Engineering CAR T Cells With mRNA-LNPs: Applying Oncology Learnings To Allergic Diseases

By Sid Kerkar, MD, Founder and CEO, AllerGene AI Therapeutics

My interest in applying CAR T cell therapy to allergic disease began at home. All three of my children were diagnosed with severe, life-threatening allergies, turning a disease I understood as a physician-scientist into something deeply personal. That reality became especially scary in 2014, when my eldest son, Alex, then 4 years old, accidentally ate a peanut butter cup and developed a severe reaction that left him struggling to breathe. At the time, I was working at the NIH. Fortunately, we had an EpiPen at home, and an ambulance reached us within 5 minutes and took him to a nearby hospital. The experience profoundly shaped my motivation to find better ways to treat severe allergic disease. Like millions of families affected by allergic disease, we came to understand the constant fear of a life-threatening reaction and the limitations of treatments that can manage an acute episode but cannot prevent the next one.

At the time, I had spent much of my scientific career thinking about a very different disease: cancer. I trained in cancer immunology and cell therapy, including at the National Cancer Institute in Steven Rosenberg’s Surgery Branch, where I studied how T cells could be harnessed to recognize and attack malignant tumor cells. As CAR-T technology began transforming the therapeutic landscape of hematologic cancers, I started asking a question prompted by my experience both as a scientist and a father: Could we use the same principles of immune-cell engineering to treat severe allergic disease? Importantly, exploring these applications does not diminish oncology's continuing importance. The same engineering advances may ultimately inform future cancer programs as well, particularly where transient or in vivo approaches offer a strategic advantage.

That question has become increasingly relevant as CAR-T builds on its transformative role in oncology and researchers explore where the same principles of immune cell engineering may apply to other serious diseases. CAR T cell therapy established that immune cells can be engineered to recognize and eliminate defined cellular targets. Now, early work in autoimmune disease is testing whether the same principle can be used against immune cells that sustain chronic disease.

This emerging experience provides an important bridge between oncology and allergy. If CAR T cells can target B cells involved in autoimmune disease, could engineered T cells also be directed against cells that drive severe allergic disease? For allergy, that question leads naturally to mast cells.

What Autoimmune Disease Is Teaching Us

The rationale for using CD19 CAR T cells in autoimmune disease grew directly from experience in B-cell malignancies. CD19 is expressed across much of the B-cell lineage, making it an effective target in diseases such as leukemia and lymphoma. Researchers recognized that eliminating B cells could also have therapeutic value in autoimmune diseases in which pathogenic B cells and autoantibodies play central roles.

Early clinical experience has generated considerable interest. Small studies in patients with severe treatment-refractory autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis, have reported deep responses following CD19 CAR-T treatment, including drug-free remissions in some patients.

These findings have introduced the possibility of an “immune reset.” Rather than chronically suppressing individual inflammatory pathways, it may be possible to eliminate a pathogenic immune cell population and allow a healthier immune repertoire to reemerge.

The significance extends beyond any one autoimmune disease. It encourages us to ask a broader question about cell therapy: Which cells are driving a disease, and can we engineer the immune system to selectively remove them?

Moving From B Cells To Mast Cells

For allergic disease, mast cells are an obvious place to investigate that question. Mast cells are central effector cells in allergic reactions. When activated, they release histamine and numerous other inflammatory mediators that can produce symptoms ranging from itching and urticaria to bronchoconstriction and life-threatening anaphylaxis.

Current allergy treatments intervene at several points in this process. Antihistamines block histamine signaling. Corticosteroids suppress inflammation. Biologic therapies can target IgE or inflammatory pathways. These approaches can be highly effective, but they generally control components of the allergic response rather than eliminating the cellular source that initiates it.

CAR-T technology raises the possibility of approaching severe allergic disease differently. If appropriate mast cell surface targets can be identified, engineered T cells could potentially recognize and eliminate disease-driving mast cell populations. A critical point is finding a target that, when engaged by a CAR-T, does not trigger mast cells to release their internal mediators. The therapeutic objective shifts from repeatedly suppressing the products of mast cell activation toward targeting the cells themselves.

The autoimmune disease analogy is useful. CD19 CAR-T therapy does not attempt to neutralize every pathogenic autoantibody individually; it targets a cellular compartment that produces and sustains disease. A mast cell-directed strategy could apply a similar principle to allergy.

Why RNA Changes The Equation

Applying CAR-T to chronic, nonmalignant disease requires a different risk-benefit calculation than its use in advanced cancer, where CAR-T has delivered important benefits for patients with otherwise limited treatment options. Conventional autologous CAR-T therapy requires collecting a patient’s T cells, genetically modifying and expanding them outside the body, administering lymphodepleting chemotherapy, and reinfusing the engineered product.

In aggressive cancers, the complexity and risks of conventional autologous CAR-T can be appropriate given the severity of disease and potential therapeutic benefit. Extending cell engineering approaches to allergic disease, however, will require technologies designed for a different clinical setting and risk-benefit threshold.

This is where advances in messenger RNA and lipid nanoparticle technology become particularly important. Targeted LNPs could potentially deliver mRNA encoding a CAR directly to T cells inside the patient. Once inside the cell, the mRNA instructs the T cell to express the CAR on its surface, temporarily converting the patient’s own T cell into a targeted therapeutic cell.

In principle, this could eliminate much of the individualized manufacturing process associated with conventional CAR-T. Instead of removing cells, engineering and expanding them in a specialized facility, and returning them weeks later, the therapeutic becomes an RNA delivery system that programs immune cells in vivo.

The transient nature of mRNA may also be an advantage. Because mRNA is naturally degraded, CAR expression does not have to be permanent. Repeat administration could potentially provide additional periods of CAR activity, while stopping treatment would allow expression to diminish.

For nonmalignant disease, that creates the possibility of treating CAR-T activity more like a controllable drug exposure rather than a permanent cellular intervention.

Delivery Is Part Of The Therapy

The promise of in vivo CAR-T depends on solving a central challenge in RNA therapeutics: delivery. An mRNA molecule encoding a CAR has little therapeutic value unless it reaches the correct cell, enters efficiently, and produces sufficient protein expression.

The lipid nanoparticle therefore becomes more than a packaging tool. It is a critical part of therapeutic design.

Many conventional LNPs naturally accumulate in the liver. Engineering CAR T cells in vivo requires a different capability: selective delivery to immune cells. Researchers are developing targeted nanoparticles that recognize specific surface markers and preferentially deliver RNA payloads to defined immune cell populations, including T cells.

This creates a modular system. The delivery vehicle helps determine which cells receive the message. The mRNA determines what those cells are instructed to express. And the CAR determines which disease-associated cells the engineered T cells recognize.

Bringing those elements together could enable more precise, controllable immune cell engineering without the manufacturing infrastructure historically associated with CAR-T.

A New Direction For Severe Allergic Disease

The potential implications extend beyond a single allergic condition. Severe food allergy, chronic urticaria, allergic asthma, mast cell disorders, and other IgE- and mast cell-driven diseases can impose substantial burdens on patients despite the availability of effective therapies.

That does not mean CAR-T should replace established allergy treatments. The safety threshold for an engineered cell therapy in nonmalignant disease must be exceptionally high. Researchers will need to identify targets that eliminate disease-driving mast cells while minimizing effects on other cells. Researchers must establish the appropriate depth and duration of depletion and carefully study the consequences of mast cell recovery.

The earliest applications are therefore likely to be in patients with severe disease for whom existing therapies are inadequate, rather than people whose allergies are readily controlled.

But the broader scientific direction is compelling. Decades of work in cancer established the scientific and clinical foundation for CAR-T, demonstrating that engineered T cells can eliminate defined cellular populations. That foundation continues to drive innovation in oncology and is now informing research into additional diseases. Autoimmune disease is beginning to show that engineered T cells may also have the potential to remove immune cell populations responsible for chronic disease. Meanwhile, mRNA and targeted LNP technologies are creating a path toward generating these cells directly inside the patient.

For me, the question has come full circle. What began with wondering whether the tools and lessons of cancer immunotherapy could have relevance to a disease affecting all three of my children has become part of a larger scientific question about the future of engineered immunity.

Allergic disease represents a logical next frontier. If we can identify the right cellular targets and engineer CAR T cells safely, selectively, and transiently inside the body, we may eventually be able to move beyond repeatedly blocking the downstream mediators of allergic inflammation.

Instead, we may be able to target the cells at their source.

About The Author:

Sid Kerkar, MD, is the Founder and CEO of AllerGene AI Therapeutics. He is a physician-scientist and biotechnology executive with extensive expertise in immunotherapy, cell therapy, and translational medicine. He trained at the National Institutes of Health under Drs. Steven Rosenberg and Nicholas Restifo, conducting research in T-cell biology and adoptive cellular therapies. Kerkar held leadership roles at Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, and Exuma Biotech, where he led R&D efforts advancing novel CAR-T technologies. He has authored more than 50 manuscripts and abstracts and received multiple NIH and NCI research awards. He earned his MD from Wayne State University School of Medicine.