ACR Convergence 2024: Systemic Lupus Erythematosus

ACR Convergence 2024: Systemic Lupus Erythematosus – Treatment: Cellular Therapy

14 Nov - 19 Nov, 24

ACR 2024

Washington, D.C, USA

14 Nov - 19 Nov, 24

ACR 2024

Washington, D.C, USA

Safety and Long-term Efficacy of CD19-CAR T-cell Therapy in 35 Patients with Autoimmune Disease

Speaker: Dr. Melanie Hagen – Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen

Key Highlights:

In discussing CD19-CAR T-cell therapy in autoimmune diseases, the speaker introduced patients who are severely ill, therapy-refractory, and progressive. These patients, including those with lupus, systemic sclerosis (SSC), and idiopathic inflammatory myopathies (IIM), are often treated with conventional therapies without success. The speaker highlighted examples of lupus patients with severe cutaneous and kidney involvement, along with SSC patients presenting with rapidly progressive skin manifestations and interstitial lung disease (ILD).

Dr. Hagen then gave an overview of the CAR-T Cell Procedure

T-Cell Collection: T cells are collected from the patient through leukapheresis. Prior to this, immunosuppressants are washed out to enhance the fitness of the T cells.

Manufacturing: The collected cells are engineered using the investigational MB19.1 product in a GMP facility.

Lymphodepletion: Lymphodepletion is performed using fludarabine and cyclophosphamide, with doses calculated based (Chimeric Antigen Receptor Therapy in Autoimmune Diseases on body surface area.

CAR-T Infusion: The CAR-T cells are infused into the patient after three days, with the dose determined by body weight.

B-cell depletion is observed within days of treatment, followed by short-term B-cell aplasia, with recovery occurring between 60-100 days. Expansion of CAR-T cells occurs by around 30 days, with a decline noted between 30-60 days.

The CAR-AID study (Chimeric Antigen Receptor Therapy in Autoimmune Diseases_ explored the safety and efficacy of CD19-directed CAR T-cell therapy in 35 patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc). Patients were heavily pretreated, with a mean disease duration of 5 years.

Methods:

The treatment involved leukapheresis, lymphodepletion with fludarabine and cyclophosphamide, and CAR T-cell infusion.

Follow-up lasted an average of 15 months.

The cohort included 19 SLE, 11 SSc, and 5 IIM patients, aged 15–81 years.

Demographics	SLE (N=19)	IIM (N=5)	SSc (N=11)	Total (N=35)
Age (Mean, Years)	28	50	42	35
Female (N, %)	14 (74%)	4 (80%)	4 (36%)	22 (63%)
Disease Duration (Years, Mean)	7	2	4	5
Prior Treatments (Mean)	7	5	4	5
Follow-Up (Months, Mean)	18	17	15	15
≥ 6 Months Follow-Up (N)	18	4	6	28
Relapse (N, %)	0 (0%)	1 (20%)	0 (0%)	1 (3%)

Results:

Safety:

Cytokine Release Syndrome (CRS) & Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS).

	SLE (19)	IIM (5)	SSc (11)	Total (35)
CRS Grade 1, N(%)	13 (68)	2 (40)	6 (55)	21 (60)
CRS Grade 2, N (%)	1 (5)	1 (20)	1 (9)	3 (9)
CRS > Grade 2, N (%)	0	0	0	0
ICAN any grade, N (%)	0	0	0	0

Immune-Cell Associated Hematotoxicity (ICAHT)

	SLE (19)	IIM (5)	SSc (11)	Total (35)
Early ICAHT any grade, N (%)	16 (84)	4 (80)	8 (73)	28 (80)
Early ICAHT aplastic, N (%)	0	0	0	0
Late ICAHT grade 3/4, N (%)	6 (32)	0	1 (9)	7 (20)
G-CSF Treatment, N (%)	7 (37)	0	1 (9)	8 (23)
Prolonged G-CSF treatment, N (%)	1 (5)	0	0	1 (3)
Bone marrow biopsy performed, N	2*	0	0	2

*Bone marrow biopsy showed reactive BM without signs of blasts or dysplasia. 1 patient showed persistent CAR-T cells at month 7.

Infections: Severe infections occurred in 7 patients, mostly pneumonia, without ICU admissions.

Clinical Efficacy: Consisted of clinical responses after 6 months

SLE: 94% of patients achieved remission (SLEDAI = 0) after 6 months.

IIM: Significant improvement in muscle strength. One patient relapsed but responded to BCMA-CAR T-cell retreatment.

SSc: Improved skin scores, stabilized gastrointestinal symptoms and ILD.

Case Study: (Hagen et al. Lancet 2024)

A young lupus patient with neurolupus, diagnosed just 9 months before seeking treatment, initially presented with arthritis and skin vasculitis. Over time, he developed rapidly progressing transverse myelitis, resulting in severe motor and sphincter muscle impairment.

The patient was treated with CAR T-cell therapy, with a 3-day prophylaxis of dexamethasone to prevent central nervous system complications.

Post-treatment, the patient showed no signs of immune cell-associated neurotoxicity (ICANS) or cytokine release syndrome (CRS).

Six months later (Video of patient was shown in ACR), he was able to walk with walking sticks, and while sphincter function was still recovering, the patient expressed significant improvement and satisfaction.

Conclusion:

After treating 35 patients with CD19 CAR T-cell therapy, the speaker concludes that it is a safe and effective treatment. The most common adverse events were low-grade cytokine release syndrome (CRS) and hematotoxicity, both of which were manageable. The therapy also helped patients to sustained reduction or removal of ongoing immunosuppressants.

Safety and Preliminary Efficacy of CD19 CAR-T Cell Treatment in Rheumatic Disease – Data from the First Part of the Phase I/II CASTLE Basket Study

Speaker: Dr. Georg Schett – Friedrich-Alexander-Universität Erlangen-Nürnberg

Key Highlights:

The CASTLE study is a Phase I/II basket trial assessing the safety and efficacy of autologous CD19-CAR-T-cell therapy in severe autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc). The therapy uses a lentiviral vector-based 2nd generation CAR-T-cell targeting CD19 with 4-1BB costimulatory domains.

Study Design and Participants:

Study Design: This study follows a Bryant and Day 2-stage optimal design, a methodology originally adapted from hematology-oncology studies.

Basket Study Setup:

Stage 1: Small basket with 8 patients.

Decision to stop or continue is based on toxicity or low response.

Stage 2: If continuation criteria are met, the study progresses to a larger basket with 16 patients.

Disease Groups in the Basket:

Systemic Lupus Erythematosus (SLE)

Idiopathic Inflammatory Myopathies (IIM)

Systemic Sclerosis (SSc)

Primary Endpoint: Toxicity after 4 weeks.

Secondary Endpoint: Efficacy after 24 weeks.

Toxicity Criteria (Grade >2):

Cytokine Release Syndrome (CRS).

ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome).

Organ toxicity.

Hematotoxicity.

Efficacy Endpoints:

Doris remission criteria.

ACR moderate or major response.

No progression of systemic sclerosis.

Inclusion Criteria

Disease-Specific Criteria:

Patients must meet inclusion criteria for the respective diseases.

Disease-specific autoantibodies are required (autoantibody-negative patients were excluded).

Active disease with clear signs:

For SLE: Active disease defined as >1 organ system with a BILAG A score or > 2 organ systems with BILAG B score.

For SSc:

Disease duration of <7 years.

mRSS score 10-35

CRP > 6 mg/L, ESR > 28 mm/h or platelets > 330 G/L

mRSS increase > 3 units or involvement of one new body area.

For IIM:

Positive muscle biopsy or MRI findings.

Presence of interstitial lung disease with active myositis.

MMT < 142, in case of active myositis

Treatment History: All patients must have failed two immunosuppressive drugs (aside from glucocorticoids). Participants: 24 patients (17 treated, 11 with ≥6-month follow-up), including cohorts for SLE, IIM, and SSc. Patients had high disease burden and had failed multiple immunosuppressive treatments.

Baseline Demographics:

Demographics	SLE	IIM	SSc	Total
Patients, N	7	3	7	17
Age, years (mean)	35	60	42	41
Female, N (%)	4 (57)	3 (100)	3 (43)	10 (56)
Disease duration, years (mean)	8	1	4	5
Prior treatments, N (mean)	6	4	4	5
Follow-up, months (mean)	9	5	5	6
>6 months follow-up, N	5	1	2	8
Relapse, N (%)	0	0	0	0

Results:

Efficacy Findings from 11 patients:

SLE: All 6 patients achieved DORIS remission.

IIM: 2 patients showed major ACR responses.

SSc: No disease progression; improved skin scores and minor lung function improvements seen across 3 patients.

B-Cell Aplasia: Peripheral B-cell depletion was sustained for 50–200 days before recovery.

CAR-T Expansion: Robust expansion of CAR T-cells was observed (~10 days post-infusion).

Safety Profile

CRS and ICANS:

CRS Grade 1 (fever) occurred in 50% of patients.

CRS Grade 2 in one patient.

No CRS Grade ≥3 or ICANS observed.

~50% received tocilizumab for CRS management.

Hematologic Toxicity:

Leukocytopenia and neutropenia (Grade 4) were common post-lymphodepletion, particularly in SLE patients, but resolved in all cases within a month.

Late-onset neutropenia (>28 days) observed in 7 patients, all resolved with G-CSF or spontaneously.

Infections: Severe infections were reported in 3 cases: one COVID pneumonia, one CMV reactivation with kidney microangiopathy, and one non-specific pneumonia.

Conclusion:

The speaker concluded, CASTLE study successfully achieved its predefined safety and efficacy criteria, paving the way for progression to Phase II. CRS was of low grade and ICANS did not occur and there were no major hematotoxicities. The findings highlight the transformative potential of CD19-CAR T-cell therapy in managing severe, refractory autoimmune diseases

Precision Targeting of Autoreactive 9G4 B Cells in Systemic Lupus Erythematosus Using Engineered Chimeric Antigen Receptor (CAR)- and Chimeric T Cell Receptor (cTCR)-T Cells

Speaker: Dr. Jin Liu – Johns Hopkins University

Key Highlights:

Dr. Liu introduced the topic by talking about CAR-T therapies, such as CD19 CAR-T, which have demonstrated significant promise in treating lupus by targeting and depleting B cells. However, these approaches were initially designed for cancer treatment, emphasizing T-cell proliferation and persistence. This adaptation presents challenges in autoimmune diseases, including global immunosuppression and cytokine release-related toxicities, such as cytokine release syndrome (CRS).

Precision Immunotherapy: A Safer Approach:

The goal of precision immunotherapy is to restore immune balance while minimizing infection risks.

Key Insight: Only 1-5% of B cells are disease-causing, with the majority supporting protective immunity.

Precision targeting spares healthy B cells, unlike pan-B cell depletion (e.g., CD19 CAR-T or monoclonal antibodies) which causes immunosuppression.

Rationale for Targeting 9G4 B Cells:

The 9G4 idiotope (9G4id) is a sequence on B cell receptors (BCRs) encoded by the IGHV4-34 gene, first identified in patients with cold agglutinin disease and high-affinity anti-dsDNA antibodies in SLE.

9G4id B cells are innately autoreactive and largely excluded from germinal center (GC) reactions in health.

In SLE, however, 9G4id B cells successfully participate in GC reactions, generating high numbers of 9G4id IgG+ memory B and plasma cells.

9G4 antibodies can account for up to 45% of total serum IgG in SLE.

9G4id antibodies include antinuclear, anti-dsDNA, anti-Ro, anti-Sm, anti-DNase1L3, and B cell reactivities, offering an opportunity for precision targeting in lupus and CAD.

Study Design and Methods:

Synthetic Receptors:

9G4 CAR-T Cells: Second-generation CAR designed for high specificity to 9G4 B cells.

Chimeric TCR-T Cells (T Cell Receptor-engineered T cells): Two designs with enhanced antigen-specific cytotoxicity and lower cytokine release.

Engineering Process: CRISPR/Cas12-based editing introduced synthetic receptors, achieving >90% receptor expression.

Validation Models:

Engineered 9G4 B cells expressing lupus-associated autoantibodies.

Co-cultures with lupus patient-derived PBMCs.

Key Findings:

Efficacy:

9G4 chimeric TCR-T cells and 9G4 CAR-T cells efficiently killed 9G4+ B cells but spared B cells with other BCRs.

Full depletion of 9G4+ B cells was observed in the presence of 9G4 chimeric TCR-T cells or 9G4 CAR-T cells, with no off-target cytotoxicity noted.

No difference in in vitro potency was observed between 9G4 chimeric TCR-T cells and CAR-T cells.

In 4-day live-cell imaging assays, elimination of 9G4+ B cells was observed with engineered T cells, but not with control T cells.

Co-culture supernatants showed that 9G4 CAR-T cells and 9G4 chimeric TCR-T cells efficiently neutralized 9G4 and anti-dsDNA antibody production.

9G4 CAR-T cells demonstrated higher specific and non-specific proliferation than chimeric TCR-T cells.

CAR-T cells showed significantly higher proliferation in the presence of target B cells, as measured by CellTrace Violet dilution.

Non-specific proliferation was observed in 9G4 CAR-T cells when exposed to normal B cells, unlike chimeric TCR-T cells.

9G4 CAR-T cells exhibited increased cytokine release compared to chimeric TCR-T cells, despite having comparable cytotoxicity.

Increased interferon-gamma secretion was observed, along with elevated levels of IL-2, granzyme A & B, and TNF (tumor necrosis factor).

Safety:

Cytokine Release: CAR-T cells had higher cytokine secretion, while cTCR-T cells showed reduced cytokine release.

Proliferation: CAR-T cells proliferated both specifically and non-specifically, whereas cTCR-T cells expanded strictly in an antigen-dependent manner.

Off-Target Effects: cTCR-T cells showed no off-target cytotoxicity against non-9G4 B cells, offering superior safety.

Clinical Implications:

Precision Targeting: Shifts from broad B-cell depletion (e.g., CD19 CAR-T cells) to selectively targeting pathogenic subsets, preserving protective immunity.

Applications: Potential treatment for SLE, cold agglutinin disease, and other autoimmune conditions involving specific autoreactive B-cell populations.

Safety Advantage: cTCR-T cells reduce risks of cytokine release syndrome and non-specific immune suppression compared to CAR-T cells.

Conclusion:

Chimeric TCR-T cells emerge as a safer and equally effective alternative to CAR-T cells for targeting autoreactive B cells. B cells carrying the 9G4 idiotope are a major source of pathogenic autoantibodies in SLE, including anti-dsDNA, anti-Ro, and anti-cardiolipin. Both anti-9G4 CAR-T cells and anti-9G4 chimeric TCR (CTCR)-T cells effectively eliminated primary SLE 9G4 B cells and cancerous 9G4 B cells.

These findings suggest that 9G4-targeted cell therapies have the potential to deplete autoreactive B cells while preserving protective immune responses, offering a promising therapeutic strategy for SLE management.

A Phase 1, Multicenter, Open-label Study to Establish the Preliminary Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of CC-97540 (BMS-986353), a CD19-directed CAR T Cell Therapy Manufactured Using a Next-generation Process, for Severe, Refractory Autoimmune Diseases

Speaker: Dr. Georg Schett – Friedrich-Alexander-Universität Erlangen-Nürnberg

Key Highlights:

Dr. Schett talked about this Phase 1 multicenter open-label trial that evaluates CC-97540 (BMS-986353), an autologous CD19-directed CAR T cell therapy, for severe, refractory autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory myopathies (IM). The CAR T cells are engineered with a 4-1BB costimulatory domain and manufactured using a novel five-day process, offering faster turnaround and scalability.

Autoimmune diseases often require lifelong immunosuppression, leading to significant unmet needs for therapies that achieve durable remission. CD19 CAR T therapy aims for deep B cell depletion to induce immune reset and potentially drug-free remission.

BMS-986353 (CC-97540) is an investigational CD19 NEX-T® CAR T-cell therapy.

Key Features:

Based on Liso-cel: BMS-986353 uses a construct similar to the FDA-approved CD19 CAR T liso-cel (Lisocabtagene maraleucel).

4-1BB Costimulation Domain: This CAR T incorporates a 4-1BB costimulation domain, which enhances T-cell activation, proliferation, and persistence.

CD19 NEX-T® Platform: This platform utilizes a shortened CAR T manufacturing process, which is expected to reduce turnaround time, allowing faster treatment for patients.

Study Design (Break free)

Inclusion Criteria: Severe SLE (primarily lupus nephritis), IM (CK elevation with severe muscle/skin involvement), and SSc (Rodnan skin score ≥15 with progression). Patients failed ≥2 prior immunosuppressants (≥1 for SSc).

Dosing: Two dose levels: 10 million cells and 25 million cells.

Lymphodepletion: Standard fludarabine and cyclophosphamide regimen.

Endpoints:

Primary: Safety /Tolerability and recommended phase 2 dose in each indication

Secondary: Preliminary efficacy and pharmacokinetics in each indication

Patient Characteristics and Treatment

Participants: 15 patients (11 SLE, 3 SSc, 1 IM).

Demographics: Predominantly young females with severe disease (e.g., SLEDAI-2K: 14 in SLE, Rodnan score: 34 in SSc).

Results:

Efficacy:

B Cell Depletion: Rapid and complete peripheral B cell depletion observed. Re-emerging B cells were naive, indicating successful immune reset.

B cells transition into an A phenotype with a loss of memory B cells, activated memory B cells, and plasma cells.

The observed B cell losses are consistent with expected outcomes of deep B cell depletion following CAR-T therapy.

In patients with > 3 months of follow-up, B cells returned at a median (range) of 113 days. (85-not reached)

In patients with SLE, repopulating B cells were mainly naïve B-cells, with very few memory B-cells, CD11c DN B-cells or plasmablasts.

Safety:

Hematologic Toxicity: 11 Grade 3-4 events, primarily short-term hematologic effects from conditioning therapy. No prolonged cytopenias (>28 days).

Infections: No Grade 3-4 infections. Observed infections were mild (e.g., asymptomatic CMV positivity).

Cytokine Release Syndrome (CRS): Occurred in most patients (Grade 1-2), with one Grade 3 event. CRS onset averaged 7 days, resolving within 2 days with tocilizumab when needed.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): One Grade 3 event resolved in 24 hours with glucocorticoids and anakinra.

Disease Activity: SLE:

Reduction in SLEDAI scores of 10 points

Median PGA score reduction of 82%

Median HAQ-DI score reduction of 60%

All patients with SLE remained off all therapies including glucocorticoids. No evidence of new disease activity in patients with SLE at up to 11 months of follow-up.

Biomarkers: Anti-dsDNA decreased over time and became negative by Day 85 (month 3). C3 and C4 reached normal range by Day 29.

Case study:

The first patient undergoing CAR-T cell therapy for lupus experienced remarkable outcomes. She achieved a positive pregnancy test at day 85 post-treatment, coinciding with the involution of CAR-T cells and the re-emergence of B cells. Remarkably, the pregnancy proceeded in a drug-free state without any lupus recurrence.

Although preeclampsia developed late in the pregnancy, she delivered a healthy male baby at 37 weeks via uncomplicated normal delivery. Both the mother and child showed no abnormalities, with the newborn displaying normal B and T cell levels. Post-pregnancy, the patient remained lupus-free, highlighting CAR-T therapy's potential resilience against stressors like pregnancy in autoimmune disease management.

Conclusion:

Preliminary results from the Phase 1 study of BMS-986353 (CC-97540) in patients with severe, refractory SLE, SSC, and IIM show promising safety and efficacy.

Safety data from the first 15 patients indicate a good safety profile with no unexpected adverse events.

Complete B cell depletion and robust CAR T cell expansion were observed, comparable to the hematology-established liso-cel treatment at the approved dose.

Efficacy data from the first 7 SLE patients showed disease activity regression, reduced autoantibodies, and a stable immunosuppression-free state for up to 11 months, with no new disease activity.

Reemerging B cells were mainly naïve, and their reappearance was not associated with lupus flare.

Dose escalation is ongoing to determine recommended phase 2 dose of BMS-986353 with optimal safety and efficacy profiles.

American College of Rheumatology Convergence 2024, November 14–19, Washington, D.C.