A trial of hypoimmune allogeneic CD19-targeting T cells in refractory systemic lupus erythematosus

Chimeric antigen receptor (CAR)-T cell therapy targeting B cells has demonstrated efficacy in severe autoimmune diseases, including systemic lupus erythematosus (SLE) [1, 2]. There are, however, important challenges associated with CAR-T cell therapy, including its high cost, lengthy and complex manufacturing process, and the necessity for patients to temporarily discontinue immunosuppressive therapy, which might pose major risks [3]. Findings from a previous study demonstrated that a T-cell receptor (TCR) complex–based chimeric antigen receptor, termed synthetic TCR and antigen receptor (STAR), improves antigen sensitivity, proliferation and persistence compared with classical CAR-T cells, and has lower dysfunction and toxicity [4]. A recently published first-in-human Phase I trial aimed to explore the safety, efficacy and mechanisms of STAR-T cells application in patients with severe refractory SLE and lupus nephritis (LN) [5]. The trial included five patients with refractory SLE and LN. The primary endpoints were safety and SLE responder index 4 (SRI-4) at Month 3. Secondary endpoints included SRI-4 at Month 6, other clinical remission measures and several patient-reported outcomes. Briefly, YTS109, a CD19-targeted STAR-T cell product, was generated from the peripheral blood mononuclear cells of a healthy donor through a multistep process, most importantly a series of genetic modifications performed using CRISPR-Cas9 to knock out genes responsible for graft-versus-host disease (GVHD), immune recognition and T-cell persistence, namely TCRαβ, PD1, HLA-A, HLA-B and CIITA, and inserting the STAR construct into TRAC (T-cell receptor alpha constant), a gene region for the TCR (Fig. 1A). All immunosuppressive therapy was discontinued before administering YTS109, with tapering to a minimal physiologically dependent dose being performed in patients on high-dose glucocorticoids. After lymphodepletion with fludarabine and cyclophosphamide, the patients received a single YTS109 infusion on Day 0. (A) Key steps in the production of YTS109: Step 1, T cells are isolated from a healthy donor; Step 2, knockout of genes encoding HLA A/B, CIITA, TRAC and PD-1; Step 3, site-specific knock in of anti-CD19 STAR into the TRAC locus using adenovirus vector; Step 4, in vitro cell expansion and magnetic-activated cell sorting for TCR− cells; and Step 5, treatment is given to patients. (B) All patients reached SRI-4 by Month 3 (primary efficacy endpoint) and maintained it by Month 6, and no patient had severe adverse events (co-primary safety endpoint). CD, cluster of differentiation; CIITA, class II; major histocompatibility complex; transactivator; CRS, cytokine release syndrome; HLA, human leukocyte antigen; M, month; MACS, magnetic-activated cell sorting; PD-1, programmed cell death protein 1; SAE, severe adverse event; SR4, SLE responder index. All patients achieved SRI-4 at Month 3 (primary efficacy endpoint) with a maintained response up to Month 6. Disease activity decreased in all patients, with four reaching a Safety of Estrogen in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of zero. One patient experienced a mild flare-up. There were no serious adverse events (co-primary safety endpoint), including signs of GVHD (Fig. 1B). Aside from these, there were several findings regarding secondary and exploratory endpoints, most importantly: (i) B-cell loss was rapid and persisted for 1–2 months with all patients reconstituting B cells afterwards; (ii) some patients achieved clearance of anti-dsDNA maintaining near-zero levels throughout the study and normalization of C3 and C4 serum levels; (iii) most patients had substantial 24-h proteinuria levels at baseline, with two patients achieving complete renal remission (