Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial

Abstract

Under compassionate use, chimeric antigen receptor (CAR) T cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIMs). Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T cell therapy (CABA-201) in the RESET-Myositis phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was observed. Creatine kinase levels decreased, and muscular strength improved post-infusion. Peripheral B cells were depleted rapidly following infusion, and the subject achieved peripheral B cell aplasia by day 15 post-infusion. Peripheral B cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline, whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4⁺ effector memory T cells and exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.

Graphical abstract

Figure 1

Systemic cellular, humoral, and clinical responses following CABA-201 cell therapy in an INMN subject (A) Gating schema used for B cell phenotype analyses in B, C, and CABA-201 cell phenotype analyses in Figure 2A. (B) B cells identified by flow cytometry at baseline through 16 weeks after CAR T cell infusion. B cells shown in oval gate as the percentage of live, single lymphocytes that are CD19⁺CD20⁺. (C) Maturation status of B cells as determined by flow cytometry at baseline through 16 weeks after CAR T cell infusion as determined by CD24 and CD38 expression. Subpopulation as follows: (I) memory B cells, (II) transitional naive (T1 and T2) B cells, (III) activated naive B cells, (IV) activated naive or activated memory B cells, (V) Plasmablasts or pre-plasmablasts. (D) B cell counts and serum BAFF levels from baseline through 16 weeks post-infusion overlaid as line plots. Left y axis represents serum BAFF levels in pg/mL (blue) and right y axis represents B cells counts as number of CD19⁺CD20⁺ cells/μL blood (orange). The x axis represents time in days from baseline through week 16 with the vertical gray shaded area indicating lymphodepletion in both (D, E, H, and I). (E) Leukocyte counts and serum IL-15 levels overlaid as line plots over time. Left y axis represents serum IL-15 levels in pg/mL (blue) and right y axis represents leukocyte counts as thousand cells/μL blood (orange). Serum levels of myositis-associated autoantibodies (F) and vaccine- or pathogen-associated antibodies (G) at baseline and 16 weeks after CAR T cell infusion. Antibodies measured by Luminex and represented as net median fluorescence intensity. (H) Serum levels of creatine kinase, a marker of skeletal muscle destruction, at baseline through 16 weeks post-infusion. (I) Disease activity assessed by manual muscle testing score 8 (MMT8) at baseline through 16 weeks post-infusion. For (D)–(G) data shown as mean ± SD of duplicate technical replicates.

Figure 2

CABA-201 drug product characterization and post-infusion pharmacokinetics and pharmacodynamics (A) Flow cytometric characterization of drug product. Top left: CAR⁺ (right gate) and CAR⁻ (left gate) T cells as a percentage of total CD3⁺ T cells. Top middle: CD4⁺ (y axis) versus CD8⁺ (x axis) CAR⁺ T cells. Top right: memory subsets of CAR T cells defined by CCR7 (y axis) and CD45RA (x axis). Populations represented as the percentage of CAR⁺ T cells that are T_EM (CD45RA^–CCR7^–), T_EMRA (CD45RA⁺CCR7^–), T_CM (CD45RA^–CCR7⁺), and T_SCM (CD45RA⁺CCR7⁺). (B) CABA-201 infusion product lysis of CD19⁺GFP⁺ target NALM6 cells. Cell lysis curves represented by number of GFP⁺ target cells over 120 h at effector to target ratios ranging from 0:1 to 1:1. (C) Pharmacokinetic response of CABA-201 in IMNM subject represented as number of CAR T cells/μL blood from baseline through 29 days post-infusion. (D) Flow cytometric characterization of CABA-201 at day 15. (E) Concentrations of IFN-γ, IP-10 (CXCL10), and IL-12p40 before and after CABA-201 infusion.