Tag Archives: CAR-T therapy

CAR T-cell Therapy: A Cure for Autoimmune Disease?

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  • F Muller et al. NEJM 2024; 390: 687-700. CD19 CAR T-Cell Therapy in Autoimmune Disease —A Case Series with Follow-up
  • JD Isaacs. NEJM 2024; 390: 758-759. (editorial) CAR T Cells — A New Horizon for Autoimmunity?

Methods: This case series enrolled 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with
fludarabine and cyclophosphamide. All patients were refractory to at least two conventional therapies.

Key findings:

  • Median follow-up was 15 months.
  • All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index.
  • Immunosuppressive therapy was completely stopped in all the patients without having relapses or worsening of their disease.

Some points from the editorial:

  • “Similar outcomes [as CAR T-cell infusion] can sometimes be achieved with autologous stem-cell transplantation but with a risk of substantial toxic effects and even death”
  • The editorial explains the potential mechanisms of how CD19 CAR T-cells therapy works in comparison to CD20 monoclonal antibodies like rituximab. “Whereas rituximab primarily depletes B cells with some secondary loss of plasmablasts, CD19 CAR T-cells have direct cytotoxicity for plasmablasts and many plasma cells.”
  • “The future trajectory of CAR T-cell therapy for autoimmunity will be driven by efficacy, safety, cost, and acceptability… if extended follow-up reinforces the current data, the benefit-to-risk ratio is likely to prove acceptable to both physician and patient, at least in certain cases of refractory disease. Therapy is individualized, difficult to scale, and expensive.”
  • Long-term safety for CAR T therapy is still poorly understood. Recently a report identified secondary cancers in patients who have received this treatment for oncologic diseases (Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med 2024;390:584-586)

My take: For now, almost all autoimmune diseases will be treated with indefinite conventional agents. Nevertheless, it is a hopeful step that a cure for these diseases may be possible.

Related blog post: Great Story -How CAR-T Came About

Ram Head Trail, St John

Great Story -How CAR-T Came About

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While chimeric antigen receptor T-cell (CAR-T) therapy does not have much to do with pediatric gastroenterology, the development of this therapy, described recently (L Rosenbaum NEJM 2017; 377: 1313-5), holds lessons about perseverance and chance that are widely applicable.

CAR-T involves genetically engineering the patient’s own T cells to kill tumor cells. It recently received FDA approval to treat patients up to 25 years of age with relapsed or refractory acute lymphoblastic leukemia.

The story of the survival of Emily Whitehead, the index patient for this therapy, is suitable for Hollywood.  The groundwork for this very expensive treatment dates back to 1893 with William Coley’s recognition of the immune system’s potential for treating cancer –he injected streptococcus into an inoperable osteosarcoma and observed tumor shrinkage.

Key Steps in this Story:

  1. University of Pennsylvania’s immunologist Carl June spent his career working on CAR-T. His wife died of ovarian cancer in 2001 and he resolved to develop this emerging immunotherapy that he had wanted for her.
  2. Barbara and Edward Netter provided key funding for this project in 2008.  They too had lost a close family member to cancer.
  3. Emily Whitehead nearly died due to CAR-T therapy which triggered cytokine-release syndrome, which was not a recognized entity at the time.  In part due to chance, extremely high levels (>1000-fold) of interleukin-6 (IL-6) were detected quickly due to the ability of the institution and prodding by the researchers to their colleagues.  This allowed the experimental use of tocilizumab, a monoclonal antibody that targets IL-6.
  4. Her survival helped reenergize this line of research.

My take (borrowed from author): “Therapeutic advances are motivated by more than money –that it’s the hope, vision, and perseverance of both patients and investigators that made this …possible.”

Acute esophageal necrosis ina a 63 year-old that resolved with conservative treatment.  “The cause is unknown..[it] occurs most commonly in the distal third of the esophagus, which is hypovascular” often in the setting of chronic disease.