Chimeric antigen receptor (CAR) T-cell therapy in dermatology: A narrative review

Introduction

The therapeutic landscape of autoimmune connective tissue and immunobullous disorders has seen a gradual shift, from broad-based conventional immunosuppressive drugs to more targeted monoclonal antibodies. While the newer treatments have revolutionised treatment, certain challenges persist, such as incomplete responses, short-term remissions and frequent relapses.^1,2

Chimeric antigen receptor (CAR) T-cell therapy is an emerging form of immunotherapy that has shown promising results in hematological malignancies such as B-cell lymphomas and multiple myeloma. CAR T-cells are genetically engineered T-cells that express a chimeric antigen receptor (CAR) which recognises antigens on tumour cells and destroy them.¹ Recently, there has been growing interest in using CAR T-cells for the treatment of B-cell–mediated autoimmune diseases, including dermatological disorders.For this narrative review, we searched the PubMed database for pre-clinical and clinical studies on CAR T-cells, CAAR (chimeric auto-antibody receptor) T-cells and CAR natural killer (NK)-cells with a focus on dermatological and rheumatological diseases, covering all articles published up to October 2025.

History and evolution of CAR T-cell treatment

CAR T-cells were first developed in 1989 by immunologists Eshhar and colleagues in Israel.³ A major advance occurred between 1998 and 2002 with the development of second-generation CAR T-cells incorporating co-stimulatory domains, which significantly enhanced T-cell activation, persistence, and efficacy. The second-generation prototype became the foundation for subsequent generations of CAR T-cells.^2,3

In 2017, a CD19-targeted CAR T-cell product (Tisagenlecleucel) became the first to receive U.S. Food and Drug Administration (FDA) approval for the treatment of refractory diffuse large B-cell lymphoma. Since then, multiple CAR T-cell products have been approved for the treatment of relapsed/refractory B-cell malignancies and multiple myeloma [Table 1], while clinical trials are underway for solid organ malignancies.^4-6

CAR T-cell therapy is now being repurposed to treat autoimmune diseases, with initial proof-of-concept demonstrated in a lupus mouse model in 2019 and subsequently in a patient with refractory systemic lupus erythematosus (SLE) in 2021. Since then, there have been reports of its use in other connective tissue diseases as well, including anti-synthetase syndrome and systemic sclerosis.⁵

Recently, a CD19-targeting CAR T-cell product has been developed in India. NexCAR19 (actalycabtagene autoleucel), the first-of-its-kind, made-in-India product, was developed by ImmunoACT, an Indian Institute of Technology (IIT) Bombay-incubated company, in collaboration with Tata Memorial Hospital. Costing substantially less than comparable therapies in the United States (₹30–40 lakh versus ₹3–4 crore), it received regulatory approval for use in non-Hodgkin lymphoma and acute lymphoblastic leukemia by the Central drugs standard control organization (CDSCO) in October 2023. NexCAR19 has been successfully administered to more than 200 patients with B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma across more than 30 hospitals spanning over 10 cities in India.^6,7

Advantages of CAR T-cell treatment over existing B-cell depleting therapies

Targeted treatments have minimised our dependence on systemic corticosteroids and other conventional immunosuppressives, while achieving better outcomes in terms of both safety and efficacy. However, durable remission remains challenging in several antibody-mediated diseases. Take the example of rituximab – a prototype B-cell depleting anti-CD20 monoclonal antibody that is now recommended as a first-line treatment for moderate-to-severe pemphigus.⁸ Complete remission rates in pemphigus with rituximab, though quite high, are still about 80%. Further, remissions are not sustained and relapses are frequent.⁹ Rituximab targets only circulating B-cells, while memory B-cells (residing in the reticuloendothelial system) and autoantibody-secreting plasma cells (which do not express the CD20 antigen) are spared. This may explain the incomplete response and frequent relapses in patients treated with rituximab.¹⁰ CAR T-cell treatment has the potential to address the limitations of the current existing treatments for B-cell mediated autoimmune diseases, including immunobullous disorders.

CAR T-cells express a chimeric antigen receptor (CAR) on their surface comprising an extracellular antigen-recognition domain and an intracellular signalling domain, connected by a hinge and transmembrane region [Figure 1]. This dual characteristic, the antigen-binding property of an antibody and the intracellular signalling machinery of a T-cell, gives the ‘chimeric’ receptor its name. The CAR ectodomain is composed of an antigen-specific murine single-chain variable fragment (scFv) that binds to the antigen (for example, CD19 expressed by B-cells) directly without requiring major histocompatibility complex (MHC) processing or restriction, unlike T-cell receptor therapy. This initiates downstream signal transduction, causing cascade of CAR T-cell activation, transcription factor expression, cell proliferation and survival and cytokine release. CAR T-cells kill the target cells (B-cells in this example) primarily through the release of cytotoxic granules containing perforin and granzymes and/or by inducing apoptosis via the Fas-FasL pathway and/or secrete cytotoxic cytokines [Figure 2].^11,12

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Figure 1:

(a) Normal T cell activation is dependent on T-cell receptor (TCR) recognizing tumour antigen through major histocompatibility complex (MHC)-I processing, (b) Chimeric antigen receptor (CAR) recognises tumour antigen (bypassing MHC-I processing) and activates the CAR-T cell.

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Figure 2:

: CAR T-cell recognises autoreactive B cell and targets CD 19 results in target cell killing by FAS-FAS ligand pathway, perforin/granzyme pathway and release of cytotoxic cytokines. (TCR: T cell receptor, CAR: Chimeric antigen receptor autologous CAR T-cells.

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Because of the natural tissue-homing and infiltrative capacity of T-cells (unlike high–molecular weight monoclonal antibodies), CAR T-cells are able to target hard-to-reach resident memory B-cells. CAR T-cells can survive and proliferate in tissues, performing continued surveillance and targeting of circulating and tissue memory B-cells, thereby providing a ‘deep’ B-cell depletion.¹³

Refinements in CAR design to enhance T-cell killing

First-generation CARs contained only the CD3ζ or Fcγ (costimulatory domain), requiring exogenous IL-2, thereby had limited expansion, stability and antitumor activity. Second- and third-generation CARs incorporated one or more co-stimulatory domains (CD28, 4-1BB, ICOS, OX40), enhancing survival, proliferation, cytotoxicity and memory while reducing exhaustion.^1,14 TRUCKs (T-cells Redirected for universal cytokine killing) are fourth-generation CARs, engineered to secrete cytotoxic cytokines at tumour sites, enhancing direct killing (such as IL-12) and immune recruitment.^14,15

Bivalent CARs are single CAR constructs containing two single-chain variable fragments (scFvs) that enable recognition of two distinct target antigens.Tandem (Tan) CARs are T-cells expressing multiple CARs via co-transduction for synergistic targeting and reduced antigen-loss relapse.¹⁴ “Smart” CAR T-cells incorporate safety switches, dual-antigen targeting or synthetic regulatory circuits (such as inducible caspase-9 or synNotch receptors) to improve potency, safety and sustained tumour control.¹⁵ Most of these advanced CAR designs remain in preclinical or early clinical development.

Preparation of CAR T-cells

CAR T-cells are genetically engineered T-cells harvested from the patient’s blood. The manufacture of autologous CAR T-cells involves several sequential steps [Figure 3].

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Figure 3:

Steps in preparation of autologous CAR T-cells.

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The patient’s T-cells are collected by leukapheresis over 4-6 hours via the technique of elutriation, a process where centrifugal force is applied to the continuous flow of anticoagulated blood and cell layers are separated based on their density. The extracted T-cells are then purified by a complex process of washing and antibody–bead–based selection and transported the laboratory either as a fresh or frozen product.^16,17 These T-cells are then genetically modified using viral vectors (such as gamma retroviral vectors or lentivirus vectors and the transposon/transposase system) to express the chimeric antigen receptor [for example, against CD19 or 20 to target B-cells or against CD138 or B-cell maturation antigen (BCMA) for plasma cells]. Viral transduction is followed by the expansion of these genetically modified CAR T-cells (7 to 12 days). The CAR T-cells are then cryopreserved, checked for quality control and release tested for safety, purity and potency (9 to 14 days) and transferred back to the hospital for patient infusion.^17,18

Before infusing the CAR T-cells, a prior lymphodepleting chemotherapy (most commonly fludarabine and cyclophosphamide) is administered. Host lymphocyte depletion creates a suitable environment for the transferred CAR T-cells to proliferate and preferentially differentiate into a memory phenotype. Following this phase, B-cells typically begin to repopulate after approximately 90–100 days, but without restoration of autoreactive antibody production, reflecting immune reconstitution. In other words, the immune system gets ‘reset’ to a more normal self-tolerant form. In addition to the ‘deep’ B-cell depletion (discussed earlier), this ‘resetting’ of the immune system forms the basis of sustained disease remission and potential cure with CAR T-cell treatment.^17,18

The cryopreserved CAR T-cells are then infused either inpatient or outpatient via gravity over approximately 30 minutes after premedication with paracetamol and antihistamines. Systemic steroids including hydrocortisone are generally avoided due to concerns about lymphotoxicity and arrested expansion.¹⁸ The infusion is generally safe, while the ensuing toxicity of the treatment varies by the type of product, dose, disease burden and patient characteristics.

Certain factors, such as older age (immunosenescence, diminished proliferative capacity), pre-collection thrombocytopenia (poor apheresis yield), prior cancer treatments (deplete the T-cell pool, induce DNA damage) and circulating blasts and natural killer cells (contaminate the apheresis product lowering the yield of functional T cells) can negatively impact T-cell extraction.^15,16 Naïve or early memory T-cells along with minimum peripheral blood lymphocyte count > 100–200 cells/mL is essential to ensure successful T-cell collection for CAR T-cell manufacturing.¹⁶

CAR T-Cell treatment in autoimmune skin diseases

CD19-targeted CAR T-cells have been used in B-cell mediated autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and Sjögren’s syndrome in preclinical studies and early compassionate-use cases with promising results.¹⁹ Overall, CAR T-cell based approaches offer a novel targeted immunotherapy strategy for both systemic as well as organ-specific autoimmune diseases, aiming to reduce autoreactivity without causing broad immunosuppression.²⁰ Table 2 summarizes the current status of CAR-T cell treatment in dermatological and rheumatological diseases.

Dermatomyositis

Pecher et al.²⁶ reported a case of dermatomyositis refractory to corticosteroids, methotrexate, azathioprine, baricitinib and rituximab who achieved marked clinical improvement with CAR T-cell treatment. Within 3 months, the patient demonstrated significant recovery in muscle strength and complete resolution of myositis on magnetic resonance imaging (MRI). Pulmonary function improved substantially (DLCO increasing from 70% to 110%), accompanied by a pronounced decline in serum muscle enzymes (creatine kinase from 5000 U/L to 150 U/L; lactate dehydrogenase from 800 U/L to 250 U/L). CD8+ T-cell subsets and inflammatory cytokines also normalized.²⁶ Subsequently, few more reports have demonstrated similar beneficial response with improvement in skin ulceration, myositis (MRI, muscle enzymes and physician global assessment), calcinosis, renal involvement and interstitial lung disease within 3 to 6 months of CAR T-cell infusion.^27,28

In September 2024, the U.S. FDA granted ‘Rare Pediatric Disease Designation’ to Descartes-08, an autologous mRNA-engineered CAR T-cell therapy targeting B-cell maturation antigen (BCMA), for the treatment of juvenile dermatomyositis. Unlike conventional CAR T-cell products (that use viral vectors), Descartes-08 employs non-integrating mRNA technology, thus conferring a lower risk of insertional mutagenesis and without the need for preconditioning chemotherapy.²⁹

Challenges

Apart from high costs and limited accessibility, potentially serious side effects like cytokine release syndrome (CRS) and neurotoxicity or immune effector cell–associated neurotoxicity syndrome (ICANS) are the major limitations associated with CAR T-cell treatment. CRS is an inflammatory syndrome with a constellation of symptoms that can be mild to fatal. Patient typically present with fever, rigors, hypotension, tachycardia, hypoxia, capillary leak and in severe cases cardiac dysfunction, respiratory failure, renal failure, hepatic failure and disseminated intravascular coagulation with a median time to onset of 2 days (range: 1–12 days).³² Early CRS can be managed with supportive measures, while severe CRS requires IL6 blocking agents (tocilizumab or siltuximab).³³ ICANS can occur with or without CRS and is the second most common adverse event. Clinical presentation typically involves neuropsychiatric symptoms such as attention deficits, language impairment, confusion, disorientation, agitation, aphasia, along with somnolence and tremors. Severe presentations may involve motor deficits, seizures, incontinence and signs of elevated intracranial pressure. Management involves a multidisciplinary approach, supportive care, corticosteroids and the use of IL6 blocking agents such as tocilizumab or, siltuximab.^34,35

These side-effects are more frequently reported in hematological malignancies, whereas a considerably lower toxicity rate has been reported in rheumatologic and dermatologic disorders. This is probably due to the lesser antigen burden in dermatological and rheumatological indications, as the killing of target cells produces a surge of cytokines leading to serious adverse events such as CRS and neurotoxicity. In hematology trials, CRS was reported in 37-93% of patients with it being > grade 3 in 1-22% of patients. ICANS was observed in 19-64% of patients with a > grade 3 toxicity in 12-32% patients.³⁶ In contrast, a systematic review of 101 adult patients with rheumatologic diseases found that most adverse events were limited to grade 1–2 CRS with only one study reporting grade ≥3 CRS. Neurotoxicity was rare, occurring in only 2 patients (1.98%).³⁷

Other reported adverse events include hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, pneumonitis, anaphylaxis and tumour lysis syndrome.³⁸ Dermatological side effects are uncommon; secondary cutaneous malignancies (such as merkel cell carcinoma after 5 months of CAR T-cell infusion), cutaneous infections and eruption secondary to lymphocyte recovery have been reported.³⁹

Conclusion

CAR T-cells offer a novel way of B-cell depletion, addressing some of the limitations of the existing treatments. Following successful results in refractory and relapsing B-cell and plasma cell malignancies, use of CAR T-cell therapy is now being explored in the treatment of B-cell mediated autoimmune diseases such as connective tissue diseases and immunobullous disorders. Innovative strategies such as CAAR T-cells, CAR T-regs and CAR NK-cells may allow more precise treatment, even of non-B cell mediated inflammatory disorders in future. High cost, long preparation time and systemic toxicities remain major challenges and overcoming them will be the key to enabling wider clinical use.