CAR T cells are one of the biggest breakthroughs in cancer medicine in recent memory. Scientists program immune cells to target malicious cells with impeccable precision. But there’s no reason that programming an immune cell to target something specific has to be limited to cancer cells.
In a new study published in Science Translational Medicine, researchers led by the mycologist Jürgen Löffler at the University Hospital Würzburg report that they successfully created CAR T cells that target the infectious fungus Aspergillus fumigatus (1).
Researchers programmed CAR T cells to target Aspergillus’s hyphae, its long stalk-like projections.
credit: MWolfin, CC0, Wikimedia Commons
A. fumigatus is a constant presence. Its spores persist in the air, and humans inhale them into their lungs several hundred times per day (2). People with healthy immune systems can remove the spores before they do any damage, but in immunocompromised patients, the spores can germinate in the linings of the lungs, causing inflammatory aspergillosis and damage to lung structure. Fungal infections are particularly common among patients on ventilators, patients receiving organ and stem cell transplants, and patients receiving chemotherapy (3).
The growing threat of resistance is eating away at patients’ medical options. That spurred Löffler to try something else. “I’ve been working for 20 years on fungal infections and on analyzing immune responses,” said Löffler. “There are major complications in many immunosuppressed patients. In the last 20 years, our treatment options haven’t changed at all.”
In a case of aspergillosis, the presence of hyphae, the root-like projections that fungi produce as they grow, indicates a more developed and invasive infection. Since these infections are often untreatable with frontline chemical antifungals, the researchers searched for an antibody that was potent enough to fight late-stage fungal infections. Löffler’s group immunized mice with proteins from A. fumigatus hyphae. The researchers isolated from the immunized mice an antibody that bound tightly and specifically to A. fumigatus hyphae. They used this antibody to generate two different CAR T cells: CD4+ and CD8+ cells.
The researchers tested the CAR T cells’ potency by measuring their ability to stimulate an immune response that physically damages fungal proteins. The CAR T cells recruited macrophages to attack and damage 30 percent of the hyphae within nine hours. The immunotherapy also specifically attacked A. fumigatus while ignoring other related fungal strains like A. terreus, A. nidulans, and A. oryzae. Most importantly, the cells attacked the established laboratory strains of A. fumigatus that the researchers used to derive the original antibody and clinical isolates of A. fumigatus taken from human patients. Clinical isolates have the opportunity to grow and evolve resistance to both antifungals and to immune responses. The CAR T cells’ ability to attack these isolates suggests that the immunotherapy may still be active even in long-term, prolonged infections.
Löffler’s team next infected mice by squirting A. fumigatus cultures into their tracheae. In comparison to untreated mice, the mice treated with the experimental CAR T thrived. In infected mice that received the treatment, the CAR T cells attacked A. fumigatus growth in the lungs and recruited macrophages to fungal growth sites, which is critical for tipping off the body’s immune system to the infection. 80% of the mice that received the experimental CAR T treatment survived. Only 25% of the mice that didn’t get the treatment survived.
“I'm excited to see this project,” said Pappanaicken Kumaresan, a microbiologist at the MD Anderson Cancer Center who works on immunotherapies for fungal infections and was not involved in this work. “In acute leukemia patients, in stem cell transplant patients, the mortality rate for fungal infections can go up to 80%,” he said. “Now there is an urgent need for new drugs because you cannot put a patient on antifungal therapy for a long period of time because of the toxicity.”
The focus on antibiotic resistance in bacteria in the media frustrates Löffler. “Fungal infections are always neglected in big conferences. They are somewhere, but not in the center. Viral infections, bacterial infections, and then somewhere fungal infection. We must bring fungal infections more in to the focus of the scientific world,” he said.
References
- Seif, M. et al. CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models. Sci Transl Med 14, eabh1209 (2022).
- Mousavi, B. et al. Aspergillus species in indoor environments and their possible occupational and public health hazards. mazu-cmm 2, 36–42 (2016).
- Meersseman, W., Lagrou, K., Maertens, J. & Wijngaerden, E. V. Invasive Aspergillosis in the Intensive Care Unit. Clinical Infectious Diseases 45, 205–216 (2007).
- Mølgaard-Nielsen, D., Pasternak, B. & Hviid, A. Use of Oral Fluconazole during Pregnancy and the Risk of Birth Defects. N Engl J Med 369, 830–839 (2013).
- van de Veerdonk, F. L., Gresnigt, M. S., Romani, L., Netea, M. G. & Latgé, J.-P. Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 15, 661–674 (2017).
