First-in-human study of CTX130, a CD70-directed allogeneic CAR T therapy, in adult T-cell leukemia/lymphoma: Clinical and genomics findings from a long-term follow-up of subgroup analysis from the cobalt-LYM Phase 1 trial

Abstract

Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive malignancy of CD4+ T cells, linked to prior infection with human T-lymphotropic virus type I (HTLV-I). Relapsed ATLL is associated with a dismal prognosis and there are no established effective therapies. CD70 is an emerging immunotherapeutic target in ATLL, where it is aberrantly expressed and contributes to immune evasion, serving as a promising target for CAR-T cell therapy. Here, we report outcomes from six patients with relapsed/refractory ATLL who were treated with CTX130, an allogeneic CRISPR-Cas9-engineered CAR-T therapy targeting CD70, as part of the Phase 1 COBALT-LYM trial. Analyses included safety, therapeutic activity, and molecular correlates of response, with next-generation sequencing (NGS) data available for four patients. Methods Our study is based on a single-arm, open-label Phase I trial evaluating CTX130 in patients with T-cell malignancies conducted at centers across the USA, Australia, and Canada. Here, we report data from our Montefiore Medical Center cohort of patients with relapsed/refractory ATLL who had received ≥ one prior systemic therapy and had an ECOG performance status of 0-1. Eligible patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to CTX130 infusion, with repeat dosing permitted per protocol. The primary endpoint was safety, with secondary endpoints of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Additionally, four patients underwent mutational profiling by NGS at NeoGenomics to gain insight into the mutational landscapes relevant to ATLL biology and therapeutic response. Results Between August 28, 2020, and May 30, 2023, six patients with pre-treated ATLL from our center were enrolled in the COBALT-LYM trial and treated with CTX130. Long-term follow-up data was collected through July 2025. The median age at infusion was 54 years (range: 33-72), with a median of one prior line of therapy (range: 1-5). Two patients (29%) had the acute/leukemic subtype and five (71%) had the lymphomatous subtype, per Shimoyama criteria. CTX130 dose levelsranged from 3 ×10⁷ to 9×10⁸ CAR-T cells, and three patients received a second infusion. No cases of CRS or ICANS were observed. Other serious adverse events included infections and neutropenia. The ORR was 50% (3 out of 6 patients) with two patients achieving a complete response (CR) and one patient with a partial response (PR). As of May 30, 2023, the median PFS was 2.5 months and the mOS was 7.8 months. As of July 15, 2025, two of the six subjects were still alive, with the longest survival being 37.5 months. In addition, NGS was performed in four patients. In two patients with paired pre- and post-CTX130 infusion samples, changes in variant allele frequencies (VAFs) of several genes were observed, including the acquisition of new mutations and dynamic shifts in clonal architecture. Notably, one long-term survivor developed a STAT3 mutation post-treatment, which has previously been associated with favorable outcomes in ATLL. These findings suggest that ATLL may exhibit genomic plasticity and clonal adaptation under sustained immunological pressure, potentially contributing to more indolent disease phenotypes in select patients. Conclusions: Our subgroup analysis demonstrates that CTX130, an allogeneic CRISPR-Cas9-engineered CAR-T therapy targeting CD70, shows promising efficacy and a manageable safety profile in relapsed/refractory ATLL. An ORR of 50% was observed, which is notable given the historically poor outcomes in treating relapsed/refractory ATLL. Importantly, two patients remain long-term survivors, representing the first documented durable remissions observed in our center's ATLL CAR-T program. These findings support further development of CD70-directed CAR-T therapies, with next-generation CTX131 currently being evaluated in a follow-up clinical trial. We also provide evidence that CAR-T cell pressure can drive clonal evolution toward more favorable disease phenotypes. To our knowledge, this is the first and largest reported study of CRISPR-Cas9-modified allogeneic CAR-T cells in ATLL, demonstrating feasibility, manageable toxicity, and durable responses in a subset of patients. Our findings warrant larger studies to refine patient selection for CAR-T therapy and identify genomic predictors of benefit.