Recent advances in immunotherapies against infectious diseases

Abstract

Immunotherapies are disease management strategies that target or manipulate components of the immune system. Infectious diseases pose a significant threat to human health as evidenced by countries continuing to grapple with several emerging and re-emerging diseases, the most recent global health threat being the SARS-CoV2 pandemic. As such, various immunotherapeutic approaches are increasingly being investigated as alternative therapies for infectious diseases, resulting in significant advances towards the uncovering of pathogen-host immunity interactions. Novel and innovative therapeutic strategies are necessary to overcome the challenges typically faced by existing infectious disease prevention and control methods such as lack of adequate efficacy, drug toxicity, and the emergence of drug resistance. As evidenced by recent developments and success of pharmaceuticals such as monoclonal antibodies (mAbs), immunotherapies already show abundant promise to overcome such limitations while also advancing the frontiers of medicine. In this review, we summarize some of the most notable inroads made to combat infectious disease, over mainly the last 5 years, through the use of immunotherapies such as vaccines, mAb-based therapies, T-cell-based therapies, manipulation of cytokine levels, and checkpoint inhibition. While its most general applications are founded in cancer treatment, advances made towards the curative treatment of human immunodeficiency virus, tuberculosis, malaria, zika virus and, most recently COVID-19, reinforce the role of immunotherapeutic strategies in the broader field of disease control. Ultimately, the comprehensive specificity, safety, and cost of immunotherapeutics will impact its widespread implementation.

Keywords: T-cells; checkpoint inhibition; immunotherapy; infectious disease; vaccine.

Figure 1.

Immunotherapeutic advances employed against infectious disease. Most prominent types of immunotherapies described fall under three major categories, namely: (A) T-cell engineering strategies that use genetically modified patient-derived T-cells which are transiently cultured in vitro to express CARs. Such CAR T-cells provides a non-major histocompatibility complex driven recognition of abnormal cells and thus aid in enhanced targeting and elimination of diseased cells. The activity of native lymphocytes such as T-cells and natural killer (NK) cells can be enhanced through multiple ways as illustrated in panel B. (B) Activation of lymphocytes is accomplished through approaches such as vaccinations, that trigger immune memory response to combat invading pathogens. Checkpoint inhibition therapy aims at overcoming inhibitory signals (such as PD-1 or PD-L1) and enhances recognition of abnormal or diseased cells. Checkpoint inhibition also counteracts regulatory T-cells (T_reg) that may dampen host cytotoxic T cell responses to infections. Bispecific monoclonal antibodies (BsmAbs) can bind to 2 targets: an antigen on a diseased cell and an antigen on an immune effector like a cytotoxic T-cell (e.g. the CD3 antigen), thus bringing a cytotoxic T-cell in proximity to the cell that requires elimination. Administering proinflammatory cytokines serves to increase the immune activation of patients’ T-cells. (C) Antibody/ligand-based therapies make use of monoclonal antibodies (mAbs) or ligands that function through controlled modulation of other immune system components such as lymphocytes. Such approaches include checkpoint inhibition, BsmAbs, and cytokines. Additionally, therapeutic mAbs are used to neutralize antigen that contribute to pathogenesis such as host or pathogen surface antigens, toxins etc. Appropriately modified mAbs may also be conjugated with agents such a small molecule toxins for their targeted delivery.

Figure 2.

Immunotherapy for viral diseases. (A) Zika virus E trimers bind to entry receptors found in clathrin coated pits of target cells during the initial stages of viral infection. Monoclonal antibodies ZK2E10, ZIKV117, ZIKV195, and ZIKV190 bind to the entry receptors preventing viral binding and infection. ZIKV-195 crosslinks E protein preventing the formation of E trimers needed for viral entry. ZIKV-SigN-36 binds to the E protein resulting in the formation of aggregates which prevents viral entry. (B) IL-6 secreted by SARS-CoV-2 activated T-cells contributes to the pathogenesis related to cytokine storms during infection. Tocilizumab binds to IL-6 preventing activation of IL-6 receptor, reducing inflammation resulting from the cytokine storm. SARS-CoV-2 binding to ACE2 receptor induces viral entry into target cells. Monoclonal antibodies CB6, H4, and B38 bind to ACE2 prevent viral binding and entry. (C) Attachment of Ebola virus to the surface of macrophages is the first step of viral infection. Monoclonal antibodies M138, CA45, mb144, and FVM04 specific for Ebola glycoproteins (GP) bind to the GP and prevent their interaction with macrophages thus preventing infection. Monoclonal antibody M1382-mediated antibody-dependent cellular cytotoxicity through the recruitment of NK-cells which degranulate and activate death signaling by binding to death receptors expressed on the cell membranes of Ebola-infected macrophages. (D) The first step of HIV infection is the binding of GP120 to CD4 receptor on target cells. CD4-specific monoclonal antibodies Leronlimab, Ibalizumab, and UB-421 bind to CD4 receptor on T-cells prevent viral GP120 from binding to the receptor, thus prevent viral entry and infection. GP120-specific antibodies VRC07, VRC01, 3BNC117, VRC26.25, CAP256, and PGDM1400 bind to GP120 on the viral envelop and prevent GP120 from binding to CD4 thus prevent viral entry into target cells. CD8 and GP120 bi-specific antibodies bind to CD8 with one arm and GP120 with the second arm bringing HIV into close proximity of cytotoxic T-cells, enhancing their capacity to target and kill the virus. (E) Dual CD4 and HIV E protein-specific CD8 CAR-T-cell binds to both CD4 and E proteins on CD4 infected T-cells, inducing cell death of the infected T-cell. The expression of C46 on the surface of the CAR-T-cell prevent the CAR T-cell itself from being infected by the HIV virus.

Figure 3.

A: (i) Mycobacterium tuberculosis can induce the expression of ligands for PD-1, CTLA-4, TIM3, and LAG3 on the surfaces of infected macrophages, thereby inhibiting T-cell activation. Using mAb targeting either receptors on the T-cell or ligands on antigen-presenting cells (APC) can disrupt the interaction between receptors and ligands, resulting in T-cell activation. (ii) Invariant natural killer T-cells recognize mycobacterial lipids presented by CD1d on APCs and subsequently secrete cytokines to mediate an immune response. (iii) Various cytokines (IL-2; IFN-γ; TNF-α; GM-CSF) are involved in the Th1 response to Mtb infection, and this effect can be supplemented by systemically administered cytokines. (iv) The novel M72/AS01E vaccine consists of an immunogenic fusion protein (M72) derived from two Mtb antigens (Mtb32 and Mtb39) in the AS01E adjuvant. Upon application, the vaccine mounts humoral (B-cell) and cell-mediated (T-cell) responses, conferring protection against active TB infection. B: (i) The bispecific mAb, MEDI3902, targets two P. aeruginosa virulence factors, part of the type-3 secretion system (PcrV) and the Psl exopolysaccharide. Binding to PcrV prevents cytotoxicity while binding to Psl favors complement-dependent opsonophagocytic killing by host effector cells. (ii) Synthetic immunobiotiocs involve the application of polymyxin B (antibiotic) conjugated to antigenic epitopes. Polymyxin B attaches to the cell surface of Gram-negative bacteria while the antigenic epitopes recruit antibodies in human serum, thereby re-engaging components of the immune system (complement system and antibody-dependent cellular cytotoxicity) against the pathogen. C: (i) Various mAbs can be used to target the S. aureus alpha-toxin, resulting in a protective strategy against the alpha-toxin-mediated killing of host immune cells. (ii) DSTA4637S, an antibody-antibiotic conjugate, specifically binds to the cell surface of S. aureus, followed by opsonophagocytosis of the conjugate, resulting in the intracellular delivery of the antibiotic to S. aureus within the host cell, ensuring more effective antibiotic bactericidal effects. (iii) The combination of antimicrobial sonodynamic therapy with anti-virulence immunotherapy involves the use of toxin-neutralizing antibodies on the surface of a nanovesicle, which is simultaneously loaded with sonosensitizers [meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS)] that produce reactive oxygen species capable of inducing bacterial cell death upon ultrasound activation.