A Single Therapy for Asthma: Engineering Long-Lived T Cells with Multi-Targeting Abilities

Jun, 2024

Asthma is a chronic respiratory condition affecting over 300 million people worldwide. For those with the most severe forms of the disease, daily medication is often required to manage debilitating symptoms such as wheezing, coughing, and breathlessness. While biologics targeting specific inflammatory pathways have improved treatment options in recent years, they only provide symptom relief and are not curative. Patients must continue lifelong therapy to maintain remission—an unsustainable solution both medically and financially.

Researchers at Tsinghua University in Beijing may have found an alternative approach that could push severe asthma into long-term remission with just a single treatment: engineering long-lived T cells with the unique ability to target multiple drivers of the condition simultaneously. In a study published in Nature Immunology, the team describes how genetically modifying immune cells called chimeric antigen receptor (CAR) T cells enabled them to eliminate eosinophils—inflammatory cells implicated in asthma—while also blocking the effects of interleukin-4 (IL-4) and IL-13, two cytokines that fuel airway inflammation and remodeling. When infused into mouse models of asthma, these multi-functional “TIF” cells alleviated symptoms durably for extended periods without recurrence.

“Our findings demonstrate proof-of-concept that a common chronic disease may be cured by engineered T cells,” says senior author Min Peng. “Compared to standard therapies requiring lifelong dosing, achieving remission of asthma or other conditions with a single administration could revolutionize chronic disease management.”

Two Key Obstacles for CAR T Therapy in Non-Cancer Settings

While CAR T cell therapies have shown remarkable success treating certain blood cancers, applying this approach to non-malignant diseases poses unique challenges. First, unlike cancers that can be eliminated by targeting tumor-specific antigens, chronic conditions involve manipulating physiological pathways within healthy tissues and organs over the long term. Secondly, current CAR T regimens rely heavily on intensive pre-conditioning with chemotherapy to “prime” the body and enhance T cell activity—a strategy unacceptable for non-life-threatening illnesses. Without the tumor burden or toxic pre-treatments, standard CAR T cells fail to expand sufficiently and don’t persist long enough to provide enduring benefits.

To address these obstacles, Peng’s team engineered T cells to home in on eosinophils, implicated in severe “type 2-high” asthma, by equipping them with a chimeric antigen receptor (CAR) recognizing the interleukin-5 receptor α chain (IL-5Rα) expressed on these inflammatory cells. However, initial versions of “IL-5 CAR T cells,” or “5T cells,” did not expand or eliminate eosinophils when infused into unaltered mouse models of asthma without pre-conditioning. This mimicked the challenge of getting CAR T cells to function effectively in non-cancer contexts without the artificial boost from chemotherapy.

Giving CAR T Cells Immortal-Like Properties Through Gene Editing

To overcome this limitation, the researchers took inspiration from their previous work inducing “immortal-like” properties in CAR T cells through selective gene editing. They targeted two genes, BCOR and ZC3H12A, and found double knockout generated by CRISPR/Cas9 conferred the ability to bypass dependence on pre-conditioning chemotherapy and expand robustly even in lymphocyte-replete conditions.

Introducing the same BCOR/ZC3H12A mutations into their IL-5 CAR T cells, dubbed “5TIF cells,” now permitted vigorous population growth following infusion. Expression analysis showed 5TIF cells displayed hybrid features of stem-like memory T cells and exhausted T cells—characteristics thought to underlie their longevity. In mouse models, 5TIF cells effectively eliminated eosinophils for over a year with no signs of diminishing.

Importantly, simply eliminating eosinophils through 5TIF cells provided only partial relief of asthma symptoms, as the condition also involves dysregulated type 2 immune responses driven by IL-4 and IL-13. To overcome this, the team engineered 5TIF cells to secretable an IL-4 mutein, a protein variant that competitively binds IL-4 receptors but does not initiate downstream signaling. These new “5TIF4 cells” both targeted eosinophils for depletion and actively suppressed IL-4/IL-13-mediated inflammation through the secreted mutein.

Testing 5TIF4 Cells in Multiple Disease Models

Across several mouse models of asthma mimicking key clinical scenarios, a single infusion of 5TIF4 cells alleviated symptoms far more robustly than 5TIF cells alone. In acute, memory, and chronic disease variants inducing eosinophilia and airway remodeling through ovalbumin (OVA) or house dust mite (HDM) challenge, 5TIF4 dominated over 5TIF in reducing lung inflammation, fibrosis, eosinophils, and inflammatory cytokines while inhibiting IgE/IgG1 antibody production for extended periods even after disease re-exacerbation.

Surprisingly, 5TIF4 outperformed the IL-4 mutein protein-based therapy currently in clinical trials for difficult-to-control asthma, emphasizing their unique ability to achieve durable local protein expression through tissue-resident T cells. Further, in an interleukin-33-mediated model independent of adaptive immunity, 5TIF4 still repressed eosinophilia and symptoms, demonstrating versatility beyond antigen-specific adaptive responses.

Lastly, administering 5TIF4 to a model of established asthma, rather than as prevention, alleviated features such as airway hyperreactivity to the same degree as in earlier disease, validating their therapeutic potential even after condition onset. Importantly, no toxicity or autoimmunity was observed in any studies, unlike traditional chemotherapy-based CAR T regimens. Together, these results position engineered CAR T cells targeting multiple pathways simultaneously as a viable cure for severe asthma.

Humanizing the Approach

To validate the approach’s translatability, the researchers applied their gene-editing strategy to engineer the same 5TIF4 functionality in human T cells. Cultured from healthy donors, integrating the IL-5 CAR, IL-4 mutein cassette and BCOR/ZC3H12A knockout produced human “h5TIF4” cells capable of long-term persistence, eosinophil depletion and mutein secretion in immune-deficient mice, mirroring rodent versions. Single-cell transcriptional profiling revealed h5TIF4 populations maintaining the hybrid memory-exhaustion signature conducive to prolonged survival.

With this proof-of-concept established using human cells, Peng believes their approach could offer lifelong remission of severe asthma, as well as other chronic eosinophilic diseases, through a single infusion. Compared to established biologics requiring injection regimens exceeding a decade, achieving remission from a one-time cell therapy would transform patient quality-of-life. While requiring further exploration and fine-tuning, this study represents an encouraging proof-of-principle that engineered T cells may provide cures for conditions currently managed only through lifelong drug cocktails. The researchers plan to continue advancing this strategy towards clinical testing with the goal of ultimately liberating asthma and related patients from the burden of daily disease management.

 

Reference(s)

  1. Lambrecht, B.N., Hammad, H. CAR T cells put the brakes on asthma. Nat Immunol 25, 935–937 (2024). https://doi.org/10.1038/s41590-024-01851-8

 

Click TAGS to see related articles :

ASTHMA | DRUG DEVELOPMENT | DRUG TARGET | MEDICINE | RESPIRATORY

About the Author

  • Dilruwan Herath

    Dilruwan Herath is a British infectious disease physician and pharmaceutical medical executive with over 25 years of experience. As a doctor, he specialized in infectious diseases and immunology, developing a resolute focus on public health impact. Throughout his career, Dr. Herath has held several senior medical leadership roles in large global pharmaceutical companies, leading transformative clinical changes and ensuring access to innovative medicines. Currently, he serves as an expert member for the Faculty of Pharmaceutical Medicine on it Infectious Disease Commitee and continues advising life sciences companies. When not practicing medicine, Dr. Herath enjoys painting landscapes, motorsports, computer programming, and spending time with his young family. He maintains an avid interest in science and technology. He is a founder of DarkDrug

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