Cell therapy for tuberculosis and infectious diseases?
Authors: Michael Dumiak
Journal: The Lancet Microbe (2021)

As researchers get a better grasp on complex molecular mechanisms powering the human immune system and interactions between hosts and pathogens, a technique best seen in cancer treatment—immunotherapy, or immunomodulation—is drawing interest in infectious diseases, including the old killer tuberculosis. This approach could help treatment and, indirectly, curb the drug-resistance menace of one of the world's most deadly infectious diseases, projected to have killed as many as 1·8 million people in 2020. Unconventional T cells are a category of immune cells suggested to have potential in tuberculosis immunotherapy. They are lymphocytes that can target non-classical antigens (eg, lipids or lipid-like molecules) and, unlike other kinds of T cells, they are not restricted by the host genotype—a limitation by which T cells derived from one person cannot recognise antigens presented by cells from another person. They include protein-1 restricted mucosal-variant T (MAIT) cells and γδ T cells. Unconventional T cells are activated during infection with Mycobaterium tuberculosis and, as noted by Nadia Caccamo (University of Palermo, Palermo, Italy), can recognise lipids in the mycobacterial cell wall, making them potentially promising vehicles for immunotherapies such as adoptive cell transfer or for enhancing vaccine formulations. Using murine models, Daniel Barber (National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA) and colleagues have shown that inducing MAIT cell responses during chronic tuberculosis infection can enhance bacterial control, although this might be more complicated in primate or human MAIT cells. Research into T cell therapies for infectious diseases more broadly is growing, says Sam Afkhami (McMaster University, Hamilton, ON, Canada), especially for viral diseases such as chronic hepatitis B and cytomegalovirus infection. T cell therapies for bacterial infections are less thoroughly investigated, but this might be changing. “There's merit in shining the spotlight on unconventional T cells and their role in tuberculosis immunity”, Afkhami says. Immunotherapies target or manipulate components of the immune system and aim to enhance or augment immune responses to combat gaps or defects in natural host immunity. But biomarkers and immune correlates need to be better understood in tuberculosis, or fashioning effective cell-based interventions will be a challenge, says Afkhami. Immunotherapy falls under the umbrella of host-directed therapies which include small-molecule drugs directed at host cell responses as well as so-called biologics, such as antibodies that can block viral entry. Adoptive cell transfer is in a different area of immunomodulation. Stefan Kaufmann (Max Planck Institute for Infection Biology, Berlin, Germany) thinks host-directed therapies for bacterial pathogens and parasites are really only possible in the near term by repurposing existing drugs. For example, the diabetes medication metformin has shown potential for reducing chronic lung inflammation and enhancing immune response, but confirmation is needed through clinical trials, and combinations with existing tuberculosis treatments should be considered. Although Kaufmann acknowledges interesting aspects of unconventional T cells, he considers their use as therapeutics unlikely anytime soon. There are perhaps better prospects for host-directed therapies as adjunctive support to novel vaccines. There is no current preventive pre-exposure or post-exposure vaccine for tuberculosis for adults; the one tuberculosis vaccine that is available, BCG, is a century old and only effective when given to children and infants. A therapeutic vaccine that could stop tuberculosis from progressing—or a host-directed immunoantibiotic that sped up the current grueling course of tuberculosis treatment—could put a dent in the threat of pathogen-developed drug resistance. WHO statistics show an estimated 558 000 cases of multi-drug resistant tuberculosis emerged in 2017. Easing the course of treatment would improve patient adherence, damping the spread of drug-resistant tuberculosis. Matteo Zignol (WHO Global Tuberculosis Programme) considers new research—even high-end molecular investigations—to be vital for future treatment and prevention of tuberculosis. This could even be true despite the fact that populations in low-income countries (LIC), which make up 70–80% of tuberculosis-infected individuals, might find innovations such as immunotherapies difficult to afford. Genetically modified adaptive T cell therapy (CAR-T) for cancers cost hundreds of thousands of US$ a year and require sophisticated centers to administer yet, notes Markus Maeurer (Champalimaud Foundation, Lisbon, Portugal), it is becoming standard of care. And some treatments that started off as out of the reach of LIC, such as antiretroviral therapies in HIV, have now become much more accessible. However, Zignol calls for the involvement communities earlier on in research. “We can’t afford to develop a new approach and then think about how to get it to the people in need. Engagement with civil society has to be done earlier”, he says. WHO has set preferred profiles for potential tuberculosis vaccines and this year, it will start to develop a target profile for biomarkers.