Cellular Therapy for Systemic Autoimmune Diseases: New Opportunities for Future Research and Interdisciplinary Collaboration.

Introduction

Contemporary evidence demonstrates that the incidence of autoimmune diseases (AIDs) has been increasing over time. 1 Affecting approximately 1 in 10 individuals, AIDs disproportionately affect women 1 as well as individuals with low income, unemployment, or low education level. 1 , 2 Although advances in clinical development have expanded treatment options for certain AIDs (eg, rheumatoid arthritis [RA]), 3 therapeutic progress remains slow for the majority of systemic AIDs (sAIDs), and many of these diseases have just one or two approved therapies. Very importantly, most currently available sAID therapies do not induce drug‐free remission, and the proportion of individuals dying from complications of sAIDs has not improved over the past 20 years. 4 , 5 , 6 , 7

The advent of cellular therapies now promises to transform the treatment landscape in sAIDs. 8 , 9 Considered a potentially curative treatment strategy, cellular therapies use engineered components of the immune system to induce death of the target cell. Given that many sAIDs share common pathogenic mechanisms (eg, loss of immune tolerance against self‐antigen, autoantibody production by B lymphocytes and plasma cells), 10 cellular therapies that target CD19 may halt pathogenic B cell activities. 11

A recently published uncontrolled case series demonstrated that 18 patients with sAIDs (n = 8 systemic lupus erythematosus [SLE], 5 SSc, 5 idiopathic inflammatory myopathy [IIM]) achieved sustained clinical improvement after a single transfusion of anti‐CD19 chimeric antigen receptor‐T (CAR‐T) cells. 12 All patients had severe and treatment‐resistant disease, and most had evidence of internal organ involvement (eg, proliferative renal nephritis, interstitial lung disease [ILD]). In addition to clinical efficacy and a reduction in immunomodulatory medication use, the study discovered that a naïve nonclass‐switched B cell phenotype emerged, and most autoantibodies either disappeared or showed a reduced titer following CAR‐T. 12

Although this trial lacked a comparator arm, the fact that the patients in this study had failed multiple previous immunomodulatory therapies suggests that the observed clinical improvement was attributable to CAR‐T rather than the natural history of the underlying disease. In light of these 12 and other similar findings, 13 , 14 clinical development in this therapeutic area has greatly accelerated. As of the time of this publication, nearly 200 clinical trials are actively recruiting or soon to be recruiting patients with sAID to test novel and diverse immune cell generation strategies (N = 90 for SLE, N = 50 for SSc, N = 30 for IIM) ( Clinicaltrials.gov search, May 5, 2025) (Table 1 ).

Despite the impressive early results and a palpable sense of excitement, 15 , 16 numerous unanswered questions remain regarding the proper place of cellular therapies in sAID, and further research is needed to understand the long‐term safety and efficacy of this novel approach. 17 , 18 An opportunity also exists for rheumatologists to learn from oncologists who have been involved in the development and clinical application of immune cell therapies for over 50 years. To this end, the National Cancer Institute's Center for Cancer Research and the National Institute of Arthritis and Musculoskeletal and Skin Diseases recently held a two‐day workshop on cellular therapies for two distinct fibrotic diseases, SSc and chronic‐versus‐host disease (cGVHD). Stakeholders from diverse backgrounds (eg, academic medicine, industry, regulatory agencies, advocacy groups, National Institutes of Health [NIH] office for women's health) convened to discuss four themes: (1) novel SSc and cGVHD cellular therapies; (2) advancement of personalized medicine in these disease areas; (3) challenges in drug development trial design; and (4) overcoming obstacles to implementing cellular therapy trials. 19 In particular, the workshop sought to bridge basic science research, drug discovery/development and clinical studies, and foster collaboration between specialists in rheumatology and in cellular therapy/transplantation/oncology to leverage mutual expertise, execute clinical trials, and bring the clinical development of these novel therapies to fruition. 20 Here, we summarize key lessons from this workshop and also provide a narrative review on this topic to contextualize the workshop recommendations and make practical recommendations for improving cellular therapy clinical development for sAIDs.

Leveraging basic science research to propel clinical development for sAID

The role of B cells

B cells have been implicated in sAID pathogenesis for decades via mechanisms ranging from autoantibody production that triggers end‐organ damage to the propagation of inflammation. 21 Increased B cell receptor (BCR) signaling is associated with B cell hyperreactivity with up‐regulated CD19 expression and activation of B cell survival signals such as B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). Levels of these factors correlate with disease activity in various sAIDs, including SLE, Sjögren disease, and SSc. 22 , 23 Moreover, several bleomycin‐induced skin and lung fibrosis models have shown BAFF enrichment in target organs, with reversal by a BAFF antagonist to alter the balance of the regulatory and Beff cells in a scleroderma‐like cGVHD mouse model. 24

Therapies targeting B cells can modify disease course in patients with sAID. For example, belimumab, approved for use in SLE, 25 is now under study for the treatment of SSc and connective tissue disease associated ILD. Several other trials targeting the BAFF/APRIL pathway are underway. 26 , 27 , 28 Given B cells’ critical role in sAID pathogenesis, B cell depletion strategies including the anti‐CD20 antibody rituximab have been extensively used in SSc, SLE, and RA, along with hematologic malignancies including lymphoma and chronic lymphocytic leukemia (CLL). Although B cell depletion through pharmacological treatments, such as rituximab, can lead to complete responses, they may not induce sustained remission, and the long‐term risks of these agents for sAID management remain a concern.

The role of T cells

Changes in the T cell microenvironment with the emergence of self‐reactive T cell clones have been demonstrated in virtually all sAIDs. Down‐regulation by specific T cell subsets, including regulatory T cells (Treg cells expressing FOXP3), lead to reduction in proinflammatory cytokines such as interleukin (IL)‐4 and IL‐13. 29 Another subpopulation of long‐lived circulating T cells, called resident memory T cells (Trm) can reignite a lesion in the healthy appearing skin and trigger increased T cell receptor signaling such as cAKT1, PIKR2 and HLA‐C, and JAK‐STAT in activated APC, IL‐17 activation, and DC maturation. 30 , 31 Finally, interaction with profibrotic macrophages induces tissue fibrosis via TGF‐β signaling and promotes epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (endo‐MT).

Myeloablative autologous stem cell transplantation can “reset the immune clock” by eliminating self‐reactive T cell clones and allowing Treg repopulation. 32 , 33 However, given the infectious complication risk, the need for high chemotherapy doses (that may be prohibitive for patients with baseline organ dysfunction) and transplant‐related mortality, alternative targeted T cell treatments have been explored.

Engineered T cells

CAR‐T is a genetically modified T cell product engineered to recognize a specific target. This process involves leukapheresis to collect a patient's cells, cell processing for genetic engineering, and cell reinfusion to the patient (Figure 1 ). Patients require lymphodepletive chemotherapy (typically involving fludarabine and cyclophosphamide) before CAR‐T cell infusion to facilitate in vivo expansion. As demonstrated in Figure 2 , T cells are genetically engineered to target the antigen of interest (Figure 2 ). Yescarta (tisagenlecleucel) was first Food and Drug Administration (FDA)–approved in 2017 for targeting CD19 cells in relapsed refractory acute lymphoblastic leukemia (ALL). Several additional treatments have gained FDA approval for B cell malignancies, including multiple myeloma and refractory lymphoma, leading to long‐lasting remissions in responders. 34 As illustrated in Figure 3 , these cellular products generally include a receptor recognizing the antigen of interest, transmembrane domain, CD3 signaling, and co‐stimulatory domains for signal enhancement and an intracellular signaling domain (Figure 3A ). Currently, FDA‐approved CAR‐T products are autologous and require up to four weeks of manufacturing time. Patients typically require hospital admission to monitor adverse events including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Complete responders to CAR‐T do not require further treatment.

A recent study of CD19‐targeting CAR‐T in patients with SLE, SSc, and RA demonstrated sustained remission, including cessation of immunomodulatory therapy and decreased autoantibody titers, 12 and several B cell‐targeting constructs are being tested in other AIDs such as myasthenia gravis. 17 , 35 , 36 B cell aplasia, a side effect of B cell directed CAR‐T and their persistence, lasted about four months, suggesting that T cell persistence may not be necessary for longstanding effects, in contrast to hematologic malignancies for which T cell persistence may be required to maintain remission.

A second B cell‐targeting treatment approach centers around bispecific T cell engagers (BITEs). These antibodies target two distinct cells: one target being the cell type of interest and the other target being T cells (Figure 3B ). This structure allows T cells to be brought near the target cell, promoting their killing. BITEs have the advantages of being off‐the‐shelf products that do not require previous conditioning chemotherapy. BITEs are generally well‐tolerated, with much lower rates of CRS and ICANS than CAR‐T, making them attractive for use in sAIDs. However, repetitive treatments that are required to sustain response can lead to T cell dysfunction (termed exhaustion) and loss of efficacy. Several CD19 targeting BITEs have been approved for hematologic conditions and represent a promising novel approach to sAID therapy. For example, teclistimab, a BCMA targeting BITE used in multiple myeloma, was successful in treating aggressive SLE and resulted in a durable, drug‐free remission. 37 Similarly, six patients with aggressive RA treated with the CD3xCD19 BITE blinatomumab (FDA‐approved for the treatment of ALL) all showed decreased disease activity and autoantibodies. 38

NK cells

NK cells serve diverse functions, contributing not only to innate immune response through cytolytic functions and antibody‐dependent cellular cytotoxicity but also potential interactions with the adaptive immune system and reduction of cancer risk. 39 , 40 They do not rely on previous antigen recognition and do not express T cell receptors; in contrast to allogeneic CAR‐T, GVHD susceptibility with CAR‐NK treatment is minimal, making CAR‐NK another suitable target for off‐the‐shelf use. 41 However, the durability of CAR‐NK in peripheral blood and lymphoid organs is more limited than CAR‐T cells.

A promising phase I/II study for patients with refractory B cell lymphomas using cord blood derived anti CD19 CAR and IL‐15 expressing NK cells showed a promising 48 % response rate with no CRS or GVHD. 42 Patients who achieved a response at day 30 had a 70 % likelihood of staying in remission, but complete response rates were lower than the historical autologous CAR‐T cells. CAR‐NK constructs for refractory acute myelogenous leukemia and multiple myeloma displayed excellent tolerability with varying efficacy. 43 , 44 , 45 There are currently no FDA‐approved CAR‐NK cell treatments, although several constructs are under investigation for sAIDs. 46

Limitations of existing cellular therapy studies

Despite the rapidly growing evidence on cellular therapies for sAIDs, these data should be interpreted in the context of certain limitations based on the design of cellular therapy trials in this area. For example, existing studies are relatively small (<20 patients) and lack a control arm, making it difficult to determine whether the observed treatment effects are due to the intervention versus the natural history of disease. This is a particular concern for conditions such as SSc, for which the spontaneous improvement in skin disease in the absence of therapy is not uncommon. Designing multicenter studies with greater sample sizes is essential to further prove the efficacy of cellular therapies for sAID. In addition, given the incurable nature of rheumatologic diseases, longer follow‐up of the patients is required to prove the durability of the responses and treatment‐free intervals. Published studies had median follow‐up times ranging from 24 weeks to 15 months. 12 , 38 , 47

Lessons from cGVHD

Chronic graft‐versus‐host‐disease (cGVHD) is a multiorgan sAID that is a major cause of late nonrelapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo‐HCT). 48 It is estimated that 25% to 50% of patients undergoing allo‐HCT develop cGVHD, with a prevalence of 20,000 patients based on the US Medicare database. 49 , 50 One‐third of these patients develop severe cGVHD, and 70% fail to respond to first‐line therapy with glucocorticoids and require second‐line therapies. The treatment of severe cGVHD is associated with drug‐related toxicities, secondary cancer risk, decreased quality‐of‐life, and financial challenges. 51 Among patients with cGVHD, 20% develop sclerotic disease within three years following cGVHD systemic treatment. 52 Sclerosis affects the superficial and deep layers of the skin, joints, and/or fascia, and causes impaired mobility and contractures. Internal organs, including the gastrointestinal tract, liver, and lungs are affected in 17% to 45% of the cases. 53 , 54

Paralleling SSc, patients with sclerotic GVHD require prolonged and high‐dose immunosuppression that could lead to infectious complications and irreversible fibrotic organ dysfunction. 55 , 56 Several new therapies for cGVHD have been approved in the past eight years, which is a development attributable in large part to the creation of NIH consensus criteria and the standardization of terminology for the trials. 57 , 58 , 59 , 60 Despite these recent advances, glucocorticoids still remain the mainstay of cGVHD treatment, and cGVHD nonrelapse mortality remains high (22 % at 5 years; 40 % at 12 years), 61 emphasizing an ongoing unmet need.

Preclinical models and specific therapeutic agents

The early cGVHD phase is characterized by tissue injury induced inflammation and proinflammatory molecule release, such as damage‐associated molecular patterns and pathogen‐associated molecular patterns, into the extracellular space. 62 , 63 These signals can activate the innate and subsequently adaptive immune system. Alloreactive T and B cells produce cytokines, including IL‐17, which further propagate inflammation. Preclinical cGVHD models demonstrated that Treg exhaustion is an early cGVHD feature in the involved organ. In a mouse sclerodermatous‐like cGVHD model, chimeras receiving an allograft containing STAT3‐ablated donor CD4 + T cells did not develop classic clinical or pathologic alloimmune tissue injury manifestations, 64 emphasizing the critical role of alloreactivity in cGVHD pathogenesis. The net result is ongoing tissue damage, which in the later stages leads to fibrosis.

Bronchi(oli)tis obliterans syndrome (BOS) is associated with air trapping, lung fibrosis, and progressive lung function decline. A mouse model of BOS induced by cyclophosphamide/total body irradiation along with sublethal T cell doses demonstrated CD4+ T cell and B cell infiltration into cGVHD target organs, along with alloantibody deposition and fibrosis. 65 The interaction between B and T cells was also delineated, proving that donor B cells unable to form germinal centers and secrete pathogenic immunoglobulin do not induce cGVHD. Similar fibrosis profiles were shown in humans and mice in the lungs, liver, and mouth, but these models did not show any inflammatory or fibrotic changes in the skin unlike the sclerodermatous‐like cGVHD models by Hill et al and Radojcic et al, 64 , 66 depicting the heterogenous nature of cGVHD.

B cells play a crucial role in the propagation of cGVHD. Hyperactive B cells depend on the pathologic production of soluble BAFF and the presence of alloantigens that then activate B cell surface NOTCH2 expression and maintain BCR hyperresponsiveness via spleen tyrosine kinase (Syk) signaling. 67 , 68 Ibrutinib, an inhibitor of bruton tyrosine kinase that is downstream from Syk became the first FDA‐approved drug for steroid‐refractory cGVHD therapy, which led to a pivotal multicenter open label for steroid‐refractory cGVHD. Ibrutinib provided an overall response rate of 67 % at 20 weeks, and 70 % of patients had sustained remission and steroid dose reduction in this phase Ib/II trial. 69 Multiple novel agents targeting B cell pathways continue to be studied for cGVHD treatment and prevention 70 , 71 , 72 with promising outcomes. Treatment with rituximab can ameliorate the disease burden in ~60% to 80% of patients but often does not completely eradicate disease, which suggests that targeting B cells per se may not be sufficient for remission.

Similar to SSc and other fibrotic conditions, the TGF‐β pathway and macrophages play important roles in cGVHD pathogenesis. 73 , 74 , 75 In an IL‐17 dependent sclerodermatous‐like cGVHD model, donor derived tissue macrophages infiltrate organs before cGVHD manifestation in a TGF‐β CSF1R dependent manner 75 that can be therapeutically targeted by the anti‐CSF1R neutralizing monoclonal antibody, axatilimab. This antibody was recently FDA‐approved to treat steroid‐refractory patients with cGVHD. Impressive overall response rates (ORRs) were seen in the esophagus (78%), joint and fascia (76%), lungs (47%), and skin (27%). 76 More than 90% of the patients had sclerotic skin GVHD, and 44% of the patients had a reduction in sclerotic skin surface area with the FDA‐approved dosing. Pirfenidone inhibits TGF‐β production and macrophages infiltration in cGVHD skin fibrosis model and BOS models 77 and was recently used in a clinical BOS study with encouraging results. 78 Emerging therapeutic approaches include nanoparticles targeting profibrotic macrophages with siRNA as well as CAR‐T cells directed fibroblast activation protein that is expressed and up‐regulated in damaged lung and cardiac organs and in stroma of tumor models. 79 , 80

Another cGVHD therapy is targeting the Rho‐associated kinase 2 (ROCK2) pathway. It belongs to the AGC family of serine/threonine kinases and was shown to be associated with cell migration, adhesion, cytoskeleton organization, proliferation, and apoptosis. 81 , 82 ROCK2 is activated in a Th17 skewed environment and leads to STAT3 phosphorylation, which induces formation of the ROCK2/STAT3/JAK2 complex, the up‐regulation of IL‐17 and IL‐21 promoters, and the down‐regulation of Treg cells. 83 , 84 In addition, ROCK2 interacts with TGF‐β leading to actin polymerization, collagen deposition, and tissue stiffness. 85 The inhibition of this pathway by belumosudil in the sclerodermatous‐like cGVHD model resulted in a decrease in IL17 and IL21 levels and also prevented lung function decline following allogeneic HCT. 86 Further benefits included up‐regulation of phospho‐STAT5 that supports Treg cells, and down‐regulation of proinflammatory phospho‐STAT3, TGF‐β, and profibrotic gene expression. 87 Belumosudil was FDA‐approved for steroid‐refractory cGVHD based on a randomized open label phase two study of heavily pretreated patients showing a best ORR of greater than 74 % at one year, and responses in joint and fascia (76%) and skin (83%). 88

Alloreactive T cells, in addition to B cells, play a pivotal role in cGVHD pathogenesis. Similar to autoimmune conditions, cGVHD stems from the loss of central tolerance. Central tolerance involves the negative selection of autoreactive cells and expansion of Treg cells in the thymus. 89 In contrast, peripheral tolerance stems from lack of response of self‐reactive T cells or deletion after encountering peripheral self‐antigens. The ability of the graft to function without immunosuppression is contingent on the concept of operational tolerance. Operational tolerance after HCT is characterized by distinct transcriptional, phenotypic, and metabolic signatures, 89 which are lost in cGVHD. Targeting T cell populations, including post‐transplant treatment with cyclophosphamide and anti‐thymocyte globulin (ATG) are thought to reduce the incidence of acute and chronic GVHD 90 , 91 by preferentially targeting the alloreactive T cell populations. 92 Another T cell targeting agent, ruxolitinib, which acts on the Teff cell responses by down‐regulating the JAK‐SAT pathway, was approved based on an open label phase III study comparing the best available therapy vs adding ruxolitinib with an improved failure‐free survival (>18.6 vs 5.7 months). Ruxolitinib reduced symptom burden and increased the median response rate (49% vs 26 %). 93 Ruxolitinib was also used in a trial for steroid‐refractory sclerotic cGVHD, with combined partial response rates noted in skin and joints and fascia around 47%. 94

In summary, cGVHD starts with emergence of autoreactive B cells producing antibodies induced by the donor T cells. This in turn activates macrophages and causes epithelial injury that then triggers aberrant tissue repair, fibroblast proliferation, and collagen production via multiple pathways. Significant progress was made in the field by either targeting the components of adaptive immunity (as in the case with ibrutinib and ruxolitinib) or fibrotic pathways (belumosudil and axatilimab), but the knowledge as to sequencing these therapies is lacking.

Aligning on clinical trial protocol development

Eligibility criteria

Regarding the design of clinical trials to evaluate cellular therapies in sAIDs, workshop participants endorsed thoughtful collaboration between academic and industry experts in the development of protocols. Areas of uncertainty about protocols remain (Table 2 ). These include selection of eligibility criteria to ensure that study populations are representative of the majority of sAID patients of interest. For instance, many cellular therapy protocols under the development for SSc focus on a narrow spectrum of patients (relatively early diffuse cutaneous disease without ILD), limiting the generalizability of study findings. Although the purported rationale for a narrow focus is to enrich the trial cohort for patients who are likely to show ILD progression, large observational cohort studies have demonstrated that patients meeting these eligibility criteria represent less than 2% of patients with SSc. 95 Moreover, recent studies have demonstrated that ILD can occur later in the course of SSc, and there is no difference in the rate of ILD progression among patients with earlier versus later disease duration. 96 In light of these caveats, workshop participants advocated for developing evidence‐based eligibility criteria to broaden the diversity of clinical trial participants, maximize the feasibility for reaching enrollment goals, and improve the overall generalizability of the findings.

CAR ‐T washout period

Additional areas of protocol uncertainty included selecting optimal treatment washout periods, conditioning regimens, and the treatment of undesirable outcomes. In the washout period, immunomodulatory therapies are discontinued, and glucocorticoid dosages are reduced before leukapheresis to minimize a negative effect on T cells before their in vitro transduction and expansion. In the CAR‐T study by Müller et al, 12 the median washout period was three weeks and ranged from one to four weeks. However, the risks associated with stopping immunomodulatory therapies for prolonged periods must be weighed against the optimization of T cell harvesting and in vitro expansion for autologous immunotherapy. In the aforementioned study, although the washout period in one patient was only one week from azathioprine, IVIG, and glucocorticoids, no negative quantitative or qualitative effects on the CD19‐CAR‐T cell manufacturing was observed. The washout period duration should not only consider the risk of serious relapse or worsening of the underlying sAID but also the biologic half‐life and cellular fitness of the immunomodulatory therapies used, as those therapies with longer half‐lives may require longer washout periods.

Conditioning regimen

The choice of conditioning regimen represented an area of controversy. Conditioning therapy aims to induce transient lymphocyte suppression, resulting in an increase in IL‐2, IL‐7, and IL‐1 to promote CAR‐T cell engraftment and expansion. 97 Although patients with lymphoproliferative diseases require substantial CAR‐T cell expansion, which in turn increases CRS risk, the degree of lymphodepletion required for patients with sAIDs is unknown. All patients in the Müller study 12 received intravenous (IV) fludarabine and IV cyclophosphamide (of varying dosages and durations). However, a recent study used cyclophosphamide alone and demonstrated optimal CAR‐T cell expansion and clinical efficacy in a small group of patients with SLE and lupus nephritis. 98 Because rheumatologists are more experienced with using cyclophosphamide than fludarabine, it will be important for future protocols to consider testing CAR therapies using regimens that include and exclude fludarabine to determine whether this conditioning agent is truly necessary. In addition, engineering cells with RNA (rCAR‐T) rather than DNA may confer a better safety profile through more precise pharmacokinetic control over therapy in patients with sAID. 99

Management of treatment‐associated adverse events

Serious adverse events associated with CAR therapies include CRS (Table 3 ) due to the rapid release of cytokines from damaged immune cells. The frequency and severity of CRS after CAR‐T cell therapy varies between products (eg, any grade 37%–93%) 100 , 101 Symptoms include fever, fatigue, headache, arthralgia, and in some cases, a rapid evolution into hypoxia, tachycardia, hypotension, and arrhythmia, culminating in cardiopulmonary organ failure. In its early stages, CRS symptoms can overlap with those of infections, as well as sAIDs. Therefore, multidisciplinary coordination among oncologists, rheumatologists, infectious disease and critical care specialists is essential for making the correct diagnosis to ensure proper management. Involving the primary rheumatologist is central to this process because this individual can provide a unique perspective on the patient's underlying sAID given the inherent clinical heterogeneity of these diseases.

The multidisciplinary care team also needs to align on adverse event treatment. The anti‐IL6 agent tocilizumab is European Medicines Agency– and FDA‐approved for the treatment of CRS, and its prompt administration may reduce the severity of CRS. 102 Glucocorticoids are often used as second‐line therapies for CRS. However, the benefits of high‐dose glucocorticoids (eg, methylprednisolone 2 mg/kg or dexamethasone 0.5 mg/kg per day) must be weighed against risks of concurrent infection or in patients with specific sAID. For example, in patients with early diffuse SSc (the target population of most cellular therapy trials for SSc), high‐dose glucocorticoid administration can precipitate renal crisis. 103

Another serious complication of CAR‐T cell therapies is ICANS (Table 3 ), which often develops after CRS commences and can even occur after CRS resolution. 102 Some ICANS symptoms (eg, tremor, dysgraphia, mild expressive, apraxia and impaired attention, and seizures) can mimic underlying sAID symptoms. For example, patients with SLE with central nervous system involvement can also present with seizures. Although glucocorticoids treat both ICANS and neuropsychiatric lupus, it is still important to align on the underlying diagnosis of the neurologic symptoms because this can affect medicine tapering strategies and the decision to start or modify the steroid‐sparing agent for the sAID.

Given that ICANS can manifest 4 to 10 days following CAR‐T cell infusion, trial participants need protocolized close outpatient monitoring after their infusion. This can present logistical challenges for trial participants who live far distances from trial centers, and sponsors should provide funding for housing accommodations for such participants. Moreover, a recent study identified a new complication of CAR‐T cell therapy (local immune effector cell–associated toxicity syndrome [LICATS]) specific to patients with sAID. 104 Although this appears to be a self‐limited, organ‐specific toxicity, more research is needed to understand the impact of LICATS on survival and quality‐of‐life in patients with sAIDs. Finally, the long‐term risks of CAR‐T cell therapies, particularly the risk of malignancy, in patients with sAIDs are largely unknown.

Building infrastructure for cellular therapy clinical development

Partnership of oncological and rheumatologic experts

As described previously, rheumatologists and oncologists each play a unique role in executing cellular therapy trials in sAID. Whereas the rheumatologist is better equipped to deal with the disease‐specific aspects of patient selection, the timing of CAR‐T, and monitoring treatment responses, oncologists have expertise in managing cellular therapy risks and advanced facilities required for cell collection, processing, manipulation, and infusion. 18 The rheumatologist and oncologist need to work collaboratively to initiate the study and monitor patient safety throughout the trial. The entire process, from the initial site selection visit to the final participant study visit, requires ongoing communication between rheumatologists and oncologists with equal stake sharing (eg, shared start‐up funding, shared support staff, shared leadership co‐principal investigator [Co‐PI]). However, few academic centers in the United States have multidisciplinary rheumatology‐hematology/oncology research programs.

Workshop participants advocated for support for the NIH and industry sponsors for training initiatives to create new multidisciplinary rheumatology‐hematology/oncology research programs. During these training initiatives, leaders of existing multidisciplinary programs could share their expertise with other trial investigators. Academic leadership at the institutional level should mediate any conflicts that arise to ensure equal stake sharing among rheumatology and oncology and to facilitate a multidisciplinary start‐up process.

Role of the NIH

In addition to supporting training efforts, cellular therapy funding opportunities are likely to promote needed progress in this field. Academic researchers can play a pivotal role in pioneering new cellular therapy approaches without competing interests or commercial constraints. Investigator‐initiated awards can also provide academic researchers with the opportunity to study novel response biomarkers (eg, functional imaging) to further our understanding of the biologic effects of cellular therapy on individual sAIDs. Industry sponsors are often limited in their selection of study endpoints because of regulatory guidance; therefore, support and investment in academic research can uniquely complement industry studies.

NIH‐sponsored registries could facilitate the collection of long‐term safety and efficacy data related to these interventions. Because most industry sponsored trials are 52 weeks (or fewer), registry studies that facilitate the systematic and uniform collection of data could generate much needed information on sustained CAR‐T benefits and other cellular sAIDs therapies. Because cellular therapy interventions are time‐intensive and expensive, having real‐world outcome data could also motivate payers to support these interventions, particularly if such an intervention lowers the risk of future organ transplantation (ie, renal transplantation for nephritis and lung transplantation for ILD).

Industry support

Recognizing that rheumatologists typically receive no formal training in cellular therapy, the workshop participants encouraged industry partners to support the development of training programs in this area for rheumatologists. These programs should be available to interested rheumatologists at any career stage (beginning at the fellowship level). Training opportunities could include sponsoring symposia at large rheumatology conferences, creating online courses available for continuing medical education (CME) credit, and supporting an in‐person workshop for hands‐on training in cellular therapy. Although these educational initiatives require an initial investment, the long‐term benefits to industry sponsors include augmenting the number of rheumatologists equipped to execute these trials and improving collaboration between rheumatologists and oncologists.

Patient organizations

Workshop representatives from patient organizations advocated for broadening entry criteria for cellular therapy trials because many patients with SSc, for example, are interested in participating in these trials but do not meet the eligibility criteria. Patient organizations can also facilitate pathways for patients to learn about cellular therapy trials, particularly for patients who live in medical deserts. Simple but effective strategies can include having an updated list of trial names and locations on the patient organization's website, advertising for trials within patient‐ and caregiver‐directed newsletters, and offering webinars on the potential benefits and risks of cellular therapies. Cellular therapy clinical development cannot advance without patient involvement; therefore, it is vital for us to educate and empower patients to make informed decisions. At the same time, we need to listen to patients’ views and feedback to improve how these trials are conducted.

Conclusions

Participants of this ground‐breaking multidisciplinary workshop shared the excitement about the emergence of innovative cellular immunotherapies for patients with SSc, GVHD, and other sAIDs. Speakers presented compelling evidence that CAR‐T represents an exciting treatment for sAID, whereas fast emerging alternative cellular therapies, such as Treg CAR‐T, mRNA CAR‐T, and CAR‐NK cells require further exploration. Although the exact population of patients with sAID who may derive the most benefit from cellular therapies is unknown, workshop participants felt that this type of intervention may lead to the greatest improvements in patients with active inflammation and in patients who do not exhibit signs of irreversible organ damage (eg, end stage lung disease due to ILD or end stage renal disease due to lupus nephritis). In addition, disease states requiring high doses of systemic immunosuppression, especially glucocorticoids, over long periods may benefit from cellular therapies as shown by a limited number of promising studies. Importantly, workshop participants also unanimously recognized that future progress in this area depends critically on creating solid infrastructure for preclinical and clinical cellular therapy research and training. Central to this process is fostering a mutually beneficial and fruitful collaboration between oncologists and rheumatologists. Continued investment from the NIH and industry is crucial for further clinical development, as is ongoing engagement with patients and their representative organizations. Educating, empowering, and supporting clinicians, researchers, and patients on these forward‐thinking and creative therapeutic approaches will ensure timely translation of our discoveries into meaningful clinical improvements, therapeutic safety, and long‐term survival for patients with sAIDs. Measures, including the creation of long‐term safety registries (as mandated by the FDA for approved CAR‐T therapies for 15 years), standardization of outcome measures, and making trial access more equitable by providing the social and financial resources to the patients, are needed to ensure safe implementation of cellular therapies for sAIDs. In addition, efforts to improve collaboration between rheumatology and oncology, including institutional support for creating the multidisciplinary infrastructure needed to conduct these trials, are greatly needed.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Volkmann confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.

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ACKNOWLEDGMENTS

We thank the workshop co‐chairs: Steven Pavletic, John Varga, Bruce Blazar; workshop co‐sponsors: National Scleroderma Foundation, Meredith Cowden GVHD Foundation, Scleroderma Research Foundation, GVHD Alliance; the Workshop Planning Committee members: John O'Shea of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Robert Colbert of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Edward Cowen of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Daniel Kastner of the National Human Genome Research Institute, NIH, and Pravitt Gourh of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; and the workshop coordinator, Amy Swanson of the NIH.

We also thank the workshop speakers, panelists, and moderators: James Gulley, MD, PhD (Clinical Director; Deputy Director; Director, Medical Oncology Service; Senior Investigator, Co‐Director, Center for Immuno‐Oncology, National Cancer Institute, Center for Cancer Research); Lindsey A. Criswell, MD, MPH, DSc (Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases); Bruce Blazar MD, (Regents Professor, Children's Cancer Research Fund Land Grant Chair in Pediatric Oncology, University of Minnesota); Thomas A. Wynn, PhD (Vice President, and Discovery Head Inflammation & Immunology Pfizer Research & Development); Jesse Williams, PhD (Assistant Professor, Department of Integrative Biology and Physiology, University of Minnesota); Rachael Clark, MD, PhD; Martin C. Mihm, Jr, MD; and Shing‐Yiu Yip (Professor of Dermatology, Harvard Medical School); Nicholas A. Flavahan, PhD (Edward D. Miller Endowed Professor, Department of Anesthesiology and Critical Care Medicine John's Hopkins University); John Varga, MD (Chief, Division of Rheumatology, Professor of Internal Medicine, University of Michigan); Nataliya Prokopenko Buxbaum, MD (Assistant Professor of Oncology, Division of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children's Hospital); Michael L. Whitfield, PhD (Chair and Professor of Biomedical Data Science, Professor of Molecular and Systems Biology, Director, COBRE Center for Quantitative Biology, Co‐Director, Burroughs Wellcome Big Data in the Life Sciences Training Program, Geisel School of Medicine at Dartmouth); Edward Cowen, MD, MHSc (National Institute of Arthritis and Musculoskeletal and Skin Diseases); Miguel‐Angel Perales (Memorial Sloan Kettering Cancer Center); Robert Colbert (National Institute of Arthritis and Musculoskeletal and Skin Diseases); Donna Przepiorka (Food and Drug Administration); Mary Wheatley (National Scleroderma Foundation); Vicki Shanmugam (Office of Research on Women's Health, NIH, OD); Keith Sullivan, MD (Duke University); Lindsey Criswell (National Institute of Arthritis and Musculoskeletal and Skin Diseases); Steven Pavletic MD, PhD (Senior Clinician; Head, GVHD and Late Effects Section, Immune Deficiency and Cellular Therapy Program; Clinical Director, Myeloid Malignancies Program, National Cancer Institute, Center for Cancer Research); Luke Evnin (Scleroderma Research Foundation); Sophie Paczesny (University of Southern California); Lis Welniak (National Heart, Lung, and Blood Institute); Aimee Ahmed (Foundation for the NIH); Leslie S. Kean, MD, PhD (Director, Stem Cell Transplant Center, Dana‐ Farber/Boston Children's Cancer and Blood Disorders Center, Robert A. Stranahan Professor of Pediatrics, Harvard Medical School); Gerard Socie, MD, PhD (Professor of Hematology, University Paris Cité/Hematology Transplantation, AP‐HP Hospital Saint Louis, Paris); Pravitt Gourh, MD (Head, Scleroderma Genomics and Health Disparities Unit, Assistant Clinical Investigator, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Adjunct Investigator NIMHD); Joe Arron, MD, PhD (Chief Scientific Officer, Sonoma Biotherapeutics); Jonathan Epstein, MD (Interim Dean and Executive Vice President of the University of Pennsylvania Health System); Christian Stockman, MD (Assistant Professor, Institute of Anatomy Winterthurerstrasse, Switzerland); Nair Raj (Food and Drug Administration); Rachel Rosenstein (Hackensack Meridian School of Medicine); Resat Cinar (National Institute on Alcohol Aubse and Alcoholism); Leanne Peiser (Bristol Myers Squibb); Joe Arron (Sonoma Biotherapeutics); Jim Kirkland, MD, PhD (Consultant, Division of General Internal Medicine, Department of Internal Medicine, Consultant, Department of Physiology & Biomedical Engineering, Consultant, Section of Geriatric Medicine and Gerontology, Department of Internal Medicine, Mayo Clinic); Stefanie Sarantopoulos, MD, PhD (Professor of Medicine, Professor of Integrative Immunobiology, Member of the Duke Cancer Institute, Hematologic Malignancies and Cellular Therapy, Duke University); Bill Robinson, MD, PhD (Professor of Medicine, Stanford University); Elizabeth Volkmann, MD, MS (Associate Professor, Director, UCLA Scleroderma Program, Co‐Director, CTD‐ILD Program, Division of Rheumatology, Department of Medicine); Dinesh Khanna, MD, MSc (Professor of Medicine, Frederick G. L. Huetwell Professor of Rheumatology, Director, University of Michigan Scleroderma Program, Division of Rheumatology/Department of Internal Medicine); Stephanie Lee, MD, MPH (Professor, Fred Hutchinson Cancer Center); Aimee Payne (Columbia University); Eric Tkaczyk (Vanderbilt University Medical Center Max Konig, Johns Hopkins University); Vedran Radojcic (Syndax Pharmaceuticals, Inc.).

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