Recent advances in the field of anti-cancer immunotherapy

Abstract

Background: The main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index - the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein-protein interaction and deliver cytotoxic events to a tumor-specific antigen.

Review scope: It is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy.

General significance: Immunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects.

Keywords: Anti-cancer therapies; Antibodies; Cancer; Immunotherapy.

Fig. 1

Flowchart for the protocol for Phage Display Technology. V_L and V_H refer to variable light and variable heavy chains in antibodies. Various genes responsible for encoding the variable regions of antibodies are amplified from human B-cells and used to build an antibody library. The library is cloned for display on the surface of the phage. In a procedure similar to the two-hybrid system, the antibody fragment is expressed in fusion with the virus coat protein. The phage display library goes through a process of selection, whereupon those that do not bind to the selected epitopes are washed away. The ones that do are eluted and amplified by infection of Escherichia coli. After an adequate number of selection series, the specificity of the desired antibody can be assessed through Enzyme-Linked Immunosorbent Assay (ELISA) or Fluorescent-Activated Cell Sorting (FACS). Once the achieved specificity is satisfactory, the genes corresponding to the antibody's variable regions can be cloned into whole human IgG expression vectors and transfected into cells, such as HEK293, which will produce fully human mAbs (hmAbs). The antibodies will be expressed into the cell medium. At that point, the supernatant can be collected for antibody purification.

Fig. 2

Direct tumor cell killing by antibodies. This event may occur through receptor antagonist activity, which occurs when an antibody blocks dimerization, downstream signaling and kinase activation, resulting in inhibition of proliferation and, finally, apoptosis (such is the case with TACE/ADAM17 binding and the therapeutic antibody Herceptin). It can also be triggered by antibodies binding to a tumor cell surface receptor, leading to its activation and, consequently, apoptosis; which is represented by the mitochondrion. Finally, an antibody may bind to an enzyme, leading to signaling abrogation, neutralization and cell death. Conjugated antibody therapies are based around delivering a payload – for example, a drug, toxin, small interfering RNA or radioisotope – to a tumor cell.