Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

Abstract

Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient's own immune system to selectively kill cancer cells. The immune system is the body's main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.

Keywords: CAR-T cell; OX40; cathepsin D; checkpoint inhibitor; dendritic cell vaccines; drug resistance; galectin-1; immunosuppression; oncolytic viruses; tumour-induced immune evasion.

Figure 1

Chimeric antigen receptor structure. CARs follow a generic design of four components. First generation CARs are composed of an extracellular antigen binding domain synthesised from the variable heavy and light chains of mAbs (scFv), a transmembrane domain and a CD3ζ intracellular signalling domain. Second generation CARs have an additional co-stimulatory domain, typically CD28 or 4-1BB, and third generation CARs will have two of these costimulatory domains.

Figure 2

Schematic representation of CTLA-4 and anti-CTLA-4 mechanisms of action on T cell activation. (a) Following the binding of MHC-presented immunogenic peptide antigen to the TCR, the co-inhibitory cell surface receptor CTLA-4 will bind to its ligands CD80 and CD86 found on antigen presenting cells, blocking the co-stimulatory signal (brought by CD28) thus preventing continued T cell activation. (b) By blocking CTLA-4–CD80 or CTLA-4–CD86 interaction with anti-CTLA-4 Abs, T cells proliferation will be activated and will migrate towards secondary lymphoid organs.

Figure 3

Schematic representation of PD-1 and anti-PD-1/PD-L1 mechanisms of action on T cell activity. Activated T cells at secondary lymphoid organs/tumour tissue (a) will upregulate the expression of co-inhibitory cell surface receptor PD-1. Binding of PD-1 to its ligands, PD-L1 or PD-L2, found on the surface of several immune cells as well as tumour cells, will inhibit signalling downstream of the TCR, thus downregulating T cell activity. (b) Targeting PD-1 or PD-L1 with antibody therapeutics can reinvigorate exhausted T cells at the tumour site, increase the activity, consequently allowing T cell-mediated tumour cell killing.

Figure 4

Action of DC vaccine in the body. Dendritic cells are matured and loaded ex vivo with tumour associated antigens (TAA). Following administration of the vaccine, antigen-specific T cells are activated and circulate round the body searching for cancer cells expressing their respective antigen. After detecting a cancer cell, T cells dock and exert their cytotoxic activity.

Figure 5

Dendritic cell dysfunction in cancer. Tumour cells have the ability to alter the microenvironment to impair the function of dendritic cells (DCs), suppressing an anti-tumour immune response. Metabolic stress: Tumour cell can decrease the availability of nutrients and oxygen in the tumour microenvironment (TME), altering DCs metabolism and impairing their function. Reduced antigen expression: Tumour cells have the ability to alter/hide their antigens to avoid detection by the immune system. Suppressive alarmins: Expression of alarmins, e.g., MMP-2 have been found to create an immunosuppressive environment by inhibiting the secretion of IL-12 by DCs thus preventing Th1 T cell differentiation and NK cell activation. Activation of T-ref cells and myeloid-derived suppressor cells (MDSCs): Tumour cells are able to directly induce the activation of T_reg cells and MDSCs which function to suppress the immune system by inhibiting T cell production. Reduced Dendritic Cell Infiltration: Tumour cells can reduce the expression of DC chemoattractants e.g., (CC-chemokine ligand 4). Activation of Immune Checkpoints: Tumour cells hijack the immune checkpoints to prevent detection. Overexpression of CTLA-4 and PD-1 ligands reduce the amplitude to T cell activation. Secretion of Immuno-suppressive cytokines: certain cytokines (IL-6 and IL-10) prevent the maturation and activation of DCs.

Figure 6

Mechanism of action of oncolytic viruses. Attachment to cancerous cells by OVs is realised through receptors found in high quantities on their surface. OVs are replication-attenuated and cannot infect normal cells due to restrictions which limit their infectivity to proliferating cells. Once the infection is established, continuous replication will finally lead to oncolysis and the spread of neoantigens in the microenvironment. Antigen-presenting cells can therefore process the tumour-associated antigens and cause activation and recruitment of cytotoxic T cells. Both oncolysis and OV mediated anti-tumour immunity are the basic mechanisms of function of these agents.

Figure 7

Enhancement of tumouricidal effect through combination immunotherapy. OVs infection of cancerous cells (1) leads to oncolysis (2) and reverse the immunosuppression of tumour microenvironment. DAMPs and PAMs released by bursting cells are recognised by DCs and presented to T cells (3). Virus progenies or viral components can be detected as well by DCs (4). Initiation of an anti-tumour immune response by DCs (5) needs to happen before activation of antiviral immunity and most OVs are designed to delay their detection. The anti-tumour immune cells are attracted by cytokines towards the tumour (6). The response against the tumour is enhanced by immune checkpoint inhibitors (7), as downregulation of cytotoxic T cells by Tregs or cancer itself is inhibited. CAR-T cells can enter the tumour more easily due to reverse immunosuppression of the tumour microenvironment (8).