Principles of Immunotherapy: Implications for Treatment Strategies in Cancer and Infectious Diseases

Abstract

The advances in cancer biology and pathogenesis during the past two decades, have resulted in immunotherapeutic strategies that have revolutionized the treatment of malignancies, from relatively non-selective toxic agents to specific, mechanism-based therapies. Despite extensive global efforts, infectious diseases remain a leading cause of morbidity and mortality worldwide, necessitating novel, innovative therapeutics that address the current challenges of increasing antimicrobial resistance. Similar to cancer pathogenesis, infectious pathogens successfully fashion a hospitable environment within the host and modulate host metabolic functions to support their nutritional requirements, while suppressing host defenses by altering regulatory mechanisms. These parallels, and the advances made in targeted therapy in cancer, may inform the rational development of therapeutic interventions for infectious diseases. Although "immunotherapy" is habitually associated with the treatment of cancer, this review accentuates the evolving role of key targeted immune interventions that are approved, as well as those in development, for various cancers and infectious diseases. The general features of adoptive therapies, those that enhance T cell effector function, and ligand-based therapies, that neutralize or eliminate diseased cells, are discussed in the context of specific diseases that, to date, lack appropriate remedial treatment; cancer, HIV, TB, and drug-resistant bacterial and fungal infections. The remarkable diversity and versatility that distinguishes immunotherapy is emphasized, consequently establishing this approach within the armory of curative therapeutics, applicable across the disease spectrum.

Keywords: T cell therapy; antibody therapy; cancer; immunotherapy; infectious diseases.

FIGURE 1

T cell-activating Therapeutic Strategies. (A) Treg depletion – biologics such Denileukin diftitox (DD) bind to target receptors on suppressor cells and initiate apoptosis via down-stream signaling. (B) Cytokine therapy – addition of pro-inflammatory cytokines increases immune activation while the addition of anti-inflammatory cytokines reduces immune activation. MAbs specific for cytokine receptors may also be used to block cytokine stimulation of the immune system. (C) Immune checkpoint blockade – mAbs block the interaction of inhibitory receptors CTLA-4 and PD-1, resulting in the activation of effector T cells (QYResearch) (D) Chimeric antigen receptors (CARs) T cells are modified T cells with a recombinant receptor; usually a scFv that redirects the specificity of effector T cells. First generation CARs that only comprised an activation domain were prone to anergy. Due to this signaling failure, second and third generation CARs, incorporating a CD3 chain and cytoplasmic domain of a co-stimulatory receptor, like CD28 were generated. Fourth generation CARs also included constitutive or inducible expression of co-receptors or soluble cytokines together with T cell activating CAR (Golubovskaya and Wu, 2016). (E) Bispecific antibodies containing two binding arms one specific for a target antigen and a second arm specific for CD3, thereby bringing T cells into close proximity to target cells and activating T cells while bypassing the need for MHC restricted engagement. (F) Vaccines – Introduction of non-infectious component to stimulate activation of T cells and development of memory immune cells.

FIGURE 2

HIV-targeting T cell Therapies. (A) Anti-CD3 and anti-gp120 DART treatment redirects CD8+ T cell to kill HIV infected CD4+ T cells (Perreau et al., 2017). (B) PD-1 check point inhibition of latently infected CD4+ T cell results in re-activation of the T cell and induction of apoptosis (Wykes and Lewin, 2018).

FIGURE 3

Antibody-Based Therapeutic Strategies. (A) Anticancer antibodies eliminate cancer cells and cause tumor destruction by targeting cancer antigens. (B) Antibody-conjugates – (i) Immunotoxins: bind to a surface receptor of an infected cell, undergo endocytosis and intracellular trafficking to the cytosol where most toxins induce cell death; (Becker and Benhar, 2012) (ii) ADCs: combine the specificity of mAbs with the cytotoxic potential of drugs and binds to internalizing receptors on target cell and are taken up by endocytosis; Once in the cell, ADCs undergo cellular trafficking to a lysosome where lysosomal degradation results in the cleavage and release of the active drug into the cellular cytoplasm where the drug induces apoptosis; (Scotti et al., 2015) (iii) Radioimmunoconjugates: antibodies attached to a radioactive molecule, once the antibody binds the target cell, the radio-particle’s radiation interacts with target cells, resulting in cell death. (C) Anti-viral antibodies – to eliminate a viral inhibition of cell infection, viral replication, cell-cell transmission, viral release as well as mediated killing of infected cells needs to occur; Palivizumab is a neutralizing antibody that binds to RSV preventing virus-host cell interactions (Groothuis and Nishida, 2002). Most antibacterial therapeutic mAbs function by inducing complement fixation and opsonophagocytic killing (OPK) of target bacteria; Panobacumab induces macrophage OPK of Pseudomonas aeruginosa (Que et al., 2014).