CAR T‐cell therapy in autoimmune skin disease

Georg Schett Antonia Schett Autoimmune diseases (AID) are based on the loss of immune tolerance. Generation of autoimmune B cells and formation of autoantibodies are hallmarks of AID. In the skin, pemphigus vulgaris (PV) with autoantibodies against desmosomal proteins desmoglein-3 and -1, and bullous pemphigoid (BP) with autoantibodies against basal membrane proteins BP180 and BP230, represent paradigms of severe AID of the skin (Figure 1). In both, disruption of cell–cell or cell–matrix contacts leads to the formation of blisters. Also, several systemic AID, like systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and dermatomyositis (DM) affect the skin and trigger inflammation by immune complex deposition, type I interferon activation and vascular inflammation. Elimination of autoimmune B cells may provide a path to achieve sustained control of AID, even providing a chance for cure. Rituximab, a B cell-depleting monoclonal antibody against CD20, is used in autoimmune skin diseases,1 however, it does not completely deplete B cells in the tissues and may therefore rarely allow the attainment of sustained drug-free remission.2 CD19-targeted chimeric antigen receptor (CAR) T cells are ‘living drugs’ that expand in vivo upon target cell exposure (Figure 1). This homeostatic in vivo expansion allows them to eradicate the entire B-cell population.3, 4 SLE has been the first AID, where CAR T-cell therapy has been studied. Several case series, including long-term observation of the patients, have shown that CD19-CAR T cells and CD19/BCMA CAR T cells (the latter also depleting plasma cells) can lead to stable drug-free remission in SLE including abrogation of disease-associated dsDNA antibodies.5-8 Notably, SLE skin lesions, such as malar rash, discoid lupus and subacute cutaneous lupus, clear after CAR T-cell infusion. Self-limited rashes occuring during peak expansion of CAR-T cells have been reported in SLE patients, which are part of the newly described Local Immune Cell Associated Toxicity Syndrome (LICATS).9 Data from patients with DM treated with CD19-CAR T cells revealed a central role of B cells in skin lesions of this disease including heliotropic erythema, Gottron's papules and mechanic's hands showing improvement after CD19-CAR T cells.6 Finally, substantial data have been collected in SSc showing that both autologous CD19-CAR T cells as well as allogeneic CD19 CAR-T cells and CAR-NK cells are effective in SSc, improving skin thickening as evidenced by decreased modified Rodnan skin scores.6, 10-12 Remarkably, skin-specific AID, such as PV and BP, has so far not been tackled by CD19-CAR T cells. While generally no data on cell therapy in BP are available, a new cell therapy approach is in development for PV: In knowledge of the disease-associated antigen, T cells are engineered to express desmoglein-3 (termed CAAR for ‘chimeric autoantibody receptor T cell’) in order to bind and kill only those autoimmune B cells that recognize this specific antigen through their B-cell receptor.13, 14 While pre-clinical data in a PV mouse model supported this concept, no data in humans have yet been reported. One challenge of this approach could be that circulating autoantibodies could contribute to depletion of CAAR by antigen binding or competing with their binding to specific B cells. Higher and repetitive dosing of the CAAR T cells may overcome this challenge. Taken together, PV and BP, being rare life-threatening AID, provide an excellent opportunity to develop CAR T-cell therapy and reset the immune system. Little is known whether other inflammatory skin diseases may profit from cell therapy. Psoriasis is a paradigm chronic disease, which can be well controlled by current cytokine inhibitors, but awaits being cured. In psoriasis, the primary target cell seems to be T cells rather than B cells, a notion that is supported by the efficacy of alefacept—a CD2 targeting IgG-fusion protein depleting T cells.15 Though not realized to date, depletion of certain forms of resident memory T cells in the skin might be an interesting strategy to block the reappearance of psoriatic skin lesions when cytokine blockade is withdrawn.16 Interestingly, and despite data that psoriasis can occasionally exacerbate after treatment with rituximab,17 two case reports showed that CD19-CAR T cells used in patients with refractory lymphoma cleared the concomitant severe psoriasis.18, 19 In another severe inflammatory skin disease, hidradenitis suppurativa, B-cell infiltrates and even tertiary lymphoid follicles have been reported in skin lesions.20 Whether these B-cell follicles resemble a defence process against chronic bacterial infections or whether they actively participate in the inflammatory process remains to be determined. Deep B-cell depletion, such as by CD19-CAR T cells, might give an answer to this question. Adoptive transfer of polyclonal regulatory T cells (Treg) or engineered CD19-CAR-Tregs may provide another therapeutic opportunity. While a case report on successful administration of polyclonal Treg into an SLE patient with skin disease has been published, no further patients have been reported, raising doubts on the efficacy of such an approach.21 On the other hand, engineered CD19-CAR Tregs that shape an immunoregulatory environment at sites of B-cell infiltrates have shown efficacy in preclinical models of lupus.22 For CD19-CAR Tregs, hidradenitis suppurativa could again be an interesting model disease, as both B-cell infiltrates20 as well as a dysregulated Treg/TH17 axis23 have been reported. In summary, treatment with therapeutic cells provides a new powerful approach for AID. Technologies in CAR T-cell therapy rapidly evolve, for example, by (i) the manufacturing of hypoimmunogenic allogeneic CAR-expressing cells,12 (ii) the possibility to create CAR T-cell in vivo through the injection of lipid nanoparticles with a CAR payload24 and (iii) modifications of the CAR by integrating domains that improve CAR survival (e.g. interleukin-15).25 Hence, exciting times are in front with the new possibilities of cell-based therapy potentially enabling stable drug-free remission and potentially even cure of AID of the skin. The work of GS was funded by the Deutsche Forschungsgemeinschaft through the Leibnitz award. AS: none; GS: received speakers honoraria from Novartis and Janssen. Not applicable. Not applicable. Data sharing is not applicable to this article as no data sets were generated or analysed during the current study.