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Chimeric antigen receptor T-cell therapy in dermatological disorders: Expanding horizons
Fernando Javier Medina-Olivares
Facultad de Medicina, Universidad Autónoma de Nuevo León (UANL), Nuevo León, México
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© Our Dermatology Online 2025. No commercial re-use. See rights and permissions. Published by Our Dermatology Online.
ABSTRACT
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized cancer immunotherapy, particularly, in hematological malignancies, and is now being explored for dermatological and autoimmune diseases. This review examines CAR-T therapy’s potential in pemphigus vulgaris, melanoma, vitiligo, and emerging applications such as psoriasis, systemic lupus erythematosus, and hidradenitis suppurativa. Preclinical and clinical studies highlight its efficacy in targeting pathogenic immune cells, addressing immune evasion, and modulating inflammation. Challenges remain in patient eligibility, delivery logistics, manufacturing complexity, toxicity management, and economic barriers. Innovations in CAR design, outpatient therapy models, and decentralized manufacturing are being explored to overcome these limitations. Future research should focus on optimizing antigen targets, enhancing safety, and expanding accessibility. By fostering collaboration across disciplines, CAR-T therapy has the potential to transform treatment paradigms in dermatology, offering precise and durable solutions for complex diseases with unmet therapeutic needs. Continued advancements may usher in a new era of personalized immunotherapy.
Key words: CAR-T therapy, Autoimmune diseases, Dermatology, Melanoma, Pemphigus vulgaris, Vitiligo
INTRODUCTION
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a groundbreaking innovation in immunotherapy, offering unprecedented efficacy in the treatment of hematological malignancies. Its success in targeting specific antigens on malignant cells has prompted exploration into its application for other diseases, including dermatological conditions. Dermatology, a field with a wide spectrum of diseases ranging from autoimmune disorders to malignancies, represents an area where CAR-T therapy could address unmet therapeutic needs.
The scientific rationale for investigating CAR-T therapy in dermatology lies in its ability to precisely target and eliminate pathogenic immune cells. Autoimmune conditions such as pemphigus vulgaris are characterized by autoreactive B cells producing pathogenic antibodies against desmogleins, leading to epidermal blistering [1]. Current treatments, including corticosteroids and biologics such as rituximab, often result in systemic side effects and incomplete disease control, highlighting the need for more targeted and durable therapies [2].
Similarly, melanoma, a skin malignancy with a high mortality rate in advanced stages, exemplifies the limitations of existing immunotherapies due to the tumor’s ability to evade immune surveillance. CAR-T therapy offers the potential to overcome these challenges by targeting tumor-specific antigens and enhancing immune responses within the tumor microenvironment [3].
Another compelling application is vitiligo, an autoimmune disorder characterized by the destruction of melanocytes, leading to depigmentation. Despite advances in topical and systemic therapies, a large number of cases remain refractory. Modulating autoreactive T cells through CAR-T therapy could provide a novel mechanism for restoring immune tolerance and promoting repigmentation [4]. The primary issues and controversies surrounding CAR-T therapy in dermatology include safety concerns, such as cytokine release syndrome, and the technical challenges of designing CAR-T cells that would be effective in non-malignant settings. Additionally, questions remain about the cost-effectiveness and long-term outcomes of CAR-T therapy in chronic dermatological conditions [5].
The aim of this review was to evaluate the current state of knowledge regarding CAR-T therapy in dermatology, with a focus on its application in pemphigus vulgaris, melanoma, and vitiligo. We explored the underlying scientific and clinical rationales, assessed the challenges and controversies, and discussed the potential for this therapy to revolutionize the management of dermatological disorders.
POTENTIAL APPLICATIONS OF CAR-T THERAPY IN DERMATOLOGY
Pemphigus Vulgaris
Pemphigus vulgaris is a severe autoimmune blistering disease characterized by mucosal or mucocutaneous involvement, with suprabasal acantholytic blisters caused by IgG autoantibodies targeting desmogleins. These desmogleins (Dsg1 and Dsg3) are transmembrane glycoproteins essential for cell–cell adhesion within desmosomes. The disruption of desmosomal function by these autoantibodies leads to the hallmark blistering seen in the disease [6]. Autoantibody profiles are crucial in determining the clinical presentation of pemphigus vulgaris. Autoantibodies against Dsg3 are typically associated with mucosal-dominant pemphigus vulgaris, whereas autoantibodies against both Dsg1 and Dsg3 lead to mucocutaneous involvement. The pathogenicity of these autoantibodies has been demonstrated in experimental models, where they induce blistering via direct interference with desmosomal adhesion and activation of intracellular signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway [7].
The desmoglein compensation theory provides a framework for understanding the clinical manifestations of pemphigus vulgaris. In this model, the distribution of Dsg1 and Dsg3 in mucosal and cutaneous tissues explains the varying disease phenotypes. However, discordances between clinical presentations and autoantibody profiles in some patients suggest that additional factors, such as autoantibodies against other desmosomal components (e.g., desmocollin 3), contribute to the disease [8]. CAR-T therapy represents a promising therapeutic approach for pemphigus vulgaris, particularly for refractory cases. Recent advances have focused on the development of chimeric autoantibody receptor (CAAR) T cells, which are engineered to specifically target autoreactive B cells producing pathogenic autoantibodies. In preclinical studies, CAAR-T cells designed to express Dsg3 fragments selectively eliminated anti-Dsg3 B cells, reduced pathogenic autoantibody levels, and ameliorated disease severity in murine models [9]. Importantly, these CAAR-T cells demonstrated specificity, avoiding off-target effects on keratinocytes expressing Dsg3 or related proteins.
One of the significant advantages of CAAR-T therapy is its potential to provide long-lasting remission by targeting memory B cells, which are implicated in disease relapse following conventional therapies such as rituximab [10]. Moreover, CAAR-T cells can differentiate into memory T cells, potentially preventing the re-emergence of autoreactive B cell clones [11]. Challenges remain in the clinical translation of CAAR-T therapy for pemphigus vulgaris. Targeting both Dsg1 and Dsg3-reactive B cells is necessary to address the full spectrum of disease presentations and prevent epitope spreading [12]. Additionally, the high cost of CAR-T therapy poses a barrier to widespread implementation [13]. Despite these obstacles, the development of CAAR-T cells for pemphigus vulgaris represents a significant step toward curative therapy for this debilitating condition.
Melanoma
Melanoma is a highly aggressive skin cancer known for its ability to evade immune detection and resist conventional therapies. The tumor microenvironment in melanoma is characterized by significant immunosuppressive activity, driven by a network of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), which collectively dampen cytotoxic T-cell responses [14]. This immune evasion is further facilitated by immune checkpoint molecules, such as PD-1 and CTLA-4, which inhibit T-cell activation and promote an exhausted T-cell phenotype [15]. The PD-1/PD-L1 axis plays a pivotal role in melanoma’s immune evasion strategies. By expressing PD-L1, melanoma cells interact with PD-1 receptors on cytotoxic T cells, leading to impaired T-cell function, reduced cytokine production, and apoptosis of anti-tumor T cells [16]. Additionally, PD-L2, another ligand for PD-1, contributes to immune suppression in melanoma, with evidence suggesting it may play a more prominent role in certain melanoma subtypes [17]. Immune checkpoints such as CTLA-4 further exacerbate immune suppression by outcompeting CD28 for binding to CD80/CD86 on antigen-presenting cells, resulting in T-cell anergy [18].
Efforts to counteract these mechanisms have led to the development of checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4, which have demonstrated efficacy in reactivating immune responses against melanoma [19]. However, not all patients respond to checkpoint blockade, highlighting the need for additional therapeutic strategies. CAR-T therapy offers a novel approach to melanoma treatment by enabling the engineering of T cells to specifically target melanoma-associated antigens. Preclinical studies and early-phase clinical trials have explored various targets for CAR-T cells, including GD2, cMet, and hCD70, among others [20]. Despite some promising results, challenges such as tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment have limited the efficacy of CAR-T therapy in melanoma. To address these obstacles, advanced CAR designs are being developed, including armored CAR-T cells capable of secreting pro-inflammatory cytokines or resisting immunosuppressive signals [21]. Dual-targeting CARs and modifications to enhance T-cell infiltration and persistence within the tumor microenvironment are also being investigated [22]. Additionally, combination therapies involving CAR-T cells and immune checkpoint inhibitors or cytokine-based treatments hold promise for improving outcomes in melanoma patients [23].
Vitiligo
Vitiligo is a chronic autoimmune disorder characterized by the progressive destruction of melanocytes, leading to depigmented patches on the skin. The pathogenesis of vitiligo is complex, with contributions from autoimmune mechanisms, oxidative stress, and potential genetic predisposition [24]. The “convergence theory” suggests that multiple mechanisms interact to cause melanocyte loss, reflecting the heterogeneous presentation of the disease [25]. Autoimmunity plays a pivotal role in vitiligo. Cytotoxic T lymphocytes (CTLs), particularly CD8+ T cells, are highly active in vitiliginous lesions and directly target melanocytes. Studies have identified increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-17 (IL-17) in affected skin, which contribute to the recruitment and activation of immune cells [26]. Additionally, antibodies against melanocyte-specific antigens have been detected in patients, further supporting an autoimmune etiology [27].
Oxidative stress also contributes significantly to melanocyte destruction. Imbalances in reactive oxygen species (ROS) and antioxidant systems, such as reduced catalase and glutathione levels, lead to an environment conducive to melanocyte apoptosis [28]. This oxidative environment may activate immune responses, further exacerbating melanocyte loss. External factors, including exposure to phenolic compounds and UV radiation, may amplify these processes [29]. CAR-Treg therapy represents a promising approach for addressing the immune dysregulation in vitiligo. Engineered to express chimeric antigen receptors targeting melanocyte-associated antigens, such as ganglioside D3 (GD3), CAR-Tregs can restore immune tolerance by modulating cytotoxicity and reducing inflammation. In preclinical studies using humanized mouse models of vitiligo, GD3-specific CAR-Tregs demonstrated the ability to protect melanocytes, promote IL-10 production, and suppress the activity of autoreactive T cells, leading to reduced depigmentation [30].
One of the significant advantages of CAR-Tregs is their antigen specificity, which minimizes the risk of generalized immunosuppression. These engineered Tregs can be expanded ex vivo to therapeutic levels and potentially stored for future use, making them a versatile option for intermittent treatment during active disease phases [31]. Innovations such as suicide gene constructs may enhance safety by allowing the controlled inactivation of CAR-Tregs if adverse effects occur [32]. Despite these advancements, challenges remain in translating CAR-Treg therapy for vitiligo into clinical practice. Factors such as the optimization of antigen targets, delivery methods, and long-term persistence of CAR-Tregs in vivo require further investigation [33]. Additionally, the cost and scalability of manufacturing CAR-Tregs present barriers to widespread application [34].
Other Dermatological and Autoimmune Conditions
Beyond pemphigus vulgaris, melanoma, and vitiligo, CAR-T therapy shows promise for other dermatological and autoimmune conditions. Emerging evidence suggests its potential utility in other conditions. Psoriasis, a chronic inflammatory disease driven by dysregulated T-cell and cytokine activity involving IL-17 and TNF-α, has shown promising preliminary results. CD19-targeted CAR-T cells have been suggested to modulate immune states in psoriasis, as demonstrated by a case report where severe psoriasis improved significantly following CD19 CAR-T therapy, pointing to a potential role of B cells in the disease’s pathogenesis [35]. Similarly, systemic lupus erythematosus (SLE), characterized by widespread immune dysregulation and autoantibody production, has benefited from CAR-T therapy targeting CD19, achieving sustained B-cell depletion and immune reset with clinical remission in multiple cases [36]. Furthermore, CAR-T therapy has potential applications in cutaneous T-cell lymphoma (CTCL), where advanced disease stages pose significant challenges. Targeting antigens such as CD4 and CD30 with CAR-T cells is under investigation, with strategies to minimize fratricide and improve specificity [37]. Juvenile dermatomyositis (JDM), a rare inflammatory myopathy, has also shown positive outcomes with CD19 CAR-T therapy in refractory cases, achieving long-term disease improvement [38]. In scleroderma and fibrotic diseases, CAR-T cells targeting fibroblast activation protein (FAP) have shown preclinical promise, offering new therapeutic avenues [39]. Lastly, in autoimmune conditions such as alopecia areata, CAR-Treg therapy targeting specific antigens holds potential for restoring immune tolerance and preventing relapses [40].
CHALLENGES AND BARRIERS IN CAR-T THERAPY
Despite its groundbreaking potential, CAR-T therapy faces several challenges that hinder its broader adoption and efficacy. One of the foremost barriers is patient eligibility. Clinical trials often include stringent criteria, excluding patients with comorbidities or conditions such as HIV or hepatitis. However, real-world evidence from studies on lymphoma and leukemia indicates that CAR-T therapy can be effective in broader patient populations, including older individuals and those with additional diseases [41]. This suggests that expanding eligibility criteria could increase access without compromising outcomes. Another major challenge is the current delivery model for CAR-T therapy. Traditionally administered in inpatient settings within large academic medical centers, this approach limits access for patients living far from these institutions and increases costs associated with hospitalization [42]. Exploring outpatient administration and expanding CAR-T delivery to community-based oncology clinics could alleviate these issues. However, outpatient centers must develop robust safety protocols and resources to manage severe side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome [43]. Studies have demonstrated the feasibility of outpatient delivery in carefully selected patients, yet this model requires further refinement and infrastructure development [44].
The prior authorization process by insurance providers is another hurdle, particularly for patients with relapsed or refractory diseases requiring urgent treatment. Delays in obtaining authorization can lead to disease progression or disqualification from therapy [45]. Streamlined processes and standardized pre-approval mechanisms could help address these delays and ensure timely access to CAR-T therapy [46]. Additionally, the complex manufacturing process poses significant challenges. The current autologous CAR-T model involves weeks-long production times, during which patients may become ineligible due to disease progression. Innovations such as allogeneic CAR-T cells, which use pre-engineered donor cells, could reduce production times and costs, yet issues such as graft-versus-host disease remain unresolved [47]. Decentralized manufacturing models using automated systems, such as Miltenyi Prodigy or Lonza Cocoon, are being explored to shorten the “vein-to-vein” time and lower costs [48].
Therapy-related toxicities also present substantial challenges. CRS, ICANS, and tumor lysis syndrome (TLS) are common side effects that require immediate and specialized management. Physicians have developed strategies to mitigate these toxicities, including the use of IL-6 inhibitors, corticosteroids, and anticonvulsants [49]. Advances in CAR design, such as incorporating safety switches or using human-derived antibody fragments, are being explored to minimize these risks [50]. Relapse remains a concern, as not all patients achieve long-term remission. Relapses can occur due to the loss of CAR-T cell persistence or antigen escape by malignant cells. Research is ongoing to optimize CAR constructs and identify factors predicting relapse. For patients with relapsed disease, strategies such as repeat CAR-T infusions and combination therapies are under investigation [51]. Economic considerations further complicate CAR-T therapy implementation. The high cost of therapy, coupled with reimbursement challenges, poses a significant barrier. Alternative payment models, such as bundled payments or outcome-based agreements, are being explored to address these issues [52]. For instance, Novartis’ outcome-based agreement for Kymriah ensures no payment is required if patients fail to achieve remission within a specified timeframe [53].
FUTURE PERSPECTIVES AND ONGOING CLINICAL TRIALS
The ongoing evolution of CAR-T therapy underscores its transformative potential, not just in hematological malignancies but across a spectrum of autoimmune and dermatological conditions. Recent advancements in clinical research highlight promising avenues for expanding its application and improving patient outcomes. One of the most exciting developments is the exploration of CAR-T therapy in autoimmune disorders such as pemphigus vulgaris, dermatomyositis, and melanoma. For instance, the phase 1/2 RESET-PV trial (NCT04422912) is evaluating DSG3-CAART and CD19-specific CAR-T cells (CABA-201) in pemphigus vulgaris patients inadequately managed by standard therapies. This study aims to identify the optimal dosing and infusion schedule, with the goal of achieving complete and durable remission [54]. Similarly, the KYV-101 trial (NCT06298019) investigates CD19-targeted CAR-T cells in adult patients with treatment-refractory dermatomyositis. This trial seeks to determine the safety and efficacy of CAR-T therapy in modulating B-cell-mediated autoimmunity and alleviating systemic inflammation, particularly in the skin, muscles, and lungs [55].
Another groundbreaking trial (NCT04119024) focuses on using IL13Rα2 CAR-T cells in patients with advanced melanoma or metastatic solid tumors. By targeting the IL13Rα2 protein expressed on tumor cells, this study evaluates the potential of CAR-T cells to achieve targeted tumor destruction while minimizing off-target effects. The trial’s outcomes could pave the way for applying CAR-T therapy to other solid tumors, addressing a critical unmet need in oncology [56]. Beyond these conditions, CAR-T therapy is being explored for systemic autoimmune diseases such as lupus, with CD19-targeted CAR-T cells showing promise in achieving sustained B-cell depletion and immune system reset. Trials incorporating advanced manufacturing techniques, such as the T-Charge™ process used for YTB323, have demonstrated improved outcomes by reducing ex vivo culture times and enhancing CAR-T cell potency. Preliminary data from studies using YTB323 in lupus suggest significant clinical improvements with minimal adverse events, heralding a new era of faster, more effective CAR-T therapies [57]. The SBT777101 study (Regulate-HS) (NCT06361836) is evaluating the safety and efficacy of a novel CAR-Treg cell-based therapy for hidradenitis suppurativa. This investigational autologous therapy targets inflamed, disease-associated tissues, aiming to reduce inflammation and restore immune balance [58].
As the field advances, researchers are exploring strategies to overcome existing limitations. These include developing off-the-shelf allogeneic CAR-T products to reduce manufacturing timelines, incorporating safety switches to mitigate toxicities, and designing CAR constructs that target multiple antigens to address tumor heterogeneity and antigen escape. Additionally, combination therapies that integrate CAR-T cells with immune checkpoint inhibitors or cytokine modulators hold promise for enhancing efficacy and broadening the therapeutic scope.
CONCLUSION
The rapid evolution of CAR-T therapy has redefined the therapeutic landscape for a range of conditions, from hematological malignancies to complex dermatological and autoimmune diseases. Current evidence highlights its transformative potential in addressing unmet needs in pemphigus vulgaris, melanoma, vitiligo, and emerging applications such as psoriasis, systemic lupus erythematosus, and juvenile dermatomyositis. By leveraging its capacity for targeted immunomodulation and durable responses, CAR-T therapy stands at the forefront of modern immunotherapy. Despite these advances, significant challenges remain. Patient eligibility, logistical barriers in therapy delivery, complex manufacturing processes, and the management of therapy-related toxicities require continued refinement. Moreover, economic considerations, including the high costs of treatment and reimbursement challenges, underscore the need for innovative payment models and cost-reduction strategies.
Collaboration among researchers, clinicians, and industry stakeholders is essential to overcome these hurdles and expand the utility of CAR-T therapy. In the field of dermatology, where diseases often have multifactorial etiologies and significant impacts on quality of life, the integration of CAR-T therapy represents a promising horizon. Future research should focus on optimizing CAR designs, identifying novel antigen targets, and improving accessibility to ensure broader patient benefits. As we move forward, the combination of technological innovation, clinical expertise, and collaborative research efforts will be pivotal in realizing the full potential of CAR-T therapy. By addressing current limitations and exploring new frontiers, CAR-T therapy could herald a new era of personalized, effective, and accessible treatments for patients worldwide.
Statement of Human and Animal Rights
All the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 2008 revision of the Declaration of Helsinki of 1975.
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