Triple expression of B7-1, B7-2 and 4-1BBL enhanced antitumor immune response against mouse H22 hepatocellular carcinoma

Abstract

In this study, the antitumor consequences of using B7-1, B7-2 and 4-1BBL gene transfer have demonstrated the therapeutic potential of gene therapy approach for hepatocellular carcinoma.

Combination of a Bispecific Antibody and Costimulatory Antibody-Ligand Fusion Proteins for Targeted Cancer Immunotherapy

“…61 Nevertheless, in a tumor metastasis mouse model, strongest antitumor response was achieved by the transfer of T cells expanded in vitro in presence of both costimuli (CD28 and 4-1BB) 62 and also in a subcutaneous tumor model with B7.1/B7.2 and/or 4-1BBL transfected tumor cells reduced tumor outgrowth and increased survival was shown for the triple ligand combination, pointing to the benefit for combined application of CD28 and 4-1BB costimulation. 17 In summary, we have shown by means of our model system that a combinatorial approach of bispecific antibody and 2 costimulatory antibody-ligand fusion proteins is feasible, not only from the targeting point of view, but also in terms of their potential in combining successfully diverse strategies to create and influence artificially an immune response. Considering the diversity of antibodies and recombinant formats enabled by antibody and biomedical engineering technology, there is high potential for the flexible design of recombinant proteins to adapt this model system for further combinatorial approaches and dual targeting of tumor therapeutic relevance.…”

“…50 Consistent with these observations are in vivo data, where synergism of CD28 and 4-1BB costimulation was demonstrated in several mouse models with costimulatory ligandpresenting tumor cells. 9,16,17 Enhanced antitumor response monitored by tumor growth and survival was characterized by strong CTL response and long-term immunity. In vitro studies with a bispecific antibody (EpCAM ÂCD3) in the BiTE format have shown that polyclonal activation of CD4 + and CD8 + T cells was equal in terms of activation marker expression (CD69), although CD8 + T cells responded stronger with regard to proliferation and cytotoxicity.…”

“…[11][12][13][14][15] Furthermore, combined expression of B7 and 4-1BBL on tumor cells has shown a synergistic effect in eliciting an antitumor response in mouse models, presenting increased CTL activity and long-term tumor immunity. 9,16,17 Costimulatory approaches focus by definition on the promotion and modulation of an immune response without being capable to initiate it themselves. Thus, their efficacy relies essentially on an appropriate tumor-directed first signal.…”

Targeting Costimulatory Molecules to Improve Antitumor Immunity

“…In this regard, a phase II randomized controlled trial of poxiviral-based PSA-targeted immunotherapy in patients with metastatic castration-resistant prostate cancer showed that the treatment was well tolerated and associated with 44% reduction in the death rate [19]. Recently, multi-target vaccine approaches were tested in vitro , resulting in enhanced antitumor immune response against hepatocellular carcinoma and glioma cell lines [20, 21]. …”

CD4 T-cells transduced with CD80 and 4-1BBL mRNA induce long-term CD8 T-cell responses resulting in potent antitumor effects

“…In order to fully activate naive T-cells, costimulatory signals derived from CD80/CD86, CD40L, 4-1BBL, and OX40L expressed on APCs plays an essential role, along with the interaction of TCRs with the pMHC complex [15,16]. Results of other investigations show that immunization with engineered tumor cells expressing CD80 and 4-1BBL induces strong T-cell responses in mice and even confers protection against subsequent tumor challenge in some tumors [17][18][19][20]. Moreover, costimulation with 4-1BBL and CD80/CD86 allowed faster continuous T-cell proliferation than with either signal alone, and anergic T-cells that were non-responsive to ␣CD3 stimulation could be reactivated to proliferate when costimulated with 4-1BBL [21].…”