Pathogenic assaults lurk around every corner, from bacteria on surfaces to airborne viruses. Using immunotherapy for infectious disease treatment leverages the immune system to do what it does best — defend against pathogens.
Download this poster from Drug Discovery News to learn how scientists use immunotherapy to neutralize pathogens and mitigate infectious diseases.
Humans are surrounded by pathogenic assaults, from bacteria that lurk on surfaces, to airborne viruses that infect the respiratory system. As the world grapples with the ongoing pandemic, researchers focus on the body’s first line of defense: the immune system. Immunotherapy is typically thought of in the context of cancer treatment, but many of the same therapies used to activate the immune system to treat cancer may also combat infectious diseases. These therapies fall into three broad categories: engineered T cells, therapeutic antibodies, and the activation of endogenous T cells.1
Therapeutic Monoclonal Antibodies
Therapeutic antibodies are perhaps the most versatile immunotherapy treatment. Researchers use vaccines to supply therapeutic antibodies, or stimulate the production of therapeutic antibodies through various mechanisms, including introducing a dead or attenuated virus, or the RNA sequence for a viral protein.1 Monoclonal antibodies have neutralized the Zika virus, Ebola virus, and in some cases SARS-CoV-2, and are considered the treatment of choice for many bacterial pathogens.6,7,8,9
Monoclonal antibodies neutralize antigens on the surface of viral and bacterial pathogens.
Molecular engineers may conjugate monoclonal antibodies with small molecules toxins and other biological agents to ensure their targeted delivery and efficiency.
Cytokines
Physicians administer proinflammatory cytokines to activate T cells capable of destroying pathogens. However, with SARS-CoV-2 infection, macrophages and T cells may produce too many cytokines, resulting in a cytokine storm. In such cases, physicians administer immunomodulatory drugs such as Tocilizumab to decrease cytokine production.2
Engineered T Cells
Researchers genetically modify patient-derived T cells to express chimeric antigen receptors (CARs) and return them intravenously into the body, where they preferentially target specific pathogens. Bi- and trispecific CARs prevent HIV infection while efficiently killing HIV-positive cells in mouse models.3 CARs specific to cytomegalovirus (CMV) have also been described.4 Two ongoing clinical trials are exploring the ability of CAR T cell therapy to eradicate latent HIV reservoirs in humans.1 Researchers may also use adoptive cell transfer, where they manipulate and expand T cells ex vivo to combat the Zika virus.5
Checkpoint Inhibition
Similar to cancer cells, dysfunctional T cells infected with Mycobacterium tuberculosis aberrantly express inhibitory receptors such as PD-1 and PD-L1. These receptors bind to functioning T cells and dampen their ability to recognize and destroy diseased cells. Checkpoint inhibition therapy administers antibodies that bind to these inhibitory signals, allowing T cells to identify infected cells. While revolutionary for cancer, checkpoint inhibition for infectious disease is still under investigation.10,11
Bispecific Antibodies
Bispecific antibodies bind two separate targets, an antigen on the diseased cell and an antigen, such as CD3, on a cytotoxic T cell. By binding both antigens, bispecific antibodies bring diseased cells into proximity with immune effector cells, where they can be promptly eliminated. Researchers engineered a bispecific antibody that neutralizes the Zika virus and prevents the generation of resistant mutant strains.6 Clinical trials investigating the ability of engineered bispecific antibodies for Pseudomonas aeruginosa and Staphylococcus aureus bacterial pathogens are also underway. Such treatments may prevent bacterial pneumonia in high-risk patients.12,13,14
References
1. D. Ramamurthy et al., “Recent Advances in Immunotherapies Against Infectious Diseases,” Immunotherapy Advances, 1(1):1-16, 2021.
2. N. Biran et al., “Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study,” The Lancet Rheumatology, 2(10):e603–e612, 2020.
3. C.R. Maldini et al., “Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo,” Nature Methods, 26:1776–1787, 2020.
4. A. Ali et al., “Chimeric antigen receptors targeting human cytomegalovirus,” Journal Infectious Disease, 222(5):853–862, 2020.
5. R. Hanajiri et al., “Generation of Zika virus-specific T cells from seropositive and virus-naïve donors for potential use as an autologous or “off-the-shelf” immunotherapeutic,” Cytotherapy, 21(8):840–855, 2019.
6. R.N. Esquivel et al., “In vivo delivery of a DNA-encoded monoclonal antibody protects non-human primates against Zika Virus,” Molecular Therapy, 27(5):974–985, 2019.
7. J.M. Brannan et al., “Post-exposure immunotherapy for two ebolaviruses and Marburg virus in nonhuman primates,” Nature Communications, 10(1):105, 2019.
8. Y. Wu et al., “A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2,” Science, 368(6496):1274–1278, 2020.
9. M.P. Motley et al., “Monoclonal antibody-based therapies for bacterial infections,” Current Opinions in Infectious Disease, 32(3):210–216, 2019.
10. M.S. Godfrey et al. “Tuberculosis and biologic therapies: anti-tumor necrosis factor-α and beyond,” Clinics in Chest Medicine, 40(4): 721–739, 2019.
11. D.L. Barber et al., “Tuberculosis following PD-1 blockade for cancer immunotherapy,” Science Translational Medicine, 11(475):eaat2702, 2019.
12. S.O. Ali et al., “Phase 1 study of MEDI3902, an investigational anti-Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults,” Clinical Microbiology and Infection, 25(5):629.e1–629.e6, 2019.
13. B. François et al., “MASTER 1 study group. Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused by Staphylococcus aureus: first-in-human trial,” Intensive Care Medicine, 44(11):1787–1796, 2018.
14. A. Ruzin et al., “Characterisation of anti-alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin,” Clinical Translational Immunology, 7(1):e1009, 2018.