A team of researchers presented preclinical validation of a novel chimeric antigen receptor (CAR) T-cell therapy showing potent and highly selective targeting of myeloproliferative neoplasms (MPNs) driven by mutant calreticulin (mutCALR).
The results were presented at a poster session by Alexandros Rampotas, MBBS, MRCP, University of College London Cancer Institute in the United Kingdom, during the 66th American Society of Hematology Annual Meeting and Exposition held in San Diego, California.
The novel CAR-T demonstrated robust and highly selective eradication of low- and high- mutCALR expressing human cell lines in vitro, and CAR-T administration led to a dramatic reduction in leukemic burden and improved survival in NOD scid gamma (NSG) mouse xenografted with mutCALR-positive, TpoR-positive acute myeloid leukemia (AML) cells.
To evaluate CAR-T in the relevant fibrotic tumor microenvironment (TME), the researchers used scRNAseq to analyze Induced pluripotent stem cells (iPSC)-derived human bone marrow (BM) organoids co-engrafted with CAR-T cells and patient-derived CD34-positive hematopoietic stem and progenitor cells (HSPCs).
CAR-T efficacy was tested on CD34-positive HSPCs from patients with MPN (n=12), including myelofibrosis, essential thrombocythemia, and accelerated/blast phase MPN (AP/BP-MPN) with both ins5 and del52 variants (n=8) in 2D and 3D cultures.
Excellent depletion of HSPCs and extreme specificity was observed, with minimal killing of JAK2V617F-positive samples (n=4), the investigators observed.
The BM infiltration and near-complete ablation of leukemia confirmed the efficacy of the CAR-T against mutCALR-positive malignancies in vivo. CAR-Ts exposed to mutCALR-positive primary cells in the relevant TME had a twofold expansion of CD8-positive effector memory cells.
“This study…presents the first use of human organoids to evaluate immunotherapies in the relevant human tissue environment, including features of the TME, validating this as a powerful platform for pre-clinical development of targeted therapies across blood cancers,” the authors wrote.
Reference
Rampotas A, Wong Z, Gannon I. Development of a first-in-class CAR-T therapy against calreticulin-mutant neoplasms and evaluation in the relevant human tissue environment. Abstract #871. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; San Diego, California; December 7-10.
