Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2

Abstract

Summary Cancer immunotherapies under development have generally focused on either stimulating T-cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8+ T-cells. This combination therapy induces an intratumoral “cytokine storm” and extensive lymphocyte infiltration. Adoptive transfer of anti-tumor T-cells together with this combination therapy leads to robust cures of established tumors and establishment of immunological memory.

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

“…21,34 Apart from its immunostimulatory effects, IL-21 exerts direct cytotoxicity on a variety of IL-21R-expressing NHLs, including diffuse large B-cell lymphoma (DLBCL), MCL, chronic lymphocytic leukemia, and follicular lymphoma. 32,[35][36][37][38][39][40][41][42] We found that the direct apoptotic effects of IL-21 in DLBCL and MCL were mediated via activation of an IL-21R-dependent signaling pathway that leads to phosphorylation of STATs followed by upregulation of cMyc and Bax and downregulation of BCL-2 and BCL-XL. 32,35 These studies suggest IL-21 may become a potent adjuvant to cancer immunotherapy against B-cell lymphoma.…”

“…41 A recent study of IL-2 fusion with fragment constant (Fc) region (Fc/IL-2) resulted in significant tumor control in isogenic tumor models. 42 Collectively, these studies suggest fusokine therapy may represent a potent therapeutic approach to NHLs.…”

A Complement-Optimized EGFR Antibody Improves Cytotoxic Functions of Polymorphonuclear Cells against Tumor Cells

“…Two years later, the same group published another study demonstrating similar effects of b-glucan treatment on tumor elimination by anti-Her2/neu (trastuzumab) or anti-EGFR (cetuximab) in mouse tumor models (52), thus revealing the importance of the complex interplay between Fc receptors and complement receptors on granulocytes in Abbased tumor therapy. Notably, a recent study demonstrated in tumor mouse models the pivotal role of concerted actions between innate and adaptive immune responses involving neutrophils, NK cells, macrophages, and CD8 + T cells in Ab-based tumor therapy (53). Hence, enhanced activation of the effector mechanisms of granulocytes by an efficient recruitment of the complement system should be targeted for successful immunotherapy of EGFR-positive tumors.…”

The Role of Adaptive Immunity in the Efficacy of Targeted Cancer Therapies

“…Antibody-based tumor targeting fusion protein with a preferential accumulation inside tumor tissue could provide a means to reduce the administered dose and consequently systemic side effects [77]. There have been developed several anti-HER2 based fusion proteins.…”