Can chimeric antigen receptors – based therapy bring a gleam of hope for thyroid-associated ophthalmopathy and other autoimmune diseases?

Glucocorticoids with other agents

Intravenous glucocorticoids (IVGC) have been recommended as first-line treatment for moderate-to-severe and active TAO due to their anti-inflammatory and immunosuppressive effects, which are more effective and better tolerated than oral glucocorticoids [10]. In a multicenter, randomized, double-blind trial conducted by L. Bartalena et al. [11], 159 participants were randomized to three different cumulative doses of intravenous methylprednisolone, 2.25 g, 4.98 g and 7.47 g. Overall ocular improvement was more common with the 7.47 g dose (52 %) than with 4.98 g (35 %; p<0.03) and 2.25 g (28 %; p<0.01). Clinical activity scores (CAS) decreased in all groups, with the high-dose regimen showing the most significant improvements in objectively measured ocular motility and CAS. However, the improvement of IVGC on proptosis and extraocular muscle dysfunction was limited [12]. The dose of IVGC therapy needs to be closely monitored, and excessive doses may lead to adverse effects such as hepatotoxicity [13]. glucocorticoids should not be used in patients with the following contraindications: recent hepatitis, hepatic insufficiency, uncontrolled hypertension, and severe cardiovascular disease [14]. Relapse rates were high, with 33 % in the 7.47 g group, 21 % in the 4.98 g group, and 40 % in the 2.25 g group of patients with 12th week improvement in GO experiencing recurrence of orbital disease after glucocorticoid withdrawal at the exploratory 24th week visit [11].

In addition, glucocorticoids can also be combined with immunosuppressive agents for TAO treatment. Cyclosporine is a robust immunosuppressive agent that inhibit the calcineurin pathway, and reduce T-cell proliferation and IL-2 secretion. In an random clinical trials (RCT) study [15], the response rate to the combination of prednisone and cyclosporine was 59 % in participants who did not respond to monotherapy. It was better tolerated in the cyclosporine group.

Azathioprine (AZA) is an antiproliferative agent, frequently used in autoimmune diseases for reducing steroid dosage. AZA is not an effective treatment for moderately severe TAO alone [16]. But evidence from retrospective research demonstrates that AZA as a steroid-sparing agent may reduce the overall cumulative steroid dose and associated side effects [17]. Methotrexate is a widely used antimetabolic agent. In a small scale non-randomized trial in active TAO, adjunctive IVMP therapy with methotrexate is an effective and safe treatment for moderately to severely active TAO, significantly reducing disease activity and total steroid dose. And participants received 50 % fewer IVGC treatments [18]. Cyclophosphamide (CYC) is an alkylating agent that inhibits the proliferation of immune cells by disrupting cell replication and division through an alkylation reaction with DNA. Combined CYC/GCs therapy may be a therapy option for patients with TAO who do not respond well to IVGCs therapy and who relapse after withdrawal of IVGCs [19]. Of note, there are no clinical evidence-based studies comparing those immunosuppressive agents alone with IVGC for the treatment of TAO.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) inhibits the proliferation of T and B cells as well as antibody production by inhibiting inosine dehydrogenase. In addition, MMF is known to inhibit fibroblast proliferation [20]. In a multicenter, randomized, observer-masked trial (MINGO) study, 164 patients with active and moderate to severe TAO were enrolled and were randomly assigned to two groups, methylprednisolone alone and methylprednisolone with a combination of glucocorticoids. In 24th week, 38 of 72 participants (53 %) in the alone treatment group responded, and 53 (71 %) of 75 participants in the combination treatment group responded (OR=2.16, 95 % CI 1.09–4.25, p=0.026). Although no statistically significant differences were observed in response rates at 12th week and recurrence rates at 24th and 36th week, post hoc analyses suggest that the addition of MMF to GCs treatment in patients with active moderate to severe TAO improves the response rate at 24th week and improves the quality of life of patients [21]. In a meta-analysis conducted in 2022, the combination of GCs and MMF was more effective, with a more significant decrease in CAS compared with GCs monotherapy (WMD=0.29, 95 % CI 0.10–0.48; p=0.002) and a lower incidence of adverse events in the MMF treatment group (OR=0.2, 95 % CI 0.06–0.72; p=0.01) [22]. At present, the sample size of relevant studies is too small. More multicenter, randomized, controlled, double-blind trials are required to confirm these results.

Orbital radiotherapy

Orbital radiotherapy (ORT) has been used as an adjuvant treatment for active TAO for more than 60 years due to its anti-inflammatory effects and radiosensitivity of orbital lymphocytes. Given its long-term use, many prospective and retrospective studies have been performed, but the efficacy of TAO remains controversial. Two large retrospective studies have shown that radiotherapy, either with or without corticosteroids, is effective in preventing or treating compressive optic neuropathy (CON) [23]. Newly evaluated studies have further proven that ORT improves examination findings and clinical activity, including ocular mobility restrictions and CAS [24]. ORT also helps reduce the side effects of long-term glucocorticoids use, such as diabetes, liver disease, adrenal suppression, and infections [25]. However, there is level 1 evidence that ocular proptosis, eyelid retraction and soft tissue damage do not improve with ORT [26]. Although ORT is generally safe, there is a potential risk of side effects such as cataracts or radiation retinopathy.

Teprotumumab and other IGF-1R-targeting agents

IGF-1R plays an important role in the pathogenesis of TAO, so it is important to develop new drugs targeting IGF-1R. Teprotumumab is a human monoclonal antibody that binds to the extracellular portion of IGF-1R and blocks its activation. In an RCT [27], patients with active, moderately severe TAO were included and randomly assigned in a 1:1 ratio to either the teprotumumab group or the placebo group. Injections every 3 weeks for a total of eight doses in 24 weeks. 83 % (34 patients) in the teprotumumab group had a significant reduction in proptosis in 24th week, while only 10 % (4 patients) in the placebo group showed such a reduction (p<0.001). All secondary endpoints were significantly superior in the teprotumumab group compared to the placebo group, including overall response (78 % vs. 7 %), a clinical activity score of 0 or 1 (59 % vs. 21 %), a mean change in proptosis (−2.82 mm vs. −0.54 mm), diplopia response (68 % vs. 29 %), and a mean change in overall GO-QoL scores (13.79 vs. 4.43 points). In OPTIC-X study [28], it was found that patients who had an insufficient response to initial treatment or who had disease relapse may benefit from additional treatment with teprotumumab. The efficacy of teprotumumab was consistent across patient subgroups [29]. And it allows for long-term maintenance of response in most patients [29]. The majority of adverse events with teprotumumab were mild to moderate, with the greatest difference in risk of muscle cramps, hearing loss, and high glucose in the teprotumumab group compared to the placebo group [30]. The disadvantages are that teprotumumab, a newer treatment, is expensive and not available in all regions.

Linsitinib is a highly selective small molecule dual inhibitor of IGF-1R and insulin receptor. It binds to the structural domain of cytoplasmic tyrosine kinase, thereby inhibiting the intrinsic tyrosine kinase activity of IGF-1R [31]. Studies in animal models have shown that linsitinib was effective in preventing autoimmune hyperthyroidism in the early treatment group and in reducing immune infiltration in the orbit in the late treatment group. Suggesting its potential as a new approach for the treatment of TAO [32]. A phase 2b RCT is currently underway to study the efficacy and safety of linsitinib in active TAO (ClinicalTrials.gov identifier: NCT05276063). Subcutaneous injection of IGF-1R antibodies is being actively researched, a phase 1–2 RCT comparing lonigutamab with placebo is ongoing (ClinicalTrials.gov identifier: NCT05683496). Clinical trials of VRDN-001, a full antagonist of IGF-1R, are also underway, including two phase 3 RCTs in patients with active TAO (ClinicalTrials.gov identifier: NCT05176639) and patients with inactive TAO (ClinicalTrials.gov identifier: NCT06021054).

Rituximab

Rituximab (RTX) is a human-mouse chimeric monoclonal antibody that targets the antigen CD20 on B cells leading to B cell depletion. An RCT conducted in Italy compared the efficacy of rituximab and methylprednisolone in 31 participants [33]. In 24th week, the RTX group showed a 100 % reduction in CAS, which proved to be more effective than the GCs group, which showed a 69 % reduction. A meta-analysis including 152 patients with TAO showed that, compared to baseline, it reduced CAS and TSHR Antibody (TRAb) levels. While rituximab did not affect proptosis [34]. In contrast, a RCT conducted at the Mayo Clinic in the United States found no effect of rituximab compared with placebo in improving CAS, including proptosis and diplopia [35]. Comparing these two RCTs, TAO duration averaged 4.5 months in Italy [33], while it averaged 12 months in the United States [35]. Therefore, rituximab may be a more effective treatment for patients with TED of shorter duration. Injection reactions were mild in the RTX group compared to the IVMP and placebo groups, but adverse events occurred more commonly. The current evidence is inadequate to support the use of RTX in patients with TAO. Further multicenter studies are required to enroll enough participants to adequately evaluate the efficacy and safety of this new therapy [36].

Tocilizumab and other IL-6-targeting agents

IL-6 is a pro-inflammatory cytokine that can activate T and B cells and promote TSHR expression in orbital fibroblasts. In an RCT, which enrolled 32 moderate to severe TAO participants with glucocorticoids resistance, it was observed that tocilizumab was effective in reducing CAS compared to the placebo group (93.3 % vs. 58.8 %, in 16th week) [37]. In addition, at both 16th and 40th week, proptosis was reduced by 1.5 mm in the tocilizumab group, while there was no change in the placebo group. However, no significant difference in CAS was observed in 40th week. Among the adverse events, infections and headaches occupied a high proportion, and neutropenia and high cholesterol were also observed. A phase 2 RCT comparing tocilizumab and IVGCs is ongoing (ClinicalTrials.gov identifier: NCT04876534). While a Phase 3 multinational RCT is also underway to evaluate the efficacy and safety of satralizumab, an anti-IL-6 monoclonal antibody (ClinicalTrials.gov identifier: NCT05987423). A novel developed long-term anti-IL - 6 antibody, TOUR006, is currently undergoing a phase 2 RCT to compare the efficacy of TOUR006 20 mg, TOUR006 50 mg, and placebo in patients with active TAO (ClinicalTrials.gov identifier: NCT06088979).

Sirolimus

Sirolimus is a macrolide immunosuppressant used to prevent organ rejection after transplantation. It targets the mammalian target of rapamycin protein (mTOR), modulates cell growth and proliferation, and has antifibrotic characteristics by acting on GCs [38]. It can inhibit mTOR complex 1 (mTORC1), which is involved in adipogenesis, and also has a role in reducing adipogenesis [39]. In one case report, diplopia and field of binocular single vision (BSV) improved over a period of several months after sirolimus treatment, and no adverse events directly attributable to the treatment were observed [40]. A recent observational single-center clinical study compared the efficacy of sirolimus with GCs in moderate to severe active TAO [41]. The proportion of TAO responders at 24th week was significantly higher in the sirolimus group than in the GCs group (86.6 % vs. 26.6 %), and GO-QoL scores were also higher in the sirolimus group. Advantage of sirolimus is that it rarely causes side effects due to its relatively small dose. However, its efficacy has not been confirmed as the results of RCT studies are not yet available. Further randomized clinical trials are required to confirm these observations. At present, two phase 2 RCTs are underway to compare sirolimus and GCs for efficacy (ClinicalTrials.gov identifier: NCT04598815 and NCT04936854).

Batoclimab

The neonatal fragment crystallizable receptor (FcRN) has the potential to protect immunoglobulin G (IgG) from intracellular degradation and increase its half-life. Batoclimab blocks the recirculation of IgG by competitive binding to FcRN, thereby reducing pathogenic TRAb [42]. In a randomized, double-blind, placebo-controlled trial, there was a significant difference in the rate of proptosis response with Batoclimab compared to placebo at multiple early time points, but not at the primary endpoint of 12th week, which may be due to data insufficient [42]. A multicenter, quadruple-masked phase 3 study is currently underway to observe the effects of batoclimab on proptosis (ClinicalTrials.gov identifiers: NCT05517421 and NCT05524571). A Phase 3 RCT was also conducted to evaluate the efficacy and safety of efgartigimod (FcRN antagonist) compared to placebo in patients with active and moderate-to-severe TAO (ClinicalTrials.gov identifiers: NCT06307626 and NCT06307613).

However, like other ADs, the adverse effects of these therapies, little impact on long-term sequelae, and the irreversible progression of the disease remain significant limitations (Table 1). As a result, the development of new therapeutic strategies for TAO is essential.