Experimental cancer drug could streamline standard tuberculosis treatment and prevent post-TB lung disease, study suggests

"Current treatment regimens for TB are lengthy, expensive and leave patients vulnerable to relapse and lung scarring. Our research shows that adding in a host-directed therapy has extraordinary promise to solve these problems," says study senior author Sanjay Jain, M.D., a pediatric infectious diseases specialist at Johns Hopkins Children's Center and professor of pediatrics in the Johns Hopkins University School of Medicine.

Although preventable and treatable, TB has again likely become the leading cause of death globally, with an estimated 1.25 million deaths and 10.8 million new cases in 2023, according to the World Health Organization. Hundreds of thousands of these infections are resistant to gold-standard antibiotic treatments, complicating patients' recovery.

TB is caused by Mycobacterium tuberculosis, a type of bacterial species. In early stages, infected lung cells limit spread through apoptosis, a natural and tightly regulated molecular process that causes them to die. In contrast, later-stage TB infections cause uncontrolled necrosis, a different type of cell death that leads to widespread inflammation and damage to surrounding tissue. While apoptosis could be compared to controlled demolition of a building, Jain explains, necrosis is more like destruction by a bomb.

The TB-causing bacterium tilts the balance away from apoptosis and toward necrosis by prompting infected "host cells" to produce Bcl-2, a family of anti-apoptotic proteins. This hijack of a typically healthy molecular pathway has significant advantages for M. tuberculosis, says Medha Singh, Ph.D., the study's first author and a pediatric infectious diseases fellow in the school of medicine, promoting necrotic niches within the lung that prevent immune system attacks and allow the bacteria to multiply.

Although previous research has suggested inhibiting Bcl-2 as a strategy to fight TB, this host-directed therapy -- aimed at infected host cells, rather than the infective bacteria -- had never been tested using a real-world TB treatment, Singh says.

To do that in their study, the researchers began treating mice exposed to M. tuberculosis with the antibiotics rifampin, isoniazid and pyrazinamide (RHZ), considered the standard treatment for TB worldwide. In addition, they gave some of the mice navitoclax, a Bcl-2 inhibitor currently in clinical trials to treat cancer by accelerating programmed cell death.

Compared to mice that only received RHZ, those that also received navitoclax had a 40% reduction in necrotic lesions in their lungs, and the infection was less likely to spread to other organs such as the spleen over four weeks of treatment. Imaging in live animals using clinically translatable positron emission tomography (PET) technologies for apoptosis and fibrosis showed that the addition of navitoclax doubled the amount of pulmonary apoptosis and reduced lung scarring by 40% compared to standard TB treatments alone, says Laurence Carroll, Ph.D., a study author and assistant professor of radiology in the school of medicine. Although navitoclax had no effect alone on M. tuberculosis, animals that received the drug along with RHZ decreased their bacterial burden 16 times more effectively.

These results suggest that navitoclax could offer similar effects for TB patients as well as patients with other chronic bacterial infections, such as Staphylococcus aureus and non-TB mycobacteria highly prevalent in the U.S., Jain says. He adds that this idea would need to be tested in clinical trials, ideally with the help of new PET imaging approaches developed at the Johns Hopkins Center for Infection and Inflammation Imaging Research, where he serves as director, that could provide early readouts of the host-directed therapy and visualize lung scarring. If those trials are successful, he says, doctors might eventually add navitoclax or similar drugs to the standard antibiotic regimen, which could shorten the typical daily six-month course of treatment, reduce the incidence of lung scarring or post-TB lung disease, and improve outcomes for patients with drug-resistant TB.

Other Johns Hopkins researchers who contributed to this study include Mona Sarhan, Nerketa Damiba, Alok Singh, Andres Villabona-Rueda, Oscar Nino-Meza, Xueyi Chen, Yuderleys Masias-Leon, Carlos Ruiz-Gonzalez, Alvaro Ordonez and Franco D'Alessio.

This study was funded by grants from the National Institutes of Health (R01-AI153349, R01-AI145435-A1, R56-AI179012-A1, R01-AI190038, and S10-OD030381-A1).

No authors declared conflicts of interest under Johns Hopkins University School of Medicine policies.