CAR T-cell Therapy Shows Promise in Lupus, But Risks Remain | Healio Rheumatology

Recent data emerging from clinical trials are refining our understanding of chimeric antigen receptor T-cell (CAR T-cell) therapy, a promising yet complex treatment approach for autoimmune diseases like lupus. While early results suggested near-universal remission, more recent analyses indicate a more nuanced picture, with some patients experiencing disease relapse. This evolving understanding is crucial as clinicians weigh the potential benefits against the known risks, particularly cytokine release syndrome (CRS).

CAR T-cell therapy involves engineering a patient’s own T cells to recognize and attack specific cells – in the case of lupus, often B cells. The therapy has demonstrated dramatic improvements in disease activity within the first few months of treatment, and a significant proportion of patients achieve drug-free remission. However, the experience is not uniform. A recent analysis, presented at the Basic and Clinical Immunology for the Busy Clinician symposium, examined data from 145 lupus patients across 16 studies. The review, led by researchers including Philip J. Mease, MD, of Providence Swedish Medical Center and the University of Washington, revealed that while 70% of patients achieved remission according to the Definition of Remission in SLE (DORIS) criteria, and 89% achieved low disease activity, some experienced a return of symptoms after a period of initial improvement. Rheumatologists have viewed CAR T-cell therapy as revolutionary, but cost and safety concerns remain.

Understanding Remission and Relapse in CAR T-cell Therapy

Dr. Mease described these relapses as often being milder than the initial disease presentation, manifesting as mild skin issues, joint pain, or proteinuria (protein in the urine). This suggests that while the therapy may not always achieve complete and durable eradication of the disease, it can often shift lupus to a less severe form. The analysis included studies utilizing both CD19-targeted cells and those targeting both CD19 and B-cell maturation antigen (BCMA), with most patients receiving cells derived from themselves (autologous) and a smaller number receiving cells from donors (allogeneic).

The most significant adverse effect associated with CAR T-cell therapy is cytokine release syndrome (CRS). This occurs when the activated T cells release large amounts of cytokines, leading to systemic inflammation. However, in the context of lupus treatment, CRS tends to be milder than what is observed in cancer treatment, likely due to the lower number of pathogenic B cells being targeted. CRS, and another potential complication called immune effector cell-associated neurotoxicity syndrome (ICANS), can generally be managed with medications like acetaminophen, steroids, or tocilizumab. CAR T-cell therapies have shown promise as an immune reset in multiple diseases, but careful monitoring is essential.

Balancing Benefits and Risks: A Closer Look at Adverse Events

The review also highlighted instances of serious infections, including pneumonia, and, tragically, one fatality due to meningitis. Importantly, the patient who died had declined a meningitis vaccination, underscoring the importance of adhering to recommended preventative measures. This case serves as a reminder that while CAR T-cell therapy offers a novel approach to treating autoimmune diseases, it is not without risks, and patient selection and pre-treatment evaluation are critical.

Cytokine release syndrome (CRS) is a systemic inflammatory response that can occur after CAR T-cell therapy. It happens when the activated T cells release large amounts of cytokines, signaling molecules that can cause fever, nausea, fatigue, and, in severe cases, organ dysfunction. The severity of CRS can vary widely, and it is graded based on clinical symptoms. Management typically involves supportive care, such as fluids and oxygen, and medications to suppress the immune response, like tocilizumab, a monoclonal antibody that blocks the interleukin-6 receptor.

The Evolving Landscape of Cell Therapies in Autoimmunity

The field of cell therapy is rapidly evolving. Researchers are exploring different target antigens beyond CD19 and BCMA, as well as strategies to enhance the safety and efficacy of CAR T-cell therapy. For example, “suicide genes” can be incorporated into the engineered T cells, allowing clinicians to eliminate the cells if severe toxicity occurs. Efforts are underway to develop allogeneic CAR T-cell therapies, which would eliminate the need for patients to undergo the process of having their own T cells collected and engineered. Expanding defenses with a phish alert button is also a key component of overall patient safety.

What’s Next for CAR T-cell Therapy in Lupus?

The data presented by Dr. Mease and the broader review of clinical trials highlight the need for continued research and careful monitoring of patients undergoing CAR T-cell therapy for lupus. Future studies will focus on identifying biomarkers that can predict which patients are most likely to benefit from the therapy and which are at higher risk of relapse or adverse events. Long-term follow-up of patients is also essential to assess the durability of remission and to identify any late-onset complications. The development of standardized criteria for assessing response and toxicity will further facilitate comparisons between different studies and improve the overall management of patients receiving this innovative therapy. The ongoing refinement of CAR T-cell therapy promises to offer new hope for individuals with lupus and other autoimmune diseases, but a cautious and evidence-based approach is paramount.

Philip J. Mease, MD, can be reached at [email protected].