Targeted and Untargeted Fusion Proteins: Current Approaches to Cancer Immunotherapy

Chemokines, Costimulatory Molecules and Fusion Proteins for the Immunotherapy of Solid Tumors

“…Furthermore, studies show that the weak immunogenicity of tumor antigens might also be owing to inappropriate or absent expression of costimulatory molecules on tumor cells [77]. One immunotherapy approach in our laboratory and others is to provide artificial costimulatory signals in the form of agonist antibodies or, preferentially, immunoligand fusion proteins [12-14,78]. …”

“…Sturmhoefel et al demonstrated complete regression of 7-day old tumors in three murine models (MethA, P815 and MB49) and partial response in poorly immunogenic B16 melanoma tumors by treatment with soluble B7.1-Fc or B7.2-Fc fusion proteins [85]. More recently, our laboratory has generated two B7 fusion proteins (B7.1-Fc and B7.2-Fc) that significantly inhibited growth of COLON26, RENCA and WeHi tumor models in mice as single agent immunotherapy in a dose-responsive manner (Figure 3) [78,86]. Other strategies to express these costimulatory molecules on tumor cells include those by McHugh et al who constructed a recombinant glycol-lipid-anchored protein attached to the extracellular domain of human B7.1 [87].…”

“…Figure 4 illustrates the complex interaction between T cells and APCs in the immunologic synapse that results in robust immune stimulation. These interactions enhance the proliferation, cytokine response and survival of activated effector T cells and are critical for the generation of immunologic memory [12-14,78]. In contrast to B7 ligands, which act on naive lymphocytes, these T-cell costimulatory ligands act to boost responses of antigen-primed T cells and their receptors specifically and are typically upregulated following activation with TCR and CD28 signaling [12-14].…”

“…Concurrent elimination of tumor-associated suppressor cells and immune stimulation should provide improved antitumor immune responses. Indeed, as shown in Figure 9, our laboratory demonstrated that combination B7.1-Fc immunotherapy and depletion of CD25 + cells (Treg, treatment given on day 0) yielded significant improvement in tumor regression over monotherapy in both RENCA renal cell carcinoma and MAD109 lung carcinoma tumor models and was associated with increased effector T-cell tumor infiltration [78]. Another example comes from work by Hu et al in the treatment of CT26 colon carcinomas in mice [110].…”

“…Another example comes from work by Hu et al in the treatment of CT26 colon carcinomas in mice [110]. In these studies, combined Fc-mGITRL fusion protein and Treg depletion therapy yielded a significant improvement in the mean percentage tumor regression from 90% with Fc-mGITRL alone to 100% (complete tumor regression) with Fc-mGITRL and Treg d epletion [78]. …”