Is the Future of CAR T-Cell Therapy Off-the-Shelf? Genetic Engineering Could Be the Answer

The immune system is built to protect us — scanning for invaders, protecting against infections, and clearing out threats. But what happens when this intricate defense system turns on the body instead?

This is the reality for millions of people living with autoimmune diseases, where the immune system mistakenly attacks healthy cells as if they were invading agents. These chronic conditions affect around 8% of the global population and often have significant impact on quality of life (Wang et al. 2024). They range from organ-specific conditions, like type 1 diabetes and primary biliary cirrhosis, to systemic diseases, such as systemic lupus erythematosus (SLE), immune-mediated necrotizing myopathy (IMNM), and systemic sclerosis (SSc).

Why Are Autoimmune Diseases So Hard to Treat?

While we have made significant progress in understanding the molecular mechanisms behind autoimmunity, the drivers of many of these chronic conditions remain poorly understood. As a result, current treatment strategies are largely aimed at lifelong symptom management, often with immunosuppressants, which lack curative potential and are associated with short- and long-term toxicities.

More than 80 autoimmune diseases are linked to malfunctioning immune cells, often caused by the loss of tolerance to B cells, which are normally responsible for producing antibodies. When tolerance is lost, these cells can drive chronic inflammation, autoantibody production, and tissue damage (Hampe 2012). As a result, strategies to treat many autoimmune diseases involve the depletion of B cells. Monoclonal antibodies, like rituximab (anti-CD20) and belimumab (anti-BLyS), aim to reduce this burden by depleting B cells (Furie et al. 2022, Blair et al. 2018). While they can be effective in controlling disease activity, they often fail to target the underlying autoimmune mechanisms and therefore fall short of inducing durable remission. Additionally, many patients eventually relapse or fail to respond altogether, which can result in complications that can become life-threatening.

So, how do we move from disease management to a potential cure?

From Cancer to Autoimmunity: The Rise of CAR T-Cell Therapy

A possible solution to the failure of current approaches to achieve long-term remission is chimeric antigen receptor (CAR) T-cell therapy, for example, to achieve deep depletion of B cells. The basic concept underlying CAR T cells revolves around T cell receptor signaling. CAR T-cell therapy involves collecting a patient’s T cells, genetically modifying them to express synthetic receptors (CARs) that recognize specific antigens, expanding them in the lab, and infusing them back into the body to find and destroy target cells (Figure 1).

Fig. 1. Generating a CAR T-cell therapy.

In B cell cancers, such as relapsed or refractory leukemias and lymphomas, CAR T-cell therapy has been revolutionary (Abbasi et al. 2023). The first approved product, tisagenlecleucel (Kymriah) demonstrated remarkable results in patients with no other treatment options. These therapies typically target CD19, a molecule expressed on nearly all B cells, allowing for efficient and sustained B cell depletion. Since then, more CAR T-cell therapies have been approved, all for the treatment of blood cancers, including multiple myeloma and several forms of lymphoma.  

CRISPR-Engineered CARs for T-ALL

Despite the success of CAR-T cell therapy for the treatment of B cell cancers, it has been more challenging to achieve the same outcome for T cell cancers as the targeting of T cell antigens can cause the CAR T-cells to target each other (fratricide) as well as targeting healthy T cells.

To address this, genome editing techniques like CRISPR have been investigated to disrupt T cell antigens on CAR T-cells to prevent them from targeting one another (Chiesa et al. 2023). Using this approach, in one study, researchers investigated the use of CD7-targeted CAR T-cells (CAR7) to treat T cell acute lymphoblastic leukemia (T-ALL) as CD7 is highly expressed in T-ALL. T cells from healthy donors were base-edited using CRISPR to knockout CD7, preventing the CAR T-cells from attacking themselves. Additional genes were also edited to eliminate CD52 (for lymphodepletion resistance) and the T cell receptor β chain (to avoid graft versus host disease (GVHD)). To make the CAR T-cells specific for CD7, the edited cells were then transduced with a lentiviral vector to express a CD7-specific CAR.

The resulting therapy, known as base-edited CAR7 (BE-CAR7), was administered to three pediatric patients with relapsed or refractory T-ALL to investigate drug safety and therapy feasibility. Two patients demonstrated anti-leukemic responses and achieved deep remission by day 28. The third patient showed strong anti-leukemic activity. All three patients experienced a side effect known as cytokine release syndrome (CRS) as well as other expected CAR T-related toxicities, which were managed using existing transplant and cell therapy protocols, but no unexpected safety issues were reported. This study provides critical proof-of-concept that base editing can expand CAR T-cell applications to T-cell malignancies.

Looking to Autoimmune Diseases

Patient-derived CD19-targeted CAR T-cell therapies for treating autoimmune diseases have been a focus of some recent studies for their potential clinical application (Mougiakakos et al. 2021, Pecher et al. 2023). However, this approach has limited its clinical roll-out due to the eye-watering costs and low success rate due to difficulties associated with the manufacturing of a personalized product.

In an effort to address therapy accessibility, one study investigated donor-derived CAR T-cells as a more scalable and cost-effective solution to treat severe myositis and SSc (Wang et al. 2024). In this study, healthy donor T cells were transduced with a lentiviral vector to express a CD19-specific CAR. To mitigate immune rejection, the donor CAR T-cells were genetically engineered using CRISPR-Cas9 gene editing to knock out the T cell receptor alpha constant (TRAC) gene to minimize the risk of GVHD, and the HLA-A and HLA-B genes to prevent T cell-mediated rejection. To extend the in vivo potency of the therapy, HLA class II molecules were also knocked out by targeting class II major histocompatibility complex transactivator (CIITA) and PD-1.

The safety and efficacy of the therapy were investigated in three patients who experienced limited benefits from previous therapeutic interventions — one patient with refractory IMNM and two patients with diffuse cutaneous SSc. As a result of this novel anti-CD19 therapy, all three patients achieved deep B cell depletion within two weeks of treatment that persisted through the 6-month follow up period, and the patients did not experience CRS or any other serious adverse effects throughout these six months. During that same follow-up period, the CAR T-cells remained detectable, leading to complete remission and reversal of inflammation and fibrosis in all three patients. By reversing previously considered irreversible damage, this trial provided evidence of the potential for gene editing to create an effective and safe off-the-shelf CAR T-cell therapy to treat severe autoimmune diseases.

Could Gene Editing Make CAR T-Cell Therapy a Reality for T Cell Cancers and Autoimmune Diseases?

CAR T-cell therapy has had a transformational impact on B cell cancers, but there has been limited success for patients with T cell cancers and autoimmune diseases. Advances in gene editing techniques, such as CRISPR-Cas 9, are making it possible to achieve deep remission for patients with these diseases without compromising on safety and triggering immune rejection.

These studies demonstrate the value of gene editing to produce safe and effective donor-derived CAR T-cell therapies. If paired with the right manufacturing capabilities and regulatory compliance, it highlights their potential for scalable and accessible off-the-shelf cures for diseases where there are significant unmet medical needs, transforming outcomes for patients.