate Both Cytotoxic and Immunomodulatory Therapeutic Antibody Effector Functions

“…In support of this, lymphoma-specific anti-idiotype T-cell responses were detected in some patients treated with anti-CD20 rituximab (57,58). Anti-CD20 mAb treatment of lymphoma cells in vitro stimulates DC maturation and CD8 T-cell activation (59), and vaccination with huCD20 þ tumor cells and anti-huCD20 mAb treatment showed a synergistic antitumor effect in mice (60). Studies using mouse models have also demonstrated that passive administration of anti-CD20 mAbs can initiate antitumor T-cell responses and vaccinal effects (21,61).…”