Biology subjects

Velasco-Hernandez, T.

Publications and source records attributed to Velasco-Hernandez, T..

3 recordsLinked to original sources

bioRxiv2025

A platform of robust patient-derived leukemia models covering subgroups for which no cell lines exist

Preclinical cancer research requires robust model systems, especially for poor prognosis entities like acute myeloid leukemia (AML), a highly aggressive blood cancer. Here, primary tumor cells from 137 AML patients of all age groups were transplanted into immune compromised mice to generate patient-derived xenografts (PDX). From these, 23 models enable robust, virtually endless serial re-transplantation and are amenable to lentiviral genetic engineering (*PDX AML models). These models primarily originate from patients with highly aggressive, relapsed disease. Comprehensive genomic, transcriptomic, and epigenomic analyses confirmed that they replicate primary AML biology more faithfully than conventional cell lines. Notably, *PDX AML models include AML subgroups that are underrepresented or absent in existing model systems, such as cytogenetically normal or IDH1/2-mutant AML. They withstand freeze-thaw cycles, making them suitable for broad distribution and reproducibility across research institutions. Luciferase-based in vivo imaging enables real-time monitoring of tumor progression and treatment responses in preclinical trials. Surprisingly, long-term treatment, including repeated cytarabine therapy over a period of one year, showed a gradual reduction in leukemia cell proliferation, which decreased continuously after each treatment block. Collectively, our *PDX models represent a robust, versatile, and relevant platform that holds great promise to accelerate translational research for the benefit of cancer patients. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/677299v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1ead31eorg.highwire.dtl.DTLVardef@1ca702corg.highwire.dtl.DTLVardef@18a7137org.highwire.dtl.DTLVardef@edbe6_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIWe present new robust AML PDX models covering subgroups for which no cell lines exist for use in various ex vivo and in vivo applications. C_LIO_LI*PDX models enable serial transplantation, genetic engineering and better representation of primary AML biology than cell lines. C_LIO_LIOne-year in vivo trials mimicking clinical chemotherapy showed surprising gradual decline in leukemia growth after each treatment block. C_LI

cancer biology↗

bioRxiv2024

CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by high rates of induction failure and relapse, and effective targeted immunotherapies are lacking. Despite promising clinical progress with genome-edited CD7-directed CAR-T cells, which present significant logistical and regulatory issues, CAR-T cell therapy in T-ALL remains challenging due to the shared antigen expression between malignant and healthy T cells. This can result in CAR-T cell fratricide, T cell aplasia, and the potential for blast contamination during CAR-T cell manufacturing. Recently, CAR-T cells have been described that target non-pan-T antigens, absent on healthy T cells but expressed on specific T-ALL subsets. These antigens include CD1a (NCT05679895), which is expressed in cortical T-ALL, and CCR9. We show that CCR9 is expressed on >70% of T-ALL patients (132/180) and is maintained at relapse, with a safe expression profile in healthy hematopoietic and non-hematopoietic tissues. Further analyses showed that dual targeting of CCR9 and CD1a could benefit [~]86% of patients with T-ALL, with a greater blast coverage than single CAR-T cell treatments. We therefore developed, characterized, and preclinically validated a novel humanized CCR9-specific CAR with robust and specific antileukemic activity as a monotherapy in vitro and in vivo against cell lines, primary T-ALL samples, and patient-derived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR-T cells, particularly in T-ALL cases with phenotypically heterogeneous leukemic populations. Dual CCR9/CD1a CAR-T therapy may prevent T cell aplasia and obviate the need for allogeneic transplantation and regulatory-challenging genome engineering approaches in T-ALL.

immunology↗

bioRxiv2022

A comprehensive single-cell expression atlas of human AML leukemia-initiating cells unravels the contribution of HIF pathway and its therapeutic potential

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML), and is driven by rare therapy-resistant leukemia-initiating stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling keeps cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to AML-LSC function and chemoresistance and is a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we provide a comprehensive single-cell expression atlas (119,000 cells) of AML cells and AML-LSCs in paired diagnostic-relapse samples from risk-stratified patients with AML. The HIF/hypoxia pathway is attenuated in AML-LSCs compared with differentiated AML cells, but is enhanced when compared with healthy hematopoietic cells. Accordingly, chemical inhibition cooperates with standard-of-care chemotherapy to impair leukemogenesis, substantially eliminating AML-LSCs. These findings support the HIF pathway as a stem cell regulator in human AML, and reveal avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

cancer biology↗