Gene therapy of B-cell lymphoma with cytokine gene-modified trioma cells

Abstract

The trioma approach is a new immunotherapeutic strategy for treating B‐cell lymphomas. It is based on converting the tumour idiotype to a bispecific immunoglobulin that redirects the idiotype to antigen‐presenting cells. We show here that even pre‐existing tumours can be eradicated by trioma vaccination, that the trioma approach is superior to vaccination with cytokine gene‐modified autologous tumour cells and that there is a synergism between trioma immunisation and GM‐CSF gene transfer. Furthermore, we show that the immunising potential of GM‐CSF gene‐modified autologous lymphoma cells is not as dependent on the cytokine expression level as described for other tumour models, such that even minute expression rates are effective. IL‐4 gene transfer in the lymphoma model is considerably less efficient or even ineffective when more sensitive systems are used. Remarkably, trioma‐mediated effects are extinguished when IL‐4 is expressed by the trioma cell. Int. J. Cancer 83:113–120, 1999. © 1999 Wiley‐Liss, Inc.

Antitumor effector functions of T cells are dependent on in vivo priming and restricted T‐cell receptor expression

“…These engulf Ag and induce a polyvalent tumor‐specific T‐cell response. Even established A20 tumors can be eradicated by a single injection of the trioma cell line BiV25 and a long‐term memory can be induced 23…”

Specific targeting of whole lymphoma cells to dendritic cells ex vivo provides a potent antitumor vaccine

“…By targeting whole trioma cells that harbour potentially all lymphoma-derived Ag against FcγR-bearing professional APC, this approach has the potential to overcome the insufficient Ag presentation by malignant B cells and to induce a polyvalent antitumor response, as was shown by delivering trioma cells as a cellular vaccine in vivo [9,12,26]. In the present study, we set out to optimize exogenous pulsing of DC for tumor immunotherapy in a murine lymphoma model and established an ex vivo modification of the trioma approach.…”

“…5C12 is an A20 variant that was genetically engineered to express the Id as an Ig/GM-CSF fusion protein [10]. DC were prepared by culturing bone marrow precursors from BALB/c wildtype or β 2 m -/- mice in standard medium in the presence of 100 ng/ml recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) [26]. Medium was replaced every two days.…”

“…However, this immunity was not capable of conferring complete tumor protection in some mouse models in vivo [9,12]. As immunization against a panel of tumor-derived Ag turned out to be necessary for successful tumor rejection in different tumor models [9-13,26], we investigated exogenous loading of DC that relies on Ag targeting to FcγR but nevertheless can provide antigenic polyvalency. Both antigenic polyvalency and receptor-mediated Ag internalization was achieved by pulsing DC with whole tumor cells that were modified to express an FcγR specificity.…”

CCL3/MIP-1αIs a Potent Immunostimulator When Coexpressed with Interleukin-2 or Granulocyte-Macrophage Colony-Stimulating Factor in a Leukemia/Lymphoma Vaccine

“…This may be one of the reasons why, in vaccine models aiming to eradicate preestablished leukemia, GM-CSF as a single immunogen has proven comparatively ineffective. Only when vaccine cells were selected for high-producing clones or vaccine cell numbers clearly exceeded the leukemic challenge dose have benefits been observed Hsieh et al, 1997;de Vos et al, 1998;Dunussi-Joannopoulos et al, 1998;Strehl et al, 1999;Stripecke et al, 1999). In most models of acute leukemia, GM-CSF has therefore been combined with additional costimulation for induction of an effective antineoplastic immune response (Dilloo et al, 1996;Nakazaki et al, 1998;Stripecke et al, 1998).…”