Chimeric antigen receptors: "CARs" in the fast lane for rheumatology.

INTRODUCTION

The foundation of modern cell-based immunotherapy was based on the identification and characterization of specific tumor infiltrating lymphocytes (TILs) that arose as a host response to different cancer types [ 1 ]. Harnessing TIL's endogenous antitumor activity [ 2 ] achieved regression of metastatic melanoma in some patients [ 3 – 6 ]. To mimic the function of those TILs, peripheral lymphocytes were harvested from patients and modified to contain activated tumor-associated T cell receptors, thus conferring a new capacity for those lymphocytes to recognize and destroy the tumor cells when reinfused into patients [ 7 ]. As an extension of this approach, chimeric antigen receptor (CAR) technology brought a new level of innovation, enabling lymphocyte targeting encoded by the specific CAR. CARs are genetically modified T cell receptors engineered to target specific molecules and self-deliver the second activation signal to effect cytotoxicity. There have been several iterations of CARs, categorized as generations, which refer to the components of the intracellular domain affecting potency of the in vivo response (Fig. 1 ). Those CARs capable of activating without co-stimulation, via incorporation of a co-stimulatory intracellular domain, either CD28 or 4-1BB, have superiority to early generation CARs, however CD28 has been observed to result in more cytokine release events, but faster expansion and less persistence when directly compared to 4-1BB constructs [ 8 , 9 ].

Current landscape

Scientific advances in the identification of molecular and cellular events that occur during systemic lupus erythematosus (SLE) that have been targeted by current therapy with partial success. These include agents interfering with the innate and adaptive immune response [ 10 ]. Current treatments include corticosteroids which are known to contribute to damage accrual in SLE [ 11 – 13 ]. Indeed, recently approved therapies including anifrolumab and belimumab have demonstrated significant steroid sparing efficacy as key secondary end points [ 14 , 15 ], by targeting type 1 interferon receptor IFNAR1, or the B cell activating factor BAFF. Nonetheless, for lupus nephritis, complete response rates exceeding 50% in clinical trials are uncommon and risk for end organ failure persists despite long-term immunosuppressive therapy, principally for proliferative nephritis [ 16 , 17 ]. Oral calcineurin inhibition with voclosporin also showed efficacy and steroid sparing properties but complete remission rate was seen in <50% of subjects [ 15 , 18 ]. Although these therapies have resulted in major advances for the treatment of SLE there remains a need for therapies with capacity to induce reliable, long-lived drug-free remission. Combination therapies among approved agents are likely to be tested soon, yet our experience from other diseases suggests that this approach may be difficult to pursue due to lack of support by sponsors [ 19 , 20 ].

Why do chimeric antigen receptors work in autoimmune disease?

Cell-based immunotherapy has provided an alternative means of targeting B cells via their cluster of differentiation (CD) phenotype. The advantage of cell-based immunotherapy was demonstrated in CD19 + B cell malignancies where complete remission was achieved in cases refractory to antibody mediated B cell depleting therapy [ 21 – 24 ], culminating in the first CAR T cell FDA-approvals in 2017 for B-ALL and DLBCL. Early trials in autoimmunity have recently evidenced similar therapeutic capacity for drug-free remission in SLE patients who have already failed conventional and antibody based B-cell depleting therapies [ 25 ▪▪ – 28 ▪▪ ].

Previous trials targeting CD20 expressing B-cells by rituximab did not meet the primary endpoint for efficacy in SLE. The question of why CAR-T mediated approaches achieve better success than administration of monoclonal antibodies remains unanswered. In the case of the recent SLE reports, it could be the actual targeting of CD19, which is expressed on a broader range of B-cell subsets including plasmablasts, a known source of autoantibodies in SLE. Auto-antibody producing memory cells, plasmablasts and long-lived plasma cells are CD19 + /CD20 - and may not subject to depletion with rituximab therapy. This is probably a significant factor explaining failure of the EXPLORER [ 29 ] and LUNAR [ 30 ] trials, which evaluated rituximab for moderate-severe active SLE. Posthoc analysis of the LUNAR trial demonstrated rituximab response was improved in those subjects with complete depletion of peripheral B cells, while patients with rheumatoid arthritis had persistence of B cells on synovial biopsies despite rituximab therapy [ 30 , 31 ], suggesting escape. CD20 directed therapy with obinutuzumab, a more efficient B-cell depleting agent, however, has been shown to offer promise for the treatment of lupus nephritis [ 32 ]. Further analysis demonstrated significant differences in the B-depletion rates and B-cell recovery periods when compared to historical rituximab experience, but similar renal response rates were observed at 104 weeks among those who experienced B-cell recovery within 2 years and those who were still depleted [ 33 ], suggesting early B-cell depletion rather than duration of depletion might be paramount. Improvement of concurrent autoimmune disease in patients who were treated with CD19 CAR-T for malignancy also supported the notion that cell therapy to CD19 might be a more effective target than antibodies to CD20 [ 34 ]. It also raised the question whether lymphodepletion was an important part of the regimen for the success [ 35 ].

Aside from improved effector function, other potential explanations for the differences in clinical response observed between antibody and cellular therapies could include better tissue penetration and accessibility into tertiary lymphoid follicles, or concurrent use of lymphodepleting (LD) regimens, or the fact that the cell therapy pharmacokinetics suggests a longer exposure effect as a living therapeutic. These could be investigated further by trial design to understand their contribution of the observed response, including testing different LD doses, biopsy of lymph node or tissues, and evaluating for persistence of the CAR by molecular techniques.

Chimeric antigen receptor toxicities/safety

Cytokine release syndrome (CRS), characterized by fever, hypotension, and/or hypoxia [ 36 – 39 ] has been observed in most patients treated with CAR T therapy. Neurotoxicity in the form of Immune effector cell-associated neurotoxicity syndrome (ICANS) may be seen alone or in addition to CRS [ 37 , 40 ]. These reactions are currently managed with the Il-6 inhibitor tocilizumab for low grade reactions, with the addition of corticosteroids for refractory cases or concomitant ICANS [ 37 , 39 ]. In oncology, higher tumor burden leads to higher in vivo CAR-T expansion which is associated with increased rates of higher grade CRS [ 41 ]. To date, the experience of CRS and ICANS in SLE, IIM and SSc is limited, but seems to occur with lesser intensity, perhaps due to less cell mass target. In a series of 15 autoimmune disease patients treated with CD19 41BB CAR-T for autoimmune disease, cytokine-release syndrome (CRS) of grade 0 occurred in 4, grade 1 in 10, and grade 2 in 1 patient, and 6/15 patients received tocilizumab for CRS [ 28 ▪▪ ]. One grade 1 ICANS presented as vertigo two weeks after CAR-T infusion in a patient with myositis [ 28 ▪▪ ]. No prolonged (>28 days) bone marrow suppression was observed [ 28 ▪▪ ]. Newer CAR products for oncology are aimed at reducing rates of high grade CRS [ 42 , 43 ] or turning off the CARs with ‘kill switches’ to abort function [ 44 , 45 ].

Other toxicities to consider for CAR-T cell therapy include the withdrawal of background immunosuppression to allow harvesting of T-cells, thus increasing risk for disease flares. For most agents five half-lives is sufficient washout to permit optimal manufacturing of CAR products [ 46 ], though 2 studies reported continuing some immunomodulation through to leukapheresis [ 47 ▪▪ , 48 ▪▪ ]. In the majority of rheumatologic CD19 CAR-T studies, all immunosuppression has been tapered off, but subjects remained on maximum of 10 mg/day of glucocorticoid. The FDA approved CARs have a manufacturing time that can range from 21-35 days in most cases and depends on multiple factors.

Persistence of the CAR product may be associated with long-term toxicity, as recently highlighted by the FDA, which is investigating CAR positive T cell lymphoma reports in patients who have received BCMA or CD19 targeting CAR T cell therapies [ 49 ▪ ]. These may be related to the lentiviral CAR manufacturing process and/or persistence. Engineered ‘kill switches’, regulatable function, and/or use of nonlentiviral transfected cells could mitigate against toxicity arising from persistence of the cell-therapy CAR products. Notably, in the patients reported on with SLE, the CD19 CAR-T cells appears to become undetectable by FLOW cytometry but have not been tested using PCR to our knowledge.

Long-term immunosuppression and hypogammaglobinemia are a concern when using B-cell directed therapies, as has been the experience with rituximab. However, in a recent abstract report, a panel of infectious disease-associated antibodies showed minimal impact of anti-CD19 4-1BBz CAR T therapy on preexisting pathogen humoral immunity including Streptococcus Pneumoniae, Influenza A (H1N1), SARS CoV-2, Bordetella Pertussis, Hepatitis B, and Diphtheria [ 50 ▪ ], suggesting that bone marrow derived CD19 - plasma cells may be spared.

Recent studies

The initial case series evaluating CAR for autoimmune disease was by Mackensen et al. [ 27 ▪▪ ] where the entire five patient cohort of severe refractory SLE experienced drug-free (DORIS criteria) remission by three months, with maintenance of remission in follow up over 24 months in 1 subject (Table 1 ). Since then the same group has expanded their cohort to 15 patients (8 SLE, 4 systemic sclerosis [SSc], and 3 idiopathic immune myositis [IIM]) treated with a single infusion of CD19 CAR-T cells [ 28 ▪▪ ]. Median disease duration before CAR-T was 3 years [range 1–20], median follow-up after CAR-T was 12 months [range 2–28]. All eight SLE patient reached a complete remission after 3 months and maintain a SLE Disease Activity Index (SLEDAI) of 0 [ 28 ▪▪ ]. CAR-T cells rapidly expanded after infusion in all 15 subjects by day 8.6 ± 0.8, and CD19 + B cells were eliminated from peripheral blood after a mean of 5.9 ± 2.2 days in all patients. 12/15 patients experienced B-cell recovery at day 111 ± 50, with the last three patients with 77, 51 and 16 days follow-up are still B-cell aplastic at the time of the report [ 28 ▪▪ ]. The five SLE patients with >14 months follow up (maximum 24 months) remained disease free despite reconstitution of B-cells. Clinical parameters of complement factor C3 remained normal, and proteinuria was absent or at very low levels, while autoantibody seroconversion to negative persisted.

Total B cell numbers gradually increased to a median of 230 cells/μl [183; 886] at month 12 and were mostly of a naïve phenotype. The early drop of CD19 + CD27 + memory B cells increased again at month 12 indicating maturation of the B cells emerging after CAR T treatment [ 28 ▪▪ ].

In their follow up analyzing cytokine profiles before and after CAR T cell infusion, they revealed tumor necrosis factor (TNF)-α, interleukin (IL)-10, and IL-6 were reduced, and 5 of 6 had reduced SLE-associated antibodies [ 50 ▪ , 51 ▪ ]. Immunoglobulin G (IgG) responses to standard vaccines remained stable up to month 24 and were boosted by re-vaccination [ 28 ▪▪ , 50 ▪ , 51 ▪ ]. In a reference to unpublished data, they note that while CD19 - leukocytes repopulate by 3 weeks post lymphodepletion, the CD19 + compartment did not recover until 126 ± 51 days. This is likely attributable to continued surveillance of CD19 CAR-T maintaining suppression, and arguing against the premise that LD regimens alone might be responsible for the clinical response [ 50 ▪ ].

Additional experience is now available for IIM, SSc and other nonrheumatic illness including myasthenia gravis with the clinical observed responses being largely the same – that of striking clinical improvement and with tolerable safety (Table 1 ) [ 25 ▪▪ – 27 ▪▪ , 47 ▪▪ , 48 ▪▪ , 52 ▪▪ – 54 ▪▪ , 55 ▪ , 56 ▪▪ , 57 ▪▪ ]. However, two of the IIM patients from different groups had rapid improvement followed by delayed CK elevation and myalgia after CD19 CAR T [ 54 ▪▪ , 26 ▪▪ ]. In one, cell studies demonstrated an expansion in non-CAR containing T EMRA (CD45RA + CD27 - ) CD8 + T-cells, known to be important in IIM [ 54 ▪▪ ]. The authors hypothesized that the low-grade CRS stimulated expansion of preexisting autoreactive T-cells. Follow up treatment with MMF lead to clinical improvement and normalization of T EMRA CD8 + T-cells. In the other report, the transient elevation was thought to be related to CRS and spontaneous resolution was observed [ 26 ▪▪ ]. These observations suggest further scrutiny for use in myositis.

Four patients with SSc treated with CD19 CAR T have been reported, and 6 month data in three subjects demonstrate stability of disease without ongoing use of immunosuppression [ 56 ▪▪ ]. This included stabilization or improvement of lung function, improved modified Rodnan Skin Score, resolution of tendon friction rubs, improved joint counts, and resolution of digital ulcers [ 28 ▪▪ , 52 ▪▪ , 53 ▪▪ , 56 ▪▪ ].

Alternative strategies to improve safety have utilized transient transfection with RNA containing CAR, including in vivo delivery by nanoparticle [ 58 , 59 ▪ ], or in vitro following leukapheresis [ 48 ▪▪ , 60 ]. The latter of these approaches was utilized by Granit et al. in a phase1b/2a study in Myasthenia Gravis with a CD28 containing BCMA targeted RNA CAR T-cell (rCAR-T)[ 48 ▪▪ ]. This approach was notable for allowing patients to continue immunosuppression prior to collection of PBMCs and eliminating the LD preconditioning regimen which permitted outpatient infusion [ 48 ▪▪ ].

Proof of concept for chimeric antigen receptors in autoimmunity

Early studies from leukemia noted that while CD19 CAR was capable of achieving over 90% complete remission in patients with ALL, the same therapy achieved only 26% percentage responses in CLL, suggesting that differing immune microenvironments may be affecting the baseline functionality of T-cells which CAR therapies rely on to be effective [ 61 , 62 ]. The question was whether CAR T cells harvested from patients with autoimmune disease could function as expected and uniformly for those disorders in which B-cells play a central role? Ostensibly based on the early clinical reports, they might. To address this, early studies in the MRL-lpr murine model demonstrated that adoptive transfer of CD19 CAR resulted in increased lifespans, protected against glomerulonephritis for those that maintained B-cell depletion, and the CARs maintained long-term functionality [ 63 ]. In humans, manufacturing highly functional cells from patients being maintained on immunosuppression remains a challenge, but is feasible [ 47 ▪▪ , 48 ▪▪ ]. The first in human subject study, Mougiakakos et al. [ 47 ▪▪ ] report successful leukapheresis and generation of CD19-CAR T-cells from a 20 year old with severe refractory SLE and active lupus nephritis who was maintained on belimumab and hydroxychloroquine. The infused CD19 CAR-T cells rapidly expanded in vivo and resulted in depletion of circulating B-cells by day 44-day. In a more technical demonstration of feasibility, Kretschmann et al. reported harvesting suitable numbers of CD3 + T-cells for transduction with intact capacity for ex vivo expansion despite recent use of immunosuppression [ 64 ▪ ]. Indeed, these SLE-derived CARs had comparable function to healthy donor derived CD19 CAR-T cells when assessed for in vitro cytotoxic function [ 64 ▪ ].

CONCLUSION

The promise of chimeric antigen receptor in autoimmunity and future directions

The success of CAR directed to CD19 marks a turning point for the treatment of rheumatic disease. These reports demonstrate tolerability and efficacy. They also demonstrate that CAR-T cells rapidly deplete target B-cells in patients with rheumatologic disorders and have the capacity to halt autoantibody production with resolution of clinical manifestations and markers of disease. Furthermore, the initial CAR-T studies in different autoimmune disorders have suggested durability of remission despite reconstitution of B-cells, suggesting that a transient reset of humoral memory may be sufficient for durable remission in certain rheumatic disease, a distinction to the long-term surveillance required to prevent relapse in cancer.

Enhancing safety by limiting CAR transgene expression by mRNA vectors limits the risk of uncontrolled proliferation and is an evolving approach in both oncology and autoimmunity. Also, using shorter lived immune effectors such as natural killer cells, invariant NK (iNK) T cells, gamma delta (γδ) T-cells and allogenic products all could become selected for exploration in rheumatic and other autoimmune disorders, particularly if immune-reset alone proves effective. Importantly, short lived cells do not carry the same risk of graft vs host, permitting allogeneic transfer that would revolutionize access with off-the-shelf readiness. Indeed, highly specific CARs can be developed to target specific memory populations and even single populations of autoantibody producing B cells as demonstrated in Pemphigus Vulgaris [ 65 , 66 ▪ ].

If CD19 by virtue of its expression on a broader range of B cell subsets is the key target, a pilot study comparing CD19-CAR to CD19 monoclonal antibody therapy could be conducted. The CD19-targeting tafasitamab antibody therapy has not been evaluated in SLE but preclinical studies with the CD19 monoclonal antibody Inebilizumab (MEDI-551) report reduction in autoantibody after 12 weeks of treatment in Sle1 .hCD19-Tg mice [ 67 ]. As Inebilizumab is being evaluated in several autoimmune diseases, it will be interesting to compare the experience with CD19 targeted CAR therapy [ 53 ▪▪ , 67 – 69 ], ultimately setting a stage of interesting comparators for future clinical trials. It is important to consider the patient selection and the results in the reported thus far. Indeed, improvement by a CD19 directed therapy suggests the disease may driven by B cell activation factors and early plasmablast generation. However, if autoimmunity is driven by long-lived plasma cells producing autoantibodies such as to those against RNA-binding proteins, a CD19 approach may not be best [ 27 ▪▪ ].

CAR-T cell treatment represents the emergence of a new era in targeted therapeutics. The early published experience has raised the hope for a therapy that can produce long term remission in severe lupus and other diseases notoriously difficult to treat. Future studies are warranted to understand the limitations of the treatment effect seen to date. Cost, access, and safety remain important principles as the development of these technologies progresses. We must also consider the social aspects of health and strive to guarantee access to populations often affected most severely by these diseases.

Clinicians now have a tool to harness immune cells and eliminate pathologic targets. Precision and caution need to guide future development of these exciting therapeutics to keep these CARs on the road for success.

Acknowledgements

We would like to Dr Richard Bucala for his thoughtful comments during the preparation of this manuscript.

Financial support and sponsorship

None.

Conflicts of interest

N.J. – none, F.K. – Astra Zeneca, Aurinia, Cabaletta Bio, Atara Bio, Adicet Bio.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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47▪▪ Mougiakakos D, Krönke G, Völkl S, et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med 2021; 385:567–569. The first case report of CD19 CAR T cells in a patient with severe lupus who had failed treatment with Rituximab and Belimumab. They find that following treatment, dsDNA becomes negative, complement normalizes, and proteinuria decreases from >2000 to <250 mg/g of Cr, and SLEDAI to 0.

48▪▪ Granit V, Benatar M, Kurtoglu M, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, nonrandomised phase 1b/2a study. Lancet Neurol 2023; 22:578–590. Addressing concerns of safety with a persistent CAR product, this alternative approach to CAR T cell therapy features transiently expressed BCMA directed CAR proteins for use in Myasthenia Gravis by utilizing RNA transfection of autologous CD8 + T cells. They report no incidence of CRS or ICANS and patients had reduced MG severity scores at nine month follow up.

49▪ FDA. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA, Available at: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous .2023. (Accessed 8 December 2023). This report addresses findings of CAR-positive T cell malignancy in patients who had received previous treatment with CD19- or BCMA- directed autologous CAR T cell therapy.

50▪ Nunez D, Patel D, Volkov J, et al. Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy. Mol Ther Methods Clin Dev 2023; 31:101104. This paper seeks to understand the immune response to CD19-CAR in 6 SLE patients who had received CAR therapy by analyzing paired samples prior to and 3 months following CAR therapy. They identify reduction in several key inflammatory cytokines, decreases in SLE-associated antibodies, and minimal effect on preexisting humoral immunity.

51▪ Basu S, Nunez D, Patel D, et al. Deep serological profiling of SLE patients treated with anti-CD19 4-1BBz CAR T-cells. ACR Convergence 2023; 1561965. Building off Nunez et al. , this poster presentation from ACR analyzes serologies of 8 patients with SLE who achieved sustained remission following CD19-CAR, now at 6 months of follow up. The observed effects on reduced systemic inflammation persist with minimal effect on preexisting pathogen humoral immunity, and yet a decrease in SLE associated antibodies in many patients.

52▪▪ Taubmann J, Knitza J, Müller F, et al. Efficacy and safety of Car-T-cell treatment in refractory antisynthetase syndrome – data of the first three patients [abstract]. In: ACR Convergence 2023, p. suppl 9. Building off their initial case report, this abstract from ACR reports on three antisynthetase syndrome patients treated with CD19-CAR out to one year follow up in patient one. The results thus far are striking for suggesting CAR can potentially resolve lung and muscle inflammation with drug free remission.

53▪▪ Bergmann C, Müller F, Distler JHW, et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis 2023; 82:1117–1120. The first report of CD19-CAR in a patient with severe refractory systemic sclerosis. Following treatment, the patient had stable pulmonary fibrosis and PFTs at 3 and 6 month follow up with seroconversion of autoantibodies.

54▪▪ Pecher A-C, Hensen L, Klein R, et al. CD19-targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome. JAMA 2023; 329:2154–2162. In this case report of a patient with antisynthetase syndrome who had previously treated with rituximab, CD19-CAR induced clinical and serologic remission. It is additionally notable for their finding of expanded T EMRA population following infusion, potentially in response to the grade I CRS, suggesting future studies may need to address the T cell compartment simultaneously.

55▪ Qin C, Tian DS, Zhou LQ, et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results. Signal Transduct Target Ther 2023; 8:5. This study features one of the largest cohorts in autoimmune CAR trials, featuring 12 patients undergoing BCMA CAR therapy for relapsed/refractory neuromyelitis optica spectrum disorder. During follow up most patients had stable or improved neurologic disability measures and 11/12 achieved drug free remission without relapse.

56▪▪ Bergmann C, Müller F, Auth J, et al. 6 Months-follow up data of systemic sclerosis patients treated with CD 19 targeting CAR-T cells [abstract]. In: ACR Meeting Abstracts, p. suppl 9. Expanded cohort now reporting three CD19-CAR treated SSc 3 patients with infusion well tolerated and showing reduction to absence for ANA and anti RNP-III antibodies. At 6 month endpoint mRSS, HAQ-DI, and EUSTAR activity improved, and lung function parameters remained stable to improve in one patient.

57▪▪ Taubmann J, Müller F, Boeltz S, et al. OP0141 long term safety and efficacy of CAR-T cell treatment in refractory systemic lupus erythematosus-data from the first seven patients. Ann Rheum Dis 2023; 82:93–94. Here, Taubmann et al. report the longest follow up to date regarding the safety and efficacy of CD19-CAR in seven SLE patients. Not only were complications of infusion minimal, limited to Grade I CRS, all patients achieved drug-free, flare-free, DORIS remission criteria, with the longest now out to 22 months.

58. Parayath NN, Stephan SB, Koehne AL, et al. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat Commun 2020; 11:6080.

59▪ Rurik JG, Tombácz I, Yadegari A, et al. CAR T cells produced in vivo to treat cardiac injury. Science 2022; 375:91–96. This paper highlights several novel approaches to the CAR T cell pipeline by pioneering for the first time an in vivo transduction with mRNA containing lipid nanoparticles. This preclinical study has implications both for eliminating the rate limiting step of leukapheresis and naturally limiting long term safety concerns through inherently transient CAR expression.

60. Lin L, Cho SF, Xing L, et al. Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma. Leukemia 2021; 35:752–763.

61. Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563–571.

62. Porter DL, Hwang W-T, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7:303ra139.

63. Kansal R, Richardson N, Neeli I, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med; 11. Epub ahead of print 6 March 2019. doi:10.1126/scitranslmed.aav1648.

64▪ Kretschmann S, Völkl S, Reimann H, et al. Successful generation of CD19 chimeric antigen receptor T cells from patients with advanced systemic lupus erythematosus. Transplant Cell Ther 2023; 29:27–33. In a demonstration of preclinical feasibility CD19-CAR T cells generated from patients with SLE are compared to those generated from healthy controls. They demonstrate successful Leukapheresis and ex vivo expansion to clinically feasible numbers, and comparable functionality of SLE derived CAR T cells in in vitro assays.

65. Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016; 353:179–184.

66▪ Lee J, Lundgren DK, Mao X, et al. Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. J Clin Invest 2020; 130:6317–6324. Lee et al. introduce targeting of a single B-Cell population by utilizing an autoantigen extracellular domain in their CAR for targeting. Eliminating merely a single population of auto-antibody producing B-cells as opposed to total B-cell depletion limits complications that arise from immunosuppression and hypogammaglobinemia with the latter approach.

67. Gallagher S, Yusuf I, McCaughtry TM, et al. MEDI-551 treatment effectively depletes B cells and reduces serum titers of autoantibodies in mice transgenic for Sle1 and human CD19. Arthritis Rheumatol 2016; 68:965–976.

68. Schiopu E, Chatterjee S, Hsu V, et al. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther; 18. Epub ahead of print 2016. doi:10.1186/S13075-016-1021-2.

69. Streicher K, Sridhar S, Kuziora M, et al. Baseline plasma cell gene signature predicts improvement in systemic sclerosis skin scores following treatment with inebilizumab (MEDI-551) and correlates with disease activity in systemic lupus erythematosus and chronic obstructive pulmonary disease. Arthritis Rheumatol 2018; 70:2087–2095.