Cancer immunotherapies: A hope for the uncurable?

Abstract

The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are crucially needed. In the review, we will discuss various forms of cancer immunotherapies that are being tested or already in the clinic. Moreover, we also highlight future directions to improve such therapies.

Keywords: antibodies; cancer; immunotherapy; oncolytic virotherapy; syngergistic effects.

FIGURE 1

The structure of an antibody. Antibodies are made up of two identical heavy chains andlight chains. The heavy chains are connected to each other via disulfide bridge and the light chainsare connected to the upper part of the heavy chains. Both heavy and light chains consist of variable (V) and constant regions (C). The heavy chain contains three constant domains (CH1-CH3) and onevariable domain (VH) while the light chain has one constant domain (CL) and one variable domain (VL). Moreover, the variable chains have three complementary determining regions which dictatethe specificity of the antibody. Antibodies can also be classified into two structures; the Fc and Fabregion. The Fc regions contains the CH2 and CH3 domains and is important to elicit Fc-effectormechanisms. The Fab regions compromise of CH1, VH, CL1 and VL regions and are important forepitope binding. Figures were created with BioRender.com.

FIGURE 2

The distrubion, structure and function of Fc receptors. The different types of Fc-g and Fc-a receptors found in humans. All activating Fc receptors contain an immunoreceptor tyrosine-basedactivation motif (ITAM) while inhibitory Fc receptors have an immunoreceptor tyrosine-basedinhibitory motif (ITAM) or none. Figures were created with BioRender.com.

FIGURE 3

IgG1 effector mechanisms. When an IgG antibody opsonizes a cancer cell it can elicitvarious effector functions. It can interact with C1q complement protein leading to the formation ofmembrane attack complex (MAC) leading to CDC. The Fc region can also bind to activating Fcg-Rs onNK cells or macrophages to elicit ADCC or ADCP, respectively. Neutrophils express a high level ofinhibitory Fcg-Rs leading to very little activation. Figures were created with BioRender.com.

FIGURE 4

IgA effector mechanisms. IgA effector mechanisms differ from IgG antibodies. IgAantibodies do not activate CDC, since they do not have a C1q binding site. The Fc region of IgA bindsto Fca-R on neutrophils cells or macrophages to elicit ADCC or ADCP, respectively. However, since NKcells do not express Fca-R, IgA antibodies do not activate such immune population. Figures were created with BioRender.com.

FIGURE 5

CTLA-4 suppression. Naive T-cells migrate to lymph nodes to become activated. Activationis usually provided by both MHC (loaded with an antigen) and co-stimulation from B7 (interacting with CD28) provided by a DC. After early stimulation, CTLA-4 is translocated to the surface of DCswhich then competes with B7 to bind to CD28 and downregulates T-cell activation. Whether a naiveT-cells undergoes activation or anergy is dependent on the balance of between CD28:B7 andCD28:CTLA4 signalling. Figures were created with BioRender.com.

FIGURE 6

PD-1 inhibition. PD-1 is usually expressed on effector T-cells and binds to either PD-L1 or PD-L2. PD-L1 can be expressed both on immune cells and tumours. Therefore, PD-1 can inhibiteffector T-cells at different stages of an immune response. After PD-L1 is activated by the receptor,they can initiate a signalling complex able to counteract MHC and B7 signalling. Figures were created with BioRender.com.

FIGURE 7

Adenovirus genome replication. DNA replication begins with the pTP-Pol complex invadesand serves as a primer to begin DNA replication (1). Pol protein then begins to synthesize the newDNA strand and displaces the original strand (2) which is then coated with DBP. As soon as the firststrand is completed it can then be used for template recycling (3). The displaced strand covered inDBP then circularizes because of the complementary ITR regions (4). The circularized DNA strand isthen used as a template and evaded by the pTP-Pol complex to begin the synthesis of thecomplementary strand (5 and 6) until completion (7). Figures were created with BioRender.com.

FIGURE 8

Enhancing oncolytic adenoviral therapy. Oncolytic adenoviruses have a specific tumortropism which can be utilized to arm such viruses with immunomodulatory genes. This then leads tothe expression and secretion of the immunomodulatory proteins in the tumor microenvironmentwhich increases immune infiltration. Figures were created with BioRender.com.

FIGURE 9

Different types of cancer immunotherapies. Cancer immunotherapies can come in differentfrom such as antibody therapy, ICI, oncolytic virotherapy, cancer vaccines, adoptive cell therapy orcytokine therapy. Figures were created with BioRender.com.