CCTx-001, A FIRST IN CLASS AUTOLOGOUS ANTI-IL-1RAP CAR T-CELL THERAPY FOR THE TREATMENT OF RELAPSED/REFRACTORY AML
Topic:
Acute myeloid leukemia – Biology & translational research
Background:
Relapsed/refractory acute myeloid leukaemia (r/AML) poses significant therapeutic challenges, necessitating novel treatment strategies. While allogeneic hematopoietic stem cell transplantation remains the only curative option, outcomes for r/r AML are poor, highlighting the urgent need for effective therapies. Interleukin-1 Receptor Accessory Protein ( IL-1RAP ) is specifically and significantly up-regulated on AML cells and correlates with poor prognosis and MRD in AML patients, supporting its potential as a therapeutic target.
Aims:
To develop a first in class autologous anti-IL-1RAP CAR T-Cell therapy, to demonstrate its preclinical activity, and to evaluate its safety and clinical activity in adult patients with r/r AML.
Methods:
We have developed a 3rd generation autologous CAR T-cell therapy ( CCTx-001), engineered to express a novel IL-1RAP-directed CAR. CCTx-001 is designed to specifically target AML blasts and leukemic stem cells while sparing healthy hematopoietic stem cells and circulating immune cells. CCTx-001 incorporates a proprietary anti-IL-1RAP scFv, an IgG1 hinge region, CD28 and 4-1BB co-stimulatory domains and the CD3ζ signalling domain. CCTx-001 was tested in different in vitro and in vivo AML models.
Results:
CCTx-001 selectively eliminates IL-1RAP+ cells in vitro in an antigen-specific manner. CCTx-001 rapidly induces interferon gamma release and cytotoxicity of IL-1RAP+AML cells with varying expression levels of IL-1RAP, but not in IL-1RAP- control cells. In addition, CCTx-001 inhibits the in vivo tumour growth of AML cells expressing low to high level IL-1RAP. Moreover, the functionality of CCTx-001 remains unaffected by soluble IL-1RAP. Biodistribution analyses further confirm the expansion and persistence of CCTx-001 CAR T-cells in vivo, correlating with a reduction in AML cell levels in murine models
Summary/Conclusion:
CCTx-001 is a potential promising therapy for relapsed/refractory AML, offering targeted and effective treatment options for patients in need. Based on this data, the RESOLVE AML 001 study (NCT06281847) is being conducted. This study is a seamless adaptive Phase 1/2 trial evaluating CCTx-001 in adult patients with r/r AML across 4 dose levels (0.5-10×106/kg) using a BOIN design. Patients will receive lymphodepletion with fludarabine (30 mg/m2/day for 4 days) and cyclophosphamide IV ( 300 mg/m2/day for 3 days). The enrolment for RESOLVE-AML 001 trial is set to begin in Q2 2024, with completion expected by Q3 2027.
Keywords:
CAR-T, Relapsed acute myeloid leukemia, AML, Clinical trial
