Current Trends in Cancer Immunotherapy

Abstract

The search for an effective drug to treat oncological diseases, which have become the main scourge of mankind, has generated a lot of methods for studying this affliction. It has also become a serious challenge for scientists and clinicians who have needed to invent new ways of overcoming the problems encountered during treatments, and have also made important discoveries pertaining to fundamental issues relating to the emergence and development of malignant neoplasms. Understanding the basics of the human immune system interactions with tumor cells has enabled new cancer immunotherapy strategies. The initial successes observed in immunotherapy led to new methods of treating cancer and attracted the attention of the scientific and clinical communities due to the prospects of these methods. Nevertheless, there are still many problems that prevent immunotherapy from calling itself an effective drug in the fight against malignant neoplasms. This review examines the current state of affairs for each immunotherapy method, the effectiveness of the strategies under study, as well as possible ways to overcome the problems that have arisen and increase their therapeutic potentials.

Keywords: CAR T-cell therapy; cancer; cytokine therapy; immune checkpoint inhibitors; immunotherapy; oncolytic viruses; vaccines.

Figure 1

(A) Localized in the adjacent tumor tissue, the immature CD14⁺ dendritic cells (DCs) internalize the captured tumor antigen, become mature CD14⁺ DCs and migrate to the lymph node for presentation to naïve lymphocytes, in particular CD8⁺ T-cells, CD4⁺ T-cells and CD19⁺ B-cells, which are in constant recirculation. After that, activated lymphocytes exit from the lymph node, activated CD19⁺ B-cells produce corresponding antibodies and activated CD4⁺ T-helpers and CD8⁺ cytotoxic T-lymphocytes (CTLs) migrate to the tumor niche. At the same time, the primary tumor releases chemokines that attract FOXP3^hi Tregs. (B) In the lymph node, mature CD14⁺ DCs present tumor antigens to naïve lymphocytes, activated CD4⁺ T-helpers release interleukin (IL)-2 for clonal expansion of activated CD8⁺ CTLs and help naïve B-cells on the border of the B-cell zone of the lymph node. In addition, naïve B-cells may capture tumor antigens from the lymph and, after internalizing, activated B-cells proliferate and, furthermore, they can present tumor antigens to naïve CD4⁺ T-cells. All in all, activated lymphocytes leave the lymph node. (C) There are two mechanisms that occur in the tumor niche: escape or elimination. Elimination of the tumor, in the main, occurs due to activated CD8⁺ CTLs and CD56⁺ natural killer (NK)-cells. Activated CD19⁺ B-cells only help activated CD8⁺ CTLs and CD56⁺ NK-cells by releasing interferon-γ (IFN-γ) and IL-12, which enhance the cytotoxic effects, and also produce cytotoxic antibodies that cause a cell-mediated immune response. Activated CD4⁺ T-helpers and CD56⁺ NK cells release pro-inflammatory cytokines like IFN-γ and tumor necrosis factor alpha-α (TNF-α), that enhance each other. Apoptotic tumor cells release antigens that stimulate immune cells. On the other hand, primary tumors can inhibit effector immune cells by releasing soluble antigens and anti-inflammatory chemokines that attract FOXP3^hi Tregs, thereby creating a tumor microenvironment. Moreover, antibodies produced by activated CD19⁺ B-cells may block access to tumor cell for activated CD8⁺ CTLs.

Figure 2

Binding of CD80/CD86 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) keeps CD8⁺ T-cell in an inactivate state, that do not let them kill tumor cells. An anti-CTLA-4 antibody blocks the binding and activated CD8⁺ CTLs can eradicate tumor cells. The binding of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) helps tumor cells avoid apoptosis, inhibiting activated CD8⁺ CTLs. Anti-PD-1 and anti-PD-L1 antibodies block the binding and enable activated CD8⁺ CTLs to kill tumor cells.