Dr. Yajing ZHANG

In 2013, at just 21 years old, Lingling (pseudonym) was diagnosed with systemic lupus erythematosus (SLE). Since then, she has faced long-term treatment, frequent relapses, and significant changes to her appearance. Over the next decade, repeated flare-ups brought her immense physical suffering and psychological stress. In the summer of 2024, her condition relapsed for the third time, with severe swelling throughout her body and impaired kidney function. She was even given a critical condition notice. Standard treatments could no longer control her illness, leaving her and her family in a difficult situation.

From her initial diagnosis through the following ten years, Lingling sought care at multiple hospitals and received treatments including corticosteroids, immunosuppressants, and mesenchymal stem cell infusions. Although these therapies occasionally brought temporary relief, relapses were unavoidable. The frequent hospitalizations and relentless pain left her uncertain about the future. She admitted that the most difficult part was not the treatment itself, but the loss of her youth to illness and the changes in her appearance caused by long-term medication side effects, which placed enormous pressure on her mentally.

In October 2024, Lingling learned through a patient community about the clinical exploration of CAR-T cell therapy for lupus. After further research and consultation, she reached out to Professor Yajing Zhang, Director of Rheumatology and Immunology at Beijing GoBroad Boren Hospital. With extensive experience in autoimmune diseases and CAR-T clinical research, Professor Zhang and her team carefully evaluated Lingling's condition and designed a CAR-T treatment plan.

Before starting treatment, the medical team optimized her overall condition, managing swelling, improving nutrition, and addressing complications. Lingling then successfully received an autologous CAR-T cell infusion. During the process, she experienced mild fever and bone marrow suppression, which were effectively controlled under close monitoring and timely care. Over time, her key health indicators improved significantly: kidney function recovered, albumin levels rose, and swelling gradually subsided.

Soon after, Lingling was discharged and returned home to recuperate. Follow-up visits confirmed that her condition remained stable, with continued improvement in energy and physical strength. Within two months, she had overcome the persistent swelling and fatigue that had troubled her for years. Her natural appearance returned, and her outlook on life became much more positive. Today, she is preparing to return to the campus where she teaches, eager to once again stand on the playground and resume her role as a physical education teacher.

 

Doctor's Commentary

According to Professor Zhang, CAR-T cell therapy works by genetically modifying a patient's own T cells to specifically recognize and eliminate overactive B cells, thereby restoring immune balance in lupus. For patients who do not respond well to conventional therapies, this offers a new treatment option. Lingling's case demonstrates both the potential of CAR-T in autoimmune disease and the importance of team-based, individualized medical management for complex conditions.

 

*Important Note

This case represents the real experience of one patient and is shared for health education purposes only. CAR-T cell therapy for lupus is still in the clinical research stage. Whether it is appropriate for an individual patient must be determined by professional physicians based on specific medical conditions. Patients should always seek medical advice and avoid self-treatment or unverified approaches.

Yuri, a 39-year-old from Russia, began experiencing bone pain and fatigue in 2023, later accompanied by nosebleeds and gum bleeding. After a comprehensive examination, he was diagnosed with IgA-κ type multiple myeloma, classified as R-ISS Stage III, indicating a high-risk profile. He underwent multiple rounds of chemotherapy and an autologous hematopoietic stem cell transplant in his home country. Although he initially achieved partial remission, the disease relapsed. The tumor cell burden increased, accompanied by complex chromosomal abnormalities and extramedullary infiltration, making the situation extremely challenging. Local doctors recommended he pursue more advanced therapies. With hope, Yuri traveled from Russia to Beijing Boren Hospital to seek further treatment under Professor Zhang Yajing's team.

 

Upon admission, Yuri's condition was highly complex. Tests revealed not only severe bone destruction but also extramedullary plasmacytomas in multiple organs including the liver, stomach, spleen, pancreas, and pelvic cavity, indicating a very high tumor burden. His treatment posed several critical challenges:

1. Heavy Tumor Burden and Rapid Progression

Whole-body nuclear imaging revealed widespread infiltration with clear systemic symptoms.

2. High Treatment Risk

Due to multiple prior treatments, Yuri's immune system was severely compromised, and he suffered significant bone marrow suppression, increasing his risk of infections and bleeding.

3. Severe CAR-T Related Complications

After receiving cutting-edge BCMA CAR-T and GPRC5D CAR-T cell therapies, Yuri experienced severe adverse reactions such as high fever, low blood pressure, arrhythmias, and even developed Hemophagocytic Lymphohistiocytosis (HLH)—a potentially life-threatening complication. The entire treatment process was fraught with danger and uncertainty.

 

Led by Professor Zhang Yajing, the team implemented a personalized and multidisciplinary approach:

• Customized Treatment Design: After ruling out contraindications, a dual-target CAR-T therapy was administered following intensive chemotherapy to maximize tumor cell clearance.
• Multifaceted Interventions to Manage Complications: To address cytokine release syndrome (CRS), the team escalated treatment—from anti-infection measures to the use of targeted drug, and vasopressor support—eventually gaining control over the symptoms.
• Cross-Disciplinary Collaboration: Experts from cardiology, infectious diseases, and critical care worked closely to monitor and manage complications like arrhythmia, hypotension, and hypoxemia.
• Dynamic Monitoring and Emergency Interventions: During the HLH outbreak, the team promptly initiated plasma exchange, alongside supportive transfusions, hemostatic therapies, and immunosuppressants. These interventions gradually calmed the inflammatory storm and maintained stable vital signs.

Each crisis was handled with precision and care. Thanks to the team's extensive experience in managing critically ill international patients, Yuri eventually made it through the most dangerous phase.

 

After 40 days of hospitalization, Yuri's vital signs stabilized, and his pain significantly subsided. Lab results confirmed that the inflammatory storm had been controlled, CAR-T cells had expanded well, and tumor markers had dropped significantly—meeting the discharge criteria.

Professor Zhang and her team developed a scientific follow-up and maintenance treatment plan to help consolidate Yuri's treatment outcomes and support his long-term recovery.

Looking back on his experience, Yuri and his family expressed heartfelt gratitude: “Here, we found not only advanced medical technology but also a team that was always there to protect me.”

The 67th Annual Meeting of the American Society of Hematology (ASH) was held in Orlando, Florida, bringing together the most cutting-edge research findings and clinical advances in the global field of hematology. At this year’s meeting, the team led by Professor Yajing Zhang from GoBroad Healthcare Group had four studies accepted, including one selected for oral presentation. These studies addressed key areas such as multi-target CAR-T therapeutic strategies, mechanistic management of complex toxicities, and immunodynamic regulation, collectively demonstrating the team’s original contributions and global vision in the field of CAR-T therapy.

In this article, Professor Zhang discusses specific studies and further shares her strategic perspective on the evolution of CAR-T therapy “from technological breakthroughs to systemic maturity,” offering an insightful and practice-oriented roadmap for the field.

Overcoming Therapeutic Bottlenecks in High-Risk Extramedullary Disease: An Integrated Strategy of Sequential BCMA and GPRC5D CAR-T Therapy

Q1. What are the major therapeutic challenges in relapsed/refractory multiple myeloma (RRMM) with bulky or extensive extramedullary disease (EMD)?

RRMM accompanied by bulky or extensive EMD represents one of the most challenging subgroups in current multiple myeloma treatment. The therapeutic difficulty arises not from a single factor, but from the convergence of multiple barriers.

First, the “sanctuary effect” and physical barriers play a critical role. Extramedullary tumor masses often have poor vascularization and are surrounded by fibrotic tissue, forming a closed microenvironment that limits the penetration of drugs and immune effector cells. As a result, conventional chemotherapy, targeted agents, and even standard CAR-T cells may fail to adequately access the tumor core.

Second, these lesions are characterized by a distinct and profoundly immunosuppressive microenvironment. Extramedullary sites are enriched with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and multiple inhibitory cytokines. CAR-T cells that infiltrate these lesions are prone to rapid functional exhaustion, making it difficult to sustain effective antitumor activity.

In addition, high tumor burden and antigen escape are particularly prominent. Under selective pressure from a single target, such as BCMA, tumor cells can downregulate or lose antigen expression, leading to immune escape and rapid disease relapse.

In essence, the treatment of extensive EMD is not merely an “intensification challenge,” but a systemic problem that requires simultaneous solutions to physical barriers, immunosuppression, and tumor evolutionary dynamics.

Q2. What is the rationale behind the integrated strategy of DCEP chemotherapy, low-dose radiotherapy bridging, and sequential BCMA and GPRC5D CAR-T therapy?

The core concept of this strategy is systematic design and stepwise implementation, rather than reliance on a single high-intensity intervention.

Phase 1: Bridging therapy — creating a “combat-ready” environment for CAR-T cells.

Bridging therapy should be viewed as an active preparatory phase rather than a passive waiting period during CAR-T manufacturing. DCEP chemotherapy helps to reduce systemic tumor burden, thereby lowering the cytotoxic pressure faced by CAR-T cells after infusion. Low-dose radiotherapy serves a dual purpose: it enables precise debulking of extramedullary lesions while also enhancing immune sensitivity. By disrupting physical tumor barriers and inducing immunogenic cell death, radiotherapy can remodel the local microenvironment, promote immune cell infiltration, and potentially induce abscopal effects.

Phase 2: Sequential CAR-T infusion — a time-oriented strategy to address antigen escape.

To overcome antigen heterogeneity and the risk of immune escape, a dual-target sequential CAR-T approach was adopted. BCMA-directed CAR-T cells are administered first to rapidly eliminate tumor cells with high BCMA expression. This is followed by GPRC5D-directed CAR-T cells to eradicate residual tumor populations with low or absent BCMA expression, thereby achieving sustained target coverage over time.

Fundamentally, this strategy optimizes the “battlefield” through effective bridging therapy and achieves continuous tumor eradication through rational temporal and spatial target deployment.

Q3. What key clinical outcomes were achieved with this integrated strategy?

This integrated approach yielded clinically meaningful and encouraging results in RRMM patients with bulky or extensive EMD. At a median follow-up of 8.5 months (range, 3–15 months), the overall response rate was 87.5%, with a stringent complete response rate of 62.5%. Importantly, 87.5% of responding patients achieved complete metabolic remission of extramedullary lesions, a result that has rarely been reported in previous studies.

Moreover, follow-up data demonstrated more durable responses, with notable improvements in both progression-free survival (PFS) and overall survival (OS). With careful and mechanism-informed management, the overall safety profile was favorable, and no unexpected severe toxicities were observed.

The key significance of this study lies in establishing a feasible, reproducible, and manageable CAR-T treatment paradigm for patients with bulky or extensive EMD — a population historically regarded as a “therapeutic no-man’s-land.”

A Holistic Strategic View of CAR-T Therapy: From Single Infusion to Full-Cycle Systems Engineering

Professor Zhang emphasized that the future of CAR-T therapy does not depend on the emergence of a single “super CAR,” but rather on the development of a scientific, dynamic, and interpretable full-cycle management framework. This framework can be summarized in three core principles:

• Upfront strategic optimization: achieving deeper and more durable responses through effective bridging therapy and rational multi-target design
• Mechanism-driven management: enabling precise toxicity control guided by mechanistic understanding
• Dynamic, longitudinal monitoring: ensuring long-term disease control through immunodynamic surveillance

Building around this framework, the team continues to develop evidence-based solutions for each critical stage of CAR-T therapy, driving the continued evolution of CAR-T therapy toward greater safety, higher efficacy, and long-term sustainability.

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening lymphoproliferative disorder characterized by marked clinical heterogeneity and complex immune dysregulation. Safe and effective therapies capable of producing durable remission have remained limited, making iMCD one of the most challenging immune-mediated rare diseases in clinical practice. While CAR-T cell therapy has significantly expanded beyond B-cell malignancies into immune-related disorders, its application in rare lymphoproliferative diseases such as iMCD is still in the early stages.

A new study, led by Dr. Yajing Zhang of GoBroad Healthcare Group as first author, with Prof. Minghui Duan of Peking Union Medical College Hospital as corresponding author, and Prof. Lu Zhang (Peking Union Medical College Hospital) together with Dr. Hongsheng Zhang (Fudan University/Yake Biotechnology) as co-corresponding authors, has been published in the international journal Hematological Oncology.

The report presents the world's first documented case of a patient with refractory HHV-8-negative iMCD achieving complete treatment-free remission lasting more than 12 months following CD19 CAR-T therapy. The findings also provide important clinical evidence supporting a B-cell–centric disease model, offering new insights into future therapeutic strategies for Castleman disease.

A 12-Year Journey Before a New Treatment Option

The patient was a 31-year-old woman diagnosed with HHV-8-negative iMCD (plasma cell/IPL subtype). During more than 12 years of disease, she underwent multiple lines of therapy—including COP, CHOP, thalidomide, bortezomib and sirolimus—but none achieved durable disease control.

Pathological examination demonstrated preserved lymph node architecture with the characteristic "onion-skin" appearance, while CD138 immunohistochemistry revealed diffuse plasma cell proliferation, consistent with the iMCD-IPL subtype.

Clinically, she experienced persistent systemic inflammation, including markedly elevated CRP, ESR and IL-6 levels, severe hypergammaglobulinemia (peak IgG: 68.0 g/L), generalized lymphadenopathy, splenomegaly and recurrent inflammatory symptoms. Limited efficacy and accessibility of conventional therapies, including IL-6 pathway inhibition, suggested that a more fundamental immune mechanism might be driving the disease.

Why CD19 CAR-T Was Selected

Years of unsuccessful treatment had significantly affected the patient's career, daily life and future plans.

After comprehensive discussions between the multidisciplinary team and the patient, several treatment options were carefully evaluated:

• Anti-IL-6 therapy (siltuximab), the current standard treatment requiring long-term administration;
• B-cell depletion with rituximab, which may provide benefit but often with limited durability;
• Additional chemotherapy and immunomodulatory therapies, which had already failed to achieve sustained disease control.

The patient hoped to achieve durable remission after a single treatment. Given her persistent inflammatory burden and evidence of abnormal B-cell activation, she and the medical team jointly decided to proceed with CD19 CAR-T therapy under an approved clinical study (ChiCTR1900025419).

Treatment Was Well Tolerated

Following standard lymphodepleting chemotherapy with fludarabine and cyclophosphamide (FC regimen), the patient received autologous CD19 CAR-T cells at a dose of 1 × 10⁶ CAR-positive T cells/kg.

The treatment demonstrated a favorable safety profile:

• Grade 1 cytokine release syndrome (CRS), presenting only as low-grade fever;
• No immune effector cell-associated neurotoxicity syndrome (ICANS);
• Peak CAR-T expansion occurred on Day 11 after infusion;
• B-cell depletion lasted from Day 7 to Day 198;
• No Grade 3 or higher treatment-related adverse events were observed.

Durable Remission and Improved Quality of Life

The patient experienced rapid and sustained clinical improvement following treatment.

Inflammatory markers—including CRP, ESR and IL-6—declined quickly and remained within normal ranges. Her anemia resolved progressively, immunoglobulin levels decreased as expected following CD19-positive B-cell depletion, and systemic symptoms disappeared completely.

More than 12 months after treatment, she continues to maintain complete remission without any ongoing therapy.

The sustained disease control has also transformed her quality of life. She has returned to work, resumed normal daily activities and begun planning for the future. Having regained confidence in her health, she is now preparing for pregnancy.

Immune Rebalancing Beyond B-Cell Depletion

Serial immune monitoring showed prolonged peripheral B-cell depletion that closely paralleled the patient's clinical remission.

At the same time, systemic inflammatory mediators—including CRP, ESR and IL-6—declined and stabilized, suggesting restoration of immune homeostasis.

These findings indicate that, in the plasma cell subtype of iMCD, B cells may play a central pathogenic role rather than simply participating in downstream inflammation. The results provide further support for the B-cell–centric disease model, suggesting that CD19 CAR-T therapy may achieve long-term disease control by eliminating pathogenic B-cell populations and restoring immune balance.

Expert Perspectives

Dr. Yajing Zhang commented that this case demonstrates the importance of revisiting disease classification and underlying mechanisms, even in patients with longstanding refractory Castleman disease.

"Future treatment may move beyond simply suppressing inflammation toward identifying the biological drivers of disease and restoring immune balance. Rare disease research often begins with careful observation of individual patients, opening new possibilities for understanding disease biology."

Prof. Minghui Duan noted that for patients with refractory Castleman disease, identifying the underlying immune abnormalities is critical.

"Rather than focusing solely on inflammatory pathways, future strategies should aim to restore immune homeostasis. CAR-T therapy has shown encouraging potential, although its clinical application requires careful patient selection, standardized management and long-term follow-up in experienced centers. For patients who respond poorly to conventional therapy, CAR-T offers an important direction for future clinical investigation."