The Potential Role of CAR T Cell Therapy in Autoimmune Diseases

Adaptive immunity, constituted by T cells and B cells, forms an integral part of the immune system. Characterized by its ability to learn and remember, adaptive immunity aims to prompt a faster immune response upon reencounter with similar threats. This learning can stem from vaccination or infections, albeit the latter typically come with higher health risks. Among these adaptive immune cells, B cells primarily produce antibodies and assist T cells, which exist in various types. Some T cells (Th1, Th17) promote inflammatory responses, others (Th2) aid B cells in antibody production, and a few (Tc, NKT) can directly eliminate virus-infected or cancerous cells. Treg cells, however, act as immune brakes to prevent excessive immune activation. T cells express unique receptors (T cell receptors) on their surfaces during development, which, upon binding with antigens from foreign pathogens or aberrant cells, activate the T cells' functions. The thymus plays a crucial role in T cell development by eliminating unfit T cells. Unfit T cells, such as those that strongly bind to normal bodily cells, undergo apoptosis within the thymus to prevent attacking healthy cells. Consequently, thymectomy, as seen in conditions like myasthenia gravis, may increase the risk of autoimmune diseases like systemic lupus erythematosus [1]. B cell quality control primarily occurs in the bone marrow, where potentially self-attacking autoantibody-producing B cells are either reprogrammed or led to apoptosis.

With this understanding, the recent buzz around “CAR T” cell therapy becomes clearer. “T” in CAR T stands for T cells, while “CAR” is an acronym for chimeric antigen receptor. In essence, CAR T therapy involves using retroviruses to insert designed genes into T cells, allowing them to express receptors that bind to cancer cells, thus enabling them to attack the cancer. CAR T cell therapy has shown notable success in treating lymphoma. Early experiments, such as those by Brentjens and colleagues at the Memorial Sloan-Kettering Cancer Center in 2003, demonstrated effective lymphoma cell elimination in mice with genetically modified T cells expressing CD19-binding receptors [2]. CD19, a glycoprotein on B cell surfaces, does not normally trigger T cell responses owing to negative selection during T cell development. In 2010, Kochenderfer and other researchers at the National Cancer Institute successfully reduced tumors in a patient with B cell lymphoma using CD19-targeted CAR T therapy. Studies indicate that CAR T therapy targeting CD19 can completely eliminate tumors in approximately 40%–54% of cases involving aggressive, treatment-resistant B cell lymphoma [3]. Long-term studies, like those by Cappell and colleagues from the National Institutes of Health, report a 51% non-recurrence rate over 3 years in B cell lymphoma treatments [4]. For relapsed or refractory B cell acute lymphoblastic leukemia in children, CD19-targeted CAR T therapy has shown a 71%–81% complete remission rates [5]. Prior to CAR T therapy, patients undergo chemotherapy to clear existing T cells, minimizing the risk of attack on modified T cells. However, this also leads to potential cytokine-release syndrome due to overactive T cells in the first month post-therapy, which might require treatment with steroids or IL-6 inhibitors. Early clinical trials saw 45%–50% of patients needing intensive care. Immunogenicity might also cause severe neurological complications, including encephalitis or cerebral edema, sometimes leading to death [6]. As CD19 also appears on normal B cells, CAR T therapy targeting CD19 could deplete normal B cells, risking repeated infections; however, this issue can be mitigated with immunoglobulin supplementation. The U.S. Food and Drug Administration approved CD19-targeted CAR T therapy for recurrent or refractory B cell lymphoma and acute lymphoblastic leukemia in August 2017, with Taiwan following suit in October 2021.

CAR T therapy's applicability extends beyond cancer treatment. For example, in systemic lupus erythematosus, patients' B cells might produce autoantibodies like anti-double-stranded DNA and anti-nuclear antibodies, causing tissue damage and disease manifestation. Mougiakakos and colleagues from the University of Erlangen-Nuremberg, supported by prior mouse model success, treated a young woman with lupus nephritis unresponsive to standard treatments with CD19-targeted CAR T therapy. Fortunately, she did not experience the common cytokine storm or neurological complications. Her anti-double-stranded DNA antibody levels normalized within 5 weeks post-treatment, complement levels restored, proteinuria significantly improved, and her lupus activity reached complete remission [7]. In a study published in October 2022, Andreas Mackensen and others shared the treatment experience of five young, treatment-resistant lupus patients achieving complete remission 3 months post-CAR T therapy, with three experiencing manageable cytokine-release syndrome. Interestingly, antibodies from past vaccinations did not significantly decrease 3 months later, suggesting that not all B cells were eliminated, preserving some beneficial ones [8]. In China, researchers like Zhang Wenli from Peking University Shenzhen Hospital suggest that CD19-targeted CAR T therapy might be more effective in early-stage lupus. As lupus progresses, late-stage differentiated B cells lose CD19, CD20, and other early-stage antigens, transforming into long-lived plasma cells capable of autoantibody production. Therefore, they developed a CAR T targeting both CD19 and B-cell maturation antigen (BCMA), which appears on mature B cells including plasma cells, aiming for a broader B cell clearance. Their first case report on a middle-aged woman with a 20-year lupus history and stage IV B cell lymphoma showed lupus stability and lymphoma non-recurrence 23 months post-CAR T therapy, with B cells recovering within 260 days without autoantibody detection. Prior to B cell recovery, the patient received immunoglobulin infusions to prevent infections [9].

At present, it is premature to conclude whether lupus can be cured by CAR T cell therapy. However, case studies reported by Fabian Müller and colleagues reveal that CAR T cell therapy has the potential to maintain disease remission in lupus for more than two years [10]. In addition to lupus, CAR T cell therapy is also being employed in patients with autoimmune inflammatory rheumatic diseases such as idiopathic inflammatory myositis and systemic sclerosis [10-13]. It must be emphasized that although published successful cases show remarkable therapeutic effects of CAR T cell therapy on autoimmune diseases, its long-term safety (including potential carcinogenic risks) and applicable clinical scenarios still require further investigation and study [14]. The case report by Alexander M. Leipold and colleagues reminds us that cytokine-release syndrome triggered by CAR T cell therapy could lead to the proliferation of pathological Th17 cells, potentially inducing autoimmune phenomena [15]. In mouse models of systemic sclerosis, accumulation and expansion of CD19-targeted CAR T cells in lesional lungs led to worsening of fibrosis, discouraging the application of CD19-targeted CAR T cell therapy in systemic sclerosis with significant interstitial lung diseases [16, 17]. Apart from a few clinical trials, CAR T cell therapy has not yet been approved for the treatment of autoimmune diseases. Meanwhile, scientists from Sonoma Biotherapeutics, including Anne-Renee van der Vuurst de Vries, presented an abstract at the American College of Rheumatology annual meeting, suggesting a seemingly less aggressive CAR T cell therapy approach: This time, they attempted to engineer Treg cells to express receptors that can recognize a type of citrullinated protein in the joints, namely citrullinated vimentin [18]. The interesting aspect of this modified CAR T therapy targeting Treg cells lies in the role Treg cells play in the immune system as a brake. When Treg cells bind with the citrullinated protein in the joints and become activated, they can inhibit effector T cells within the joints, which may be beneficial for alleviating arthritis. However, the stability of these modified Treg cells in vivo without transforming into pathological memory T cells remains to be verified, and strong proinflammatory conditions like rheumatoid arthritis can transform Treg cells into IL-17-producing cells [19-21]. A research team from Peking Union Medical College Hospital in China designed a specific type of CAR T cell (anti-fluorescein isothiocyanate CAR T cells) aiming to eliminate B cells that produce anti-citrulline antibodies, thus avoiding damage to other normal B cells, but the actual efficacy in vivo is still unclear [22]. Furthermore, Karen B. Whittington and collaborators have demonstrated the feasibility of using CAR T cells to target pathological CD4+ T cells: In mouse models, utilizing CAR T cells specific for CD4+ T cells expressing HLA-DR1 with the ability to bind type II collagen was shown to improve arthritis [23]. Given the diversity of patients with autoimmune diseases, CAR T cell therapy cannot possibly achieve a “one size fits all” solution [24]. Therefore, the appropriate design of CAR T cells as well as selection of treatment candidates will be an important point of research in CAR T cell therapy, particularly when considering the significant potential risks and high financial costs associated with the treatment. In this context, utilizing novel mRNA technologies for the production of transient CAR T cells in vivo could potentially mitigate overall treatment risks and expenditures [25]. Although significant challenges remain to be overcome, CAR T cell therapy may present a promising therapeutic avenue for currently incurable autoimmune diseases.

J.-F.Z., Y.-W.Q., and J.C.-C.W. contributed significantly to the conception, design, and execution of this article. J.-F.Z. led the conceptual framework and coordinated the overall structure of the manuscript. Y.-W.Q. conducted an extensive review of the literature and provided critical insights into the roles of B cells in autoimmune diseases. J.C.-C.W. contributed to data analysis, interpretation, and the exploration of modern therapeutic strategies. All authors actively participated in drafting, revising, and approving the final manuscript, ensuring the integrity and accuracy of the content.

James Cheng-Chung Wei is the editor-in-chief of the International Journal of Rheumatic Diseases, so he should be excluded from the peer-review process and all editorial decisions related to the acceptance of this article. Publication of this article and peer review should be handled independently by other editors to minimize bias.