https://orcid.org/0000-0003-1412-4453
Abstract
Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies—such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells—that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.
Haematopoietic stem cell transplantation is a treatment for moderate to severe early scleroderma.
Novel cell therapies are being investigated as potential disease-modifying options for the treatment of scleroderma.
Self-tolerance may be restored with enriched populations of mesenchymal, dendritic or facilitating cells.
Introduction
SSc is a rare rheumatological autoimmune disease (AD) of unknown pathology, characterized by accumulation of extracellular matrix components that causes excess deposition in various organs and tissues, including the skin (scleroderma). SSc is classified as either limited cutaneous SSc (lcSSc)—affecting the peripheral parts of the body, including fingers, hands, forearms, feet and distal portions of legs with or without face involvement—or diffuse cutaneous systemic sclerosis (dcSSc), also involving the trunk and proximal parts of the limbs. The clinical presentation of SSc is highly heterogeneous, and in addition to the skin involvement, internal organs such as the lungs, heart, kidneys and gastrointestinal tract can be affected [1, 2]. Autoantibodies may precede the development of clinical symptoms by many years, with one study finding patients who were seropositive for at least one autoantibody up to 27 years (mean = −7.4 years) prior to clinical diagnosis [3]. The ACR and EULAR updated classification criteria for SSc in 2013, going beyond the presence and extent of skin thickening to incorporate important elements of the disease, such as abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, RP and SSc-related autoantibodies [4]. The modified Rodnan skin score (mRSS) is an established clinical measure of skin fibrosis, and recent evidence demonstrates that worsening skin fibrosis (increased mRSS scores) may be an appropriate surrogate marker for long-term disease progression in SSc [5]. Prevalence varies geographically, but a recent meta-analysis of studies using the ACR/EULAR 2013 criteria found a global prevalence of 19 cases per 100 000 [6].
SSc is a disabling disease characterized by a high morbidity and mortality rate [7]. Mortality rates vary widely depending on the clinical presentation. The limited cutaneous form of SSc, which may present with late and slow organ involvement, has a relatively good prognosis, with a 10-year survival rate of over 90%. In contrast, the 10-year survival rate with dcSSc ranges broadly from 65% to 82% due to a variety of systemic complications, including progressive effects on the cardiovascular system, lungs and kidneys [1]. Regardless of clinical presentation, there is a reported cumulative 5-year mortality rate of 25% from diagnosis [8]. Cardiopulmonary complications in SSc are a leading cause of mortality, with interstitial lung disease (ILD) representing one of the major types of pulmonary complications [1]. Short-term progression of ILD in SSc was found to be associated with higher mortality rates [9]. Also contributing to early SSc-related mortality are cardiac complications in 30% of deaths and renal complications in 10% of deaths [1].
The standard of care for SSc is primarily focused on providing immunosuppression therapy, such as methotrexate, HCQ, MMF and CYC, which can impair immune responses and lead to increased infections and risk of cancer [10–12]. Treatment strategies target involved organs and are initiated as early as possible to avoid organ damage. None of the standard drug treatments for SSc have shown long-lasting beneficial effects on the overall disease; consequently, the mortality rates have not significantly changed for over 40 years [9, 13–15]. Newer pharmacological agents such as tocilizumab and nintedanib target underlying inflammatory and fibrotic pathways to slow disease progression [16, 17]. In 2016, the EULAR released updated recommendations for treating SSc that included autologous haematopoietic stem cell transplantation (HSCT) for patients with rapid and progressive SSc [18]. This was followed by support of autologous HSCT as a standard-of-care treatment for SSc from the American Society for Blood and Marrow Transplantation (ASBMT) in 2018 and the European Society for Bone Marrow Transplantation (EBMT) in 2022 [19, 20].
In the last decade, several cell-based therapies have been used to treat ADs including SSc [14, 21, 22]. In this review, we focus on the utility of HSCT for the treatment of SSc and discuss the progress in this field, the associated advantages and challenges of cellular transplant and the evolution of additional cell-based therapies for treating SSc.
HSCT for treating autoimmune diseases
A fortuitous discovery of the utility of HSCT for treating ADs occurred when patients with coincident AD and haematological malignancy or aplastic anaemia remained in long-term remission of both diseases after allogeneic stem cell transplantation [23]. Preceding this by about a decade were pioneering animal studies showing that lymphoablative conditioning followed by allogeneic or autologous marrow transplantation could prevent progression of or reverse organ damage due to genetic or antigen-induced AD [24, 25]. The mechanism of AD remission is posited on ablating the autoreactive immune cells (effector and memory cells) and replacing them with either autologous (patient’s own) or allogeneic (donor derived) haematopoietic stem cells to normalize T and B cell reconstitution so that the regenerated immune system becomes self-tolerant [26–29]. A healthy immune balance seems to be induced by autologous HSCT via a functional renewal of regulatory T cells (Tregs) as well as the establishment of a more diverse T cell receptor repertoire in patients with AD [30, 31]. B cells and regulatory B cells (Bregs) also likely play a role in the immune homeostasis following HSCT [32]. Recent data show that B cell-mediated immunoregulatory and antifibrotic mechanisms may contribute to re-establishment of self-tolerance and clinical remission after HSCT in SSc [33]. Increased numbers of newly generated Tregs and Bregs were indicative of a favourable response to HSCT in SSc, while non-responders did not display this immune rebound [34]. Immune responses, however, are multifaceted and complex, and the precise mechanisms by which HSCT is able to ‘reset’ the immune system are still incompletely understood [35].
Autologous HSCT in SSc
Autologous HSCT is becoming more widely utilized as a treatment option for severe and progressive dcSSc with internal organ involvement [36, 37]. Three pivotal randomized clinical trials (Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial [ASSIST], Autologous Stem Cell Transplantation International Scleroderma [ASTIS] and Scleroderma: Cyclophosphamide Or Transplantation [SCOT]) demonstrated that autologous transplant improved event-free survival and overall survival, when compared with traditional CYC pulse therapy [38–40]. A meta-analysis of ASSIST, ASTIS, SCOT and a retrospective study demonstrated that autologous HSCT substantially reduced all-cause mortality (risk ratio, 0.5; 95% CI, 0.33, 0.75) compared with the control group [14]. Other international observational studies investigating autologous HSCT for severe SSc also showed benefit [29, 41–45]. Table 1 summarizes published clinical studies, a systematic literature review [46], and a large registry report [47] supporting the use of autologous HSCT for the treatment of SSc. A recently initiated study known as UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis; NCT04464434) will compare the use of autologous HSCT vs use of the standard i.v. CYC pulse therapy in combination with oral MMF as an early or upfront treatment option for dcSSc, with rescue HSCT in case of treatment failure [48].
Autologous HSCT in SSc
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Farge et al. (2004) [42] | N = 57 |
| Analyses included complete, partial, or non-response and the probability of disease progression and survival after HSCT/36 months/approximately two-thirds of patients had a durable response after HSCT, progression probability was 48% (95% CI, 28, 68), and the projected survival was 72% (95% CI, 59, 75) at 5 years |
| Nash et al. (2007) [36] | N = 34 |
|
|
| ASSIST Burt et al. (2011) [38] |
|
| Improvement at 12 months/2.6 years/all 10 subjects in HSCT group improved at or before 12-month follow-up, while there was no improvement in the CYC group (odds ratio 110, 95% CI, 14.04, ∞; P = 0.00001) |
| ASTIS Van Laar et al. (2014) [40] |
|
|
|
| Snowden et al. (2017) [47] |
|
| Analysis of the development and factors influencing the outcomes of HSCT in subjects with autoimmune diseases/outcomes varied significantly depending on the disease, but there was chronological improvement in PFS, relapse or progression and non-relapse mortality for autologous HSCT |
| Del Papa et al. (2017) [41] | N = 18 |
| Analysis of disease outcomes in HSCT compared with clinically matched group treated with conventional therapies/60 months/both mRSS and ESSG scores showed a significant reduction in the HSCT group after 1 year (P < 0.002); these results were maintained until the end of follow-up |
| SCOT Sullivan et al. (2018) [39] |
|
| GRCS at 54 months/54 months/The percent of comparisons favouring transplantation on the GRCS (in the per-protocol population) were 70% vs 30% at 54 months (P = 0.004) and 71% vs 29% at 48 months (P = 0.003) |
| van Bijnen et al. (2020) [44] | N = 92 |
| EFS/median follow-up was 4.6 years/EFS estimates were 78%, 76% and 66% at 5, 10 and 15 years, respectively |
| Puyade et al. (2020) [46] |
| Systematic literature review (up to 1 February 2019) of original HRQoL data | HRQoL was evaluated by using HAQ-DI, SF-36, and EQ-5D scores/significant improvement in scores was demonstrated with HSCT treatment compared with CYC |
| Henes et al. (2021) [29] | N = 80 |
| PFS at 2 years/2 years/PFS rate at 2 years was 81.8%, the overall survival rate was 90%, the response rate was 88.7%, and the incidence of progression was 11.9% |
| Henrique-Neto et al. (2021) [43] | N = 70 |
| Analyses included disease progression and survival after HSCT/8 years/decreased mRSS at all post-transplantation time points until at least 5 years of follow-up. At 8 years post-HSCT, overall survival was 81% and PFS was 70.5% |
| Maltez et al. (2021) [45] |
| Retrospective study focused on HRQoL data/comparator: conventional care | Outcomes included scores on HAQ and the SF-36/both SF-36 physical component summary scores and HAQ scores were higher in the HSCT group supporting the use of this therapy over conventional care |
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Farge et al. (2004) [42] | N = 57 |
| Analyses included complete, partial, or non-response and the probability of disease progression and survival after HSCT/36 months/approximately two-thirds of patients had a durable response after HSCT, progression probability was 48% (95% CI, 28, 68), and the projected survival was 72% (95% CI, 59, 75) at 5 years |
| Nash et al. (2007) [36] | N = 34 |
|
|
| ASSIST Burt et al. (2011) [38] |
|
| Improvement at 12 months/2.6 years/all 10 subjects in HSCT group improved at or before 12-month follow-up, while there was no improvement in the CYC group (odds ratio 110, 95% CI, 14.04, ∞; P = 0.00001) |
| ASTIS Van Laar et al. (2014) [40] |
|
|
|
| Snowden et al. (2017) [47] |
|
| Analysis of the development and factors influencing the outcomes of HSCT in subjects with autoimmune diseases/outcomes varied significantly depending on the disease, but there was chronological improvement in PFS, relapse or progression and non-relapse mortality for autologous HSCT |
| Del Papa et al. (2017) [41] | N = 18 |
| Analysis of disease outcomes in HSCT compared with clinically matched group treated with conventional therapies/60 months/both mRSS and ESSG scores showed a significant reduction in the HSCT group after 1 year (P < 0.002); these results were maintained until the end of follow-up |
| SCOT Sullivan et al. (2018) [39] |
|
| GRCS at 54 months/54 months/The percent of comparisons favouring transplantation on the GRCS (in the per-protocol population) were 70% vs 30% at 54 months (P = 0.004) and 71% vs 29% at 48 months (P = 0.003) |
| van Bijnen et al. (2020) [44] | N = 92 |
| EFS/median follow-up was 4.6 years/EFS estimates were 78%, 76% and 66% at 5, 10 and 15 years, respectively |
| Puyade et al. (2020) [46] |
| Systematic literature review (up to 1 February 2019) of original HRQoL data | HRQoL was evaluated by using HAQ-DI, SF-36, and EQ-5D scores/significant improvement in scores was demonstrated with HSCT treatment compared with CYC |
| Henes et al. (2021) [29] | N = 80 |
| PFS at 2 years/2 years/PFS rate at 2 years was 81.8%, the overall survival rate was 90%, the response rate was 88.7%, and the incidence of progression was 11.9% |
| Henrique-Neto et al. (2021) [43] | N = 70 |
| Analyses included disease progression and survival after HSCT/8 years/decreased mRSS at all post-transplantation time points until at least 5 years of follow-up. At 8 years post-HSCT, overall survival was 81% and PFS was 70.5% |
| Maltez et al. (2021) [45] |
| Retrospective study focused on HRQoL data/comparator: conventional care | Outcomes included scores on HAQ and the SF-36/both SF-36 physical component summary scores and HAQ scores were higher in the HSCT group supporting the use of this therapy over conventional care |
ASSIST: American Scleroderma Stem Cell vs Immune Suppression Trial; ASTIS: Autologous Stem Cell Transplantation International Scleroderma; ATG: antithymocyte globulin; CD: cluster of differentiation; EBMT: European Society for Blood and Marrow Transplantation; EFS: event-free survival; EQ-5D: European Quality of Life 5-Dimensions questionnaire; ESSG: European Scleroderma Study Group; G-CSF: granulocyte-colony stimulating factor; GRCS: global rank composite scores; HAQ-DI: HAQ-Disability Index; HRQoL: health-related quality of life; HSCT: haematopoietic stem cell transplantation; mRSS: modified Rodnan skin score; PFS: progression-free survival; RCT: randomized clinical trial; SCOT: Scleroderma: Cyclophosphamide Or Transplantation; SF-36: 36-Item Short Form Survey; TBI: total body irradiation.
Autologous HSCT in SSc
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Farge et al. (2004) [42] | N = 57 |
| Analyses included complete, partial, or non-response and the probability of disease progression and survival after HSCT/36 months/approximately two-thirds of patients had a durable response after HSCT, progression probability was 48% (95% CI, 28, 68), and the projected survival was 72% (95% CI, 59, 75) at 5 years |
| Nash et al. (2007) [36] | N = 34 |
|
|
| ASSIST Burt et al. (2011) [38] |
|
| Improvement at 12 months/2.6 years/all 10 subjects in HSCT group improved at or before 12-month follow-up, while there was no improvement in the CYC group (odds ratio 110, 95% CI, 14.04, ∞; P = 0.00001) |
| ASTIS Van Laar et al. (2014) [40] |
|
|
|
| Snowden et al. (2017) [47] |
|
| Analysis of the development and factors influencing the outcomes of HSCT in subjects with autoimmune diseases/outcomes varied significantly depending on the disease, but there was chronological improvement in PFS, relapse or progression and non-relapse mortality for autologous HSCT |
| Del Papa et al. (2017) [41] | N = 18 |
| Analysis of disease outcomes in HSCT compared with clinically matched group treated with conventional therapies/60 months/both mRSS and ESSG scores showed a significant reduction in the HSCT group after 1 year (P < 0.002); these results were maintained until the end of follow-up |
| SCOT Sullivan et al. (2018) [39] |
|
| GRCS at 54 months/54 months/The percent of comparisons favouring transplantation on the GRCS (in the per-protocol population) were 70% vs 30% at 54 months (P = 0.004) and 71% vs 29% at 48 months (P = 0.003) |
| van Bijnen et al. (2020) [44] | N = 92 |
| EFS/median follow-up was 4.6 years/EFS estimates were 78%, 76% and 66% at 5, 10 and 15 years, respectively |
| Puyade et al. (2020) [46] |
| Systematic literature review (up to 1 February 2019) of original HRQoL data | HRQoL was evaluated by using HAQ-DI, SF-36, and EQ-5D scores/significant improvement in scores was demonstrated with HSCT treatment compared with CYC |
| Henes et al. (2021) [29] | N = 80 |
| PFS at 2 years/2 years/PFS rate at 2 years was 81.8%, the overall survival rate was 90%, the response rate was 88.7%, and the incidence of progression was 11.9% |
| Henrique-Neto et al. (2021) [43] | N = 70 |
| Analyses included disease progression and survival after HSCT/8 years/decreased mRSS at all post-transplantation time points until at least 5 years of follow-up. At 8 years post-HSCT, overall survival was 81% and PFS was 70.5% |
| Maltez et al. (2021) [45] |
| Retrospective study focused on HRQoL data/comparator: conventional care | Outcomes included scores on HAQ and the SF-36/both SF-36 physical component summary scores and HAQ scores were higher in the HSCT group supporting the use of this therapy over conventional care |
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Farge et al. (2004) [42] | N = 57 |
| Analyses included complete, partial, or non-response and the probability of disease progression and survival after HSCT/36 months/approximately two-thirds of patients had a durable response after HSCT, progression probability was 48% (95% CI, 28, 68), and the projected survival was 72% (95% CI, 59, 75) at 5 years |
| Nash et al. (2007) [36] | N = 34 |
|
|
| ASSIST Burt et al. (2011) [38] |
|
| Improvement at 12 months/2.6 years/all 10 subjects in HSCT group improved at or before 12-month follow-up, while there was no improvement in the CYC group (odds ratio 110, 95% CI, 14.04, ∞; P = 0.00001) |
| ASTIS Van Laar et al. (2014) [40] |
|
|
|
| Snowden et al. (2017) [47] |
|
| Analysis of the development and factors influencing the outcomes of HSCT in subjects with autoimmune diseases/outcomes varied significantly depending on the disease, but there was chronological improvement in PFS, relapse or progression and non-relapse mortality for autologous HSCT |
| Del Papa et al. (2017) [41] | N = 18 |
| Analysis of disease outcomes in HSCT compared with clinically matched group treated with conventional therapies/60 months/both mRSS and ESSG scores showed a significant reduction in the HSCT group after 1 year (P < 0.002); these results were maintained until the end of follow-up |
| SCOT Sullivan et al. (2018) [39] |
|
| GRCS at 54 months/54 months/The percent of comparisons favouring transplantation on the GRCS (in the per-protocol population) were 70% vs 30% at 54 months (P = 0.004) and 71% vs 29% at 48 months (P = 0.003) |
| van Bijnen et al. (2020) [44] | N = 92 |
| EFS/median follow-up was 4.6 years/EFS estimates were 78%, 76% and 66% at 5, 10 and 15 years, respectively |
| Puyade et al. (2020) [46] |
| Systematic literature review (up to 1 February 2019) of original HRQoL data | HRQoL was evaluated by using HAQ-DI, SF-36, and EQ-5D scores/significant improvement in scores was demonstrated with HSCT treatment compared with CYC |
| Henes et al. (2021) [29] | N = 80 |
| PFS at 2 years/2 years/PFS rate at 2 years was 81.8%, the overall survival rate was 90%, the response rate was 88.7%, and the incidence of progression was 11.9% |
| Henrique-Neto et al. (2021) [43] | N = 70 |
| Analyses included disease progression and survival after HSCT/8 years/decreased mRSS at all post-transplantation time points until at least 5 years of follow-up. At 8 years post-HSCT, overall survival was 81% and PFS was 70.5% |
| Maltez et al. (2021) [45] |
| Retrospective study focused on HRQoL data/comparator: conventional care | Outcomes included scores on HAQ and the SF-36/both SF-36 physical component summary scores and HAQ scores were higher in the HSCT group supporting the use of this therapy over conventional care |
ASSIST: American Scleroderma Stem Cell vs Immune Suppression Trial; ASTIS: Autologous Stem Cell Transplantation International Scleroderma; ATG: antithymocyte globulin; CD: cluster of differentiation; EBMT: European Society for Blood and Marrow Transplantation; EFS: event-free survival; EQ-5D: European Quality of Life 5-Dimensions questionnaire; ESSG: European Scleroderma Study Group; G-CSF: granulocyte-colony stimulating factor; GRCS: global rank composite scores; HAQ-DI: HAQ-Disability Index; HRQoL: health-related quality of life; HSCT: haematopoietic stem cell transplantation; mRSS: modified Rodnan skin score; PFS: progression-free survival; RCT: randomized clinical trial; SCOT: Scleroderma: Cyclophosphamide Or Transplantation; SF-36: 36-Item Short Form Survey; TBI: total body irradiation.
Although there has been considerable progress in autologous HSCT for SSc, this therapy is not without associated challenges. Among the most significant challenges for treating patients with autologous HSCT are the associated rates of relapse (∼34% at 3 years in the EBMT report featuring mostly autologous transplants with intermediate intensity conditioning regimens) [47]. Treatment-related mortality after autologous HSCT has been low, ranging from 3% (at 54 months) in the SCOT study [39] to 10% (at 12 months) in the ASTIS trial [40]. Despite the use of myeloablative conditioning (800 cGy of total body irradiation [TBI]) in the SCOT study, treatment-related mortality was lower than with the non-myeloablative (NMA) regimen used in ASTIS. The SCOT investigators speculated this may have been due to poor cardiopulmonary tolerability of SSc patients given higher doses of CYC used for mobilization and conditioning in ASTIS. A myeloablative high-dose TBI conditioning regimens can increase non-relapse mortality, but doses <800 cGy are generally tolerable [49].
A novel approach to potentially limit toxicity of the conditioning protocol uses a CD45-targeted antibody–drug conjugate (CD45–ADC) that targets host stem and immune cells prior to HSCT. In mice, the CD45–ADC as either a single agent or in combination with reduced-intensity conditioning had significantly less toxicity and comparable benefit for HSC engraftment as myeloablative conditioning [50]. This emphasizes the need for determining the optimum conditioning regimen for transplant, with multiple factors such as myeloablative vs NMA conditioning, dosages of CYC and antithymocyte globulin, and the use of CD34+ selection to be considered. Regimen modifications that account for scleroderma-related heart, lung and kidney comorbidities are likely to improve safety.
Allogeneic HSCT in SSc
Allogeneic HSCT has the potential to be a curative treatment for SSc with its ability to replace the autoreactive immune system with a healthy donor immune system with the potential of inducing tolerance to both autoantigens and alloantigens [51–53]. While allogeneic HSCT has a curative potential for SSc and other ADs, there are significant concerns for higher risk of treatment-related mortality and graft-vs-host disease (GvHD) when compared with autologous HSCT, and this has limited use of allografting in SSc and other ADs [53, 54]. While allogeneic HSCT is usually associated with higher treatment-related mortality compared with autologous HSCT, among the most significant barriers to successful allogenic HSCT are acute and chronic GvHD [55, 56]. In a retrospective study investigating the use and long-term outcomes of allogeneic HSCT for treating various refractory ADs, it was reported that the incidence of grades II–IV acute GvHD was 20.8% at 100 days and cumulative incidence of chronic GvHD was 27.8% at 5 years [53]. Table 2 presents a summary of allogeneic HSCT approaches to treating SSc.
Allogeneic HSCT in SSc
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Nash et al. (2006) [51] | N = 2 (HSCT) |
| mRSS score at 5 years (patient 1) or 16 months (patient 2)/not reported/patient 1 mRSS at baseline was 36 and decreased to 2–4 at 5 years post-HSCT. Patient 2 mRSS at baseline was 40 and decreased to 11 at 16 months post-HSCT |
| Greco et al. (2019) [53] | N = 128 (HSCT) |
| Not specified/median 49 months/41.4% of patients developed acute GvHD at 100 days. Incidence of grades II–IV GvHD was 20.8% (95% CI, 14.1, 28.5). Incidence of chronic GvHD was 27.8% (95% CI, 19.3, 36.9) at 5 years |
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Nash et al. (2006) [51] | N = 2 (HSCT) |
| mRSS score at 5 years (patient 1) or 16 months (patient 2)/not reported/patient 1 mRSS at baseline was 36 and decreased to 2–4 at 5 years post-HSCT. Patient 2 mRSS at baseline was 40 and decreased to 11 at 16 months post-HSCT |
| Greco et al. (2019) [53] | N = 128 (HSCT) |
| Not specified/median 49 months/41.4% of patients developed acute GvHD at 100 days. Incidence of grades II–IV GvHD was 20.8% (95% CI, 14.1, 28.5). Incidence of chronic GvHD was 27.8% (95% CI, 19.3, 36.9) at 5 years |
ATG: antithymocyte globulin; CD: cluster of differentiation; GvHD: graft-vs-host disease; HSCT: haematopoietic stem cell transplantation; MAC: myeloablative conditioning; mRSS: modified Rodnan skin score; RIC: reduced-intensity conditioning; TBI: total body irradiation.
Allogeneic HSCT in SSc
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Nash et al. (2006) [51] | N = 2 (HSCT) |
| mRSS score at 5 years (patient 1) or 16 months (patient 2)/not reported/patient 1 mRSS at baseline was 36 and decreased to 2–4 at 5 years post-HSCT. Patient 2 mRSS at baseline was 40 and decreased to 11 at 16 months post-HSCT |
| Greco et al. (2019) [53] | N = 128 (HSCT) |
| Not specified/median 49 months/41.4% of patients developed acute GvHD at 100 days. Incidence of grades II–IV GvHD was 20.8% (95% CI, 14.1, 28.5). Incidence of chronic GvHD was 27.8% (95% CI, 19.3, 36.9) at 5 years |
| Study (year of publication) | Subjects | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Nash et al. (2006) [51] | N = 2 (HSCT) |
| mRSS score at 5 years (patient 1) or 16 months (patient 2)/not reported/patient 1 mRSS at baseline was 36 and decreased to 2–4 at 5 years post-HSCT. Patient 2 mRSS at baseline was 40 and decreased to 11 at 16 months post-HSCT |
| Greco et al. (2019) [53] | N = 128 (HSCT) |
| Not specified/median 49 months/41.4% of patients developed acute GvHD at 100 days. Incidence of grades II–IV GvHD was 20.8% (95% CI, 14.1, 28.5). Incidence of chronic GvHD was 27.8% (95% CI, 19.3, 36.9) at 5 years |
ATG: antithymocyte globulin; CD: cluster of differentiation; GvHD: graft-vs-host disease; HSCT: haematopoietic stem cell transplantation; MAC: myeloablative conditioning; mRSS: modified Rodnan skin score; RIC: reduced-intensity conditioning; TBI: total body irradiation.
Greco, et al. reported data from the EBMT registry showing allogeneic HSCT-induced long-term disease control in refractory ADs, with low rates of relapse [53]. Rates of GvHD increase with recipient age and the use of peripheral blood (as opposed to bone marrow) as a stem cell source [57]. Therefore, children with refractory AD may be good candidates for allogeneic bone marrow transplantation from HLA-matched individuals conducted at an experienced centre [58]. However, allogeneic HSCT requires further investigation before it can be accepted as a treatment option for dcSSc. If individuals with ADs undergo allogeneic cellular therapy, they should be entered into clinical trials, longitudinally monitored by multidisciplinary care teams for toxicity and relapse, and have results reported to transplant registries [58].
Novel cellular therapies with the potential to treat SSc
The disease process in SSc is multifactorial, involving the immune system, the vascular system and genetic factors [59–61]. As noted above, allogeneic HSCT is one potential path to resetting the immune system if GvHD and treatment-related mortality can be minimized. Other cellular therapies also have the potential to overcome the limitations of conventional chronic immunosuppressive treatment and alleviate the symptoms of ADs [21]. Early phase results for these approaches are summarized in Table 3. Patients with very early limited cutaneous SSc at high risk of developing dcSSc should be carefully monitored and prioritized for enrolment in clinical trials investigating the efficacy and safety of these evolving cellular therapies.
Novel cellular therapies in SSc
| Study (year of publication) or NCT for ongoing trials | Subjects (published or estimated) | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Zhang et al. (2017) [84] | N = 14 (MSCT) |
| mRSS improvement at 12 months/15.6 months/mean mRSS at baseline was 20.1 and improved to 13.8 (P < 0.0001) at 12 months. Mean change in mRSS at 12 months was −6.2 points (95% CI, −3.1, −9.3) |
| Liang et al. (2018) [68] |
|
| Frequency of AEs/43.4 months/incidence of infections among all participants was 29.5%, and 12.9% for serious infections, 1.2% had malignancies and 0.2% died. |
| Farge, et al. (2022) [85] | N = 20 (MSCT) |
|
|
| NCT02213705 | N = 20 (MSCT) |
| Toxicity/NA/NA |
| NCT05016804 | N = 20 (MSCT) |
| Safety (AEs)/NA/NA |
| NCT04356287 | N = 18 (MSCT) |
| Measure of safety 1 month after first infusion/NA/NA |
| NCT05085444 | N = 9 (CD19/BCMA CAR T cell therapy) |
| (i) Dose-limiting toxicity and (ii) incidence of treatment-emergent AEs/NA/NA |
| NCT05098145 | N = 18 (FCR001) |
| (i) Incidence of recipient AEs, (ii) incidence of recipient serious AEs, (iii) occurrence of GvHD, (iv) time to neutrophil recovery, (v) time to platelet recovery/NA/NA |
| Study (year of publication) or NCT for ongoing trials | Subjects (published or estimated) | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Zhang et al. (2017) [84] | N = 14 (MSCT) |
| mRSS improvement at 12 months/15.6 months/mean mRSS at baseline was 20.1 and improved to 13.8 (P < 0.0001) at 12 months. Mean change in mRSS at 12 months was −6.2 points (95% CI, −3.1, −9.3) |
| Liang et al. (2018) [68] |
|
| Frequency of AEs/43.4 months/incidence of infections among all participants was 29.5%, and 12.9% for serious infections, 1.2% had malignancies and 0.2% died. |
| Farge, et al. (2022) [85] | N = 20 (MSCT) |
|
|
| NCT02213705 | N = 20 (MSCT) |
| Toxicity/NA/NA |
| NCT05016804 | N = 20 (MSCT) |
| Safety (AEs)/NA/NA |
| NCT04356287 | N = 18 (MSCT) |
| Measure of safety 1 month after first infusion/NA/NA |
| NCT05085444 | N = 9 (CD19/BCMA CAR T cell therapy) |
| (i) Dose-limiting toxicity and (ii) incidence of treatment-emergent AEs/NA/NA |
| NCT05098145 | N = 18 (FCR001) |
| (i) Incidence of recipient AEs, (ii) incidence of recipient serious AEs, (iii) occurrence of GvHD, (iv) time to neutrophil recovery, (v) time to platelet recovery/NA/NA |
AE: adverse event; BCMA: B cell maturation antigen; CAR: chimeric antigen receptor; CD: cluster of differentiation; FVC: forced vital capacity; GvHD: graft-vs-host disease; mRSS: modified Rodnan skin score; MSC: mesenchymal stem/stromal cell; MSCT: mesenchymal stem/stromal cell transplantation; NA: not applicable.
Novel cellular therapies in SSc
| Study (year of publication) or NCT for ongoing trials | Subjects (published or estimated) | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Zhang et al. (2017) [84] | N = 14 (MSCT) |
| mRSS improvement at 12 months/15.6 months/mean mRSS at baseline was 20.1 and improved to 13.8 (P < 0.0001) at 12 months. Mean change in mRSS at 12 months was −6.2 points (95% CI, −3.1, −9.3) |
| Liang et al. (2018) [68] |
|
| Frequency of AEs/43.4 months/incidence of infections among all participants was 29.5%, and 12.9% for serious infections, 1.2% had malignancies and 0.2% died. |
| Farge, et al. (2022) [85] | N = 20 (MSCT) |
|
|
| NCT02213705 | N = 20 (MSCT) |
| Toxicity/NA/NA |
| NCT05016804 | N = 20 (MSCT) |
| Safety (AEs)/NA/NA |
| NCT04356287 | N = 18 (MSCT) |
| Measure of safety 1 month after first infusion/NA/NA |
| NCT05085444 | N = 9 (CD19/BCMA CAR T cell therapy) |
| (i) Dose-limiting toxicity and (ii) incidence of treatment-emergent AEs/NA/NA |
| NCT05098145 | N = 18 (FCR001) |
| (i) Incidence of recipient AEs, (ii) incidence of recipient serious AEs, (iii) occurrence of GvHD, (iv) time to neutrophil recovery, (v) time to platelet recovery/NA/NA |
| Study (year of publication) or NCT for ongoing trials | Subjects (published or estimated) | Study design | Primary outcome/mean follow-up/primary results |
|---|---|---|---|
| Zhang et al. (2017) [84] | N = 14 (MSCT) |
| mRSS improvement at 12 months/15.6 months/mean mRSS at baseline was 20.1 and improved to 13.8 (P < 0.0001) at 12 months. Mean change in mRSS at 12 months was −6.2 points (95% CI, −3.1, −9.3) |
| Liang et al. (2018) [68] |
|
| Frequency of AEs/43.4 months/incidence of infections among all participants was 29.5%, and 12.9% for serious infections, 1.2% had malignancies and 0.2% died. |
| Farge, et al. (2022) [85] | N = 20 (MSCT) |
|
|
| NCT02213705 | N = 20 (MSCT) |
| Toxicity/NA/NA |
| NCT05016804 | N = 20 (MSCT) |
| Safety (AEs)/NA/NA |
| NCT04356287 | N = 18 (MSCT) |
| Measure of safety 1 month after first infusion/NA/NA |
| NCT05085444 | N = 9 (CD19/BCMA CAR T cell therapy) |
| (i) Dose-limiting toxicity and (ii) incidence of treatment-emergent AEs/NA/NA |
| NCT05098145 | N = 18 (FCR001) |
| (i) Incidence of recipient AEs, (ii) incidence of recipient serious AEs, (iii) occurrence of GvHD, (iv) time to neutrophil recovery, (v) time to platelet recovery/NA/NA |
AE: adverse event; BCMA: B cell maturation antigen; CAR: chimeric antigen receptor; CD: cluster of differentiation; FVC: forced vital capacity; GvHD: graft-vs-host disease; mRSS: modified Rodnan skin score; MSC: mesenchymal stem/stromal cell; MSCT: mesenchymal stem/stromal cell transplantation; NA: not applicable.
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) are multipotential stem cells found predominantly in the bone marrow and adipose tissue that can modulate innate and adaptive immune responses including T-lymphocytes, dendritic cells and natural killer cells [62]. They are an attractive cellular option due to proposed anti-inflammatory properties to counteract the dysregulation of the immune system, antifibrotic properties to downregulate the excessive production of collagen, and pro-angiogenic properties to counteract the widespread vasculopathy of SSc [63, 64]. Recent reviews of MSC therapy for SSc reported preclinical and clinical studies of MSCs derived from different origins, including bone marrow, adipose tissue and the umbilical cord, to treat SSc with varying positive clinical outcomes: improved lung function, enhanced circulation in the extremities, and reduced skin fibrosis and digital ulcers [65–67]. In such studies, MSC treatments were injected periorally or into affected fingers leading to fuller oral opening range, digital healing, improved hand function and decreased Raynaud’s symptoms. It was concluded that allogeneic adipose-derived MSCs are particularly suited and can be considered as a potential gold standard MSC for clinical application in SSc [66]. Retrospective, phase 1 and limited phase 2 studies suggest safety and possible efficacy of MSC therapy in SSc [67, 68]. A recent double-blind trial showed safety and efficacy trends for adipose-derived regenerative cells in a dcSSc subset with hand dysfunction [69]. Additional studies are needed to definitively prove efficacy and to define the optimal quality of cells and the cell culture conditions for safe and effective therapeutic use. A new phase 1/2 trial, CARE-SSc (NCT04356287), will include a placebo arm vs single or repeated MSC i.v. infusion treatment arms with an anticipated study completion in April 2025. However, as noted by Zhuang, et al. limitations of MSCs, such as immune rejections and potential risks of tumour formation, have prompted other approaches, such as the use of MSC-derived extracellular vesicles/secretomes/exosomes as a ‘cell-free’ therapy option [70].
Chimeric antigen receptor T cell-based therapy
Genetically modified T cells armed with chimeric antigen receptors (CARs) have the ability to attack autoreactive immune cells as well as further modulate the activity of effector and Tregs. By manipulating Tregs, CAR-based therapies have the potential to suppress both autoimmune manifestations and autoinflammatory events [71]. The utility of CAR-modified Tregs for treating ADs has been confirmed in mouse models for type 1 diabetes, ulcerative colitis, multiple sclerosis and systemic lupus erythematosus [72–76]. An early phase 1 trial (NCT05085444) using CAR T cells to target B cells in scleroderma initiated in 2021 and is anticipated to complete in 2024. Autologous CAR T cell therapy targeting B cells was recently used to successfully treat patients with systemic lupus erythematosus [77, 78]. Another type of CAR-based therapy under investigation involves a new chimeric autoantibody receptor T (CAAR T) cell. This cell, with its specific antigen, recognizes and binds to the target autoantibody-expressing autoreactive cells, subsequently destroying them. The utility of CAAR T cells for treating AD has been confirmed in a preclinical study using a humanized mouse model for pemphigus vulgaris [79], and there is interest and potential for CAAR T therapies in treating other chronic ADs [80].
Dendritic cells
Dendritic cells (DCs) are critical components of the immune system, wherein they present antigens to orchestrate both immune activation and tolerance. After recognizing self-reactive T cells, DCs with a tolerogenic effect (tolerogenic dendritic cells [tolDCs]) are then able to either deactivate them or induce the differentiation of Tregs, which subsequently are able to suppress the self-reactive T cells. These tolDCs could provide a way of tempering the effects of the autoimmune processes seen in AD [81]. The potential therapeutic utility of tolDCs has not yet been evaluated in SSc, but has been tested in clinical trials for type 1 diabetes and rheumatoid arthritis [82, 83]. While there were no adverse effects in the type 1 diabetes study, the efficacy of this treatment was not determined. In a rheumatoid arthritis study, there was some evidence of decreased disease activity due to the tolDC therapy. While the inherent properties of tolDCs appear to be advantageous for treating ADs, DCs are also known to induce fibrosis in various organs [21]; therefore, the therapeutic use of DCs in SSc should be cautiously investigated.
Facilitating cells
Facilitating cells (FCs) are a bone marrow derived CD8+TCR− cell population that enable engraftment of allogeneic haematopoietic stem cells. Studies have shown that FCs augment engraftment between major histocompatibility complex mismatched donors and recipients in mouse-to-mouse and human-to-mouse studies, even in a fully mismatched setting [86–88]. Research has demonstrated that successful engraftment of an allogeneic HSCT that contains FCs, termed FCR001 (Fig. 1), has led to sustained T cell donor chimerism [89]. Donor T cell production appears to play a critical role in inducing tolerance and maintaining chimerism and directly correlates with deletion of potentially alloreactive cells [90]. Specifically, results from a phase 2 study (NCT00497926) of FCR001 in living-donor kidney transplant (LDKT) has set the stage for the potential use of FCR001 allogeneic-based cell therapy to address AD. In the kidney study, FCR001 was administered after a NMA conditioning regimen, which included CYC, fludarabine and low-dose TBI (200 cGy) and the kidney transplant surgery. Treatment was tolerable and resulted in 26/37 (70%) kidney recipients achieving stable chimerism and withdrawal from chronic immunosuppression (IS) treatments within 1 year post-transplant. All patients have remained off IS for the full duration of follow-up (48–136 months) without kidney allograft rejection; the majority (23/26) had high levels of mixed chimerism (>95%) [91, 92]. The safety profile was consistent with that expected if a patient were to separately receive both a standard kidney transplant and an allo-HSCT with NMA conditioning. The incidence of GvHD (∼5%) was lower than typically seen for allogeneic stem cell transplants (20–70% of recipients, depending upon the type of transplant, degree of donor HLA compatibility, and the prophylaxis regimen) [93]. Notably, there has been no evidence of AD relapse in tolerized patients (i.e. those off IS, with durable chimerism after LDKT and FCR001 therapy), whereas two of four transiently or non-chimeric patients had a relapse of their underlying AD [89]. In contrast, nearly half of patients with standard kidney transplants may experience AD recurrence [94]. FCR001 has the potential to provide a cure or to minimize AD recurrence through establishing sustained healthy donor chimerism and a state of tolerance to both autoantigens and alloantigens. In addition, the ability to use an NMA regimen with very low doses of TBI (200 cGy) means that the FCR001 therapy could have improved tolerability, reduced toxicities and improved long-term outcomes in patients with dcSSc. A phase 1/2, single-arm, multicentre, open-label, proof-of-concept study in adults with dcSSc is enrolling (FREEDOM-3, NCT05098145). FREEDOM-3 is designed as a 5-year, proof-of-concept safety and efficacy study of FCR001 in adults 18–70 years old with rapidly progressive dcSSc at risk for organ failure. Patients diagnosed with dcSSc within 5 years of first non-Raynaud’s symptom with lung fibrosis or history of scleroderma renal crisis and who have not adequately responded to at least one immunosuppressive agent will be eligible.
The modified allogeneic HSCT FCR001. FCR001 is a proprietary blend of three cell types: (i) haematopoietic stem cells, progenitor cells used to rebuild the haematopoietic immune system of the recipient, (ii) facilitating cells, a mixed population of CD8+/TCR− cells that aid fast and efficient engraftment of donor HSCs to promote chimerism, and (iii) αβTCR+ T cells, a cell type that supports donor HSC engraftment but is also known to increase the risk of acute GvHD in the recipient. FCR001 utilizes an optimized number of αβTCR+ T cells in order to promote HSC engraftment while minimizing the risk of acute GvHD. GvHD: graft-vs-host disease; HSC: haematopoietic stem cell; HSCT: HSC transplant; TCR: T cell receptor
Discussion
International guidelines for the therapy of dcSSc recommend careful selection of patients for autologous HSCT, which should be performed at highly experienced centres with integrated care by rheumatology and transplant specialists [18–20, 58]. Yearly screening and early diagnosis for internal organ involvement are recommended for patients with SSc, and knowing the extent of the disease, risk of developing dcSSc, and the rate of disease progression are key in managing this disease [1, 95]. Indeed, the European Scleroderma Trials and Research (EUSTAR) observational study of 1021 SSc patients found that progressive skin fibrosis within 1 year, indicated by higher mRSS scores, was associated with worsening lung function and decreased survival during follow-up [5], and thus monitoring skin fibrosis may help clinicians to identify patients at risk of lung progression and allow more aggressive treatment. A recent study based on patients selected from the Prospective Registry of Early Systemic Sclerosis (PRESS) is the largest multicentre US study assessing baseline characteristics, treatment patterns and disease progression in patients with early at-risk or definite dcSSc in a current and real-world setting [10]. Of 301 patients analysed, there was a general trend of earlier and broader use of IS drugs (86.4% of all patients at any time during the course of the study) compared with baseline evaluation, while only five patients (1.7%) underwent HSCT, highlighting the still-limited use of this therapeutic option, even though evidence-based guidelines support its use [10, 18, 19]. This is particularly relevant data considering that Jaafar et al. demonstrated that a large number of SSc patients (71.1%) with limited skin involvement who were at high risk for developing dcSSc went on to develop dcSSc during the follow-up period [10].
The lessons learned from the PRESS registry show that the use of MMF is widespread in early dcSSc in the USA (68.8% used it at some time during the course of the study), and ∼20% of patients had worsening mRSS and forced vital capacity over the first 3 years, and 6% mortality during the first 3 years, largely due to cardiac and gastrointestinal involvement [10]. The data are supported by a recent long-term follow-up single-centre study that reported an overall inpatient mortality of 9.3% due mostly to progressive pulmonary hypertension [96].
Given the morbidity and mortality of dcSSc, curative therapies are urgently needed, and current autologous HSCT is the only therapy that has demonstrated improved long-term, event-free survival and overall survival when compared with standard-of-care IS. Allogeneic HSCT paradigms could provide a significant advantage with less recurrence and less toxicity from the NMA conditioning while also reducing the risk for GvHD. New therapeutic approaches discussed in this review have the opportunity to provide long-lasting remission in early scleroderma while reducing the morbidity associated with cellular therapy regimens.
Data availability
The data underlying this review article are available in the references cited.
Funding
This work was supported by Talaris Therapeutics.
Disclosure statement: D.K. reports personal fees from Acceleron, Amgen, Bayer, Boehringer Ingelheim, Chemomab, CSL Behring, Genentech/Roche, Horizon, Mitsubishi Tanabe Pharma and Talaris. N.K. is the Chief Medical Officer of Talaris Therapeutics, Inc. K.S. receives funding from the National Institute of Allergy and Infectious Diseases; serves on the data and safety monitoring board of Kiadis Pharma; and is an adviser for GlaxoSmithKline, Jasper Therapeutics, Magenta Therapeutics, Talaris Therapeutics and Xenikos.
Acknowledgements
Medical writing and editorial support were provided by Kelly A. Hamilton, PhD, of AlphaScientia, LLC, and funded by Talaris Therapeutics.
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