Allogeneic CAR-T therapy AVC-201 in AML positive for CD123

Abstract

Abstract Introduction: CAR-T therapy in AML has been limited by the absence of ideal target antigens, heterogeneity of the disease, and aggressive clinical course. CD123 is a promising target, overexpressed on leukemic blasts and leukemic stem cells (LCS) in most AML patients. However, CD123 is also expressed on normal hematopoietic progenitors and endothelial cells, and its targeting has been associated with significant on-target/off-tumor toxicities. AvenCell has previously demonstrated clinical proof-of-concept using a switchable autologous CD123-directed CAR-T cell product (AVC-101; EudraCT 2019-001339-30, NCT04230265), showing rapid mitigation of acute toxicities, effective repeated CAR-T cell expansion, durable clinical responses, and a favorable safety profile. The AVC-201 platform represents a next-generation allogeneic, modular CAR-T technology incorporating a controllable on/off switch mechanism via a targeting module (TM), an adapter enabling CAR activation, analogous to that employed with AVC-101 but with the further advantage of an immediate off-the-shelf treatment using healthy donor T cells. Methods: Adults with recurrent/relapsed (RR) or MRD+ AML were eligible if they met key inclusion criteria, including ECOG performance status ≤1, CD123 expression on ≥20% on leukemic blasts, adequate organ function, lack of available SoC treatment options, and HLA-B and -C compatibility with available allogeneic CAR-Ts. The ongoing dose escalation follows a classical 3 + 3 design, with a CAR-T cell dose of 500 million and escalating TM doses (2.4, 4.8, and 9.6 mg/day). Lymphodepletion (LD) consists of fludarabine and cyclophosphamide for three days. A single infusion of the cellular product Allo-RevCAR01-T is administered. The TM is delivered via continuous intravenous infusion over a 20-day induction cycle and subsequent 12-day consolidation cycles, with recovery intervals of 7-14 days between cycles. Results: Dose escalation has reached dose level (DL) 12 (500 million Allo-RevCAR01-T cells plus 2.4 mg/day dose of R-TM123). Higher dose levels (DL15 and DL18) remain under investigation. A total of 10 patients have received the induction treatment cycle, and three patients have completed at least one consolidation cycle. The median age of the treated participants was 62.5 years (range 43-74 years). The enrolled cohort was heavily pretreated, with a median of 5.5 prior lines of therapy. Half of the patients (5/10) were classified as adverse risk and half (5/10) as intermediate risk at screening, according to European LeukemiaNet (ELN) 2022 criteria. No dose-limiting toxicities (DLTs) or treatment-related adverse events (TRAEs) beyond Grade 2 have been observed to date, regardless of patient age or prior treatment intensity. Cytokine release syndrome (CRS) was reported in six patients, all Grade 1–2. Expansion of the Allo-RevCAR01-T cels was robust and appears superior to that seen with autologous CAR-T cells in AVC-101, with the highest peak at 73,000 RevCAR-T/ml of blood on day 13. Notably, a 74-year-old patient with 7 prior lines of therapy achieved a CRi, including a reduction in BM blasts from 58% at baseline to 2.5% at the end of the induction cycle. Re-administration of the TM in this patient triggered functional reactivation of RevCAR cells, evidenced by a Grade 2 CRS on Day 2 of the second TM cycle. Comprehensive safety data and available expansion, persistence, and clinical efficacy data from the Phase 1a dose escalation will be presented at the meeting. Conclusions: AVC-201 has shown a favorable safety and tolerability profile, with no dose-limiting toxicities observed so far. The RP2D has yet to be established. Repeated administration of the targeting module has led to clinically meaningful anti-leukemic activity, including a CRi in a heavily pretreated patient with a significant disease burden at baseline. The switchable, modular AVC-201 platform enables rapid deactivation of CAR-T cells, offering a built-in safety mechanism. Based on encouraging safety and preliminary signals of biological activity and clinical efficacy, the study is planned to advance into the Phase 1b dose-expansion stage following completion of the ongoing Phase 1a dose-escalation phase.