CD123-CAR T cell therapy / St. Jude Children's Research Hospital - LARVOL DELTA

Dual CD123 and B7-H3 CAR T Cells Potentiate Immune Responses and Remodel the Tumor Microenvironment in Pediatric Gliomas (SNO 2025) - "In vivo, CD123 CAR T-cells were administered intratumorally as monotherapy or in combination with B7-H3 CAR T-cells. Targeted depletion of CD123+ TAMs enhances B7-H3 CAR T-cell efficacy by mitigating immunosuppressive signaling while preserving beneficial myeloid support. This dual-targeting strategy offers a mechanistically guided approach to overcoming TME-driven resistance in DIPG and other pHGG."

Biomarker • CAR T-Cell Therapy • Clinical • Tumor microenvironment • Brain Cancer • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • CD123 • CD276 • IL3RA

Dual CD123 and B7-H3 CAR T Cells Potentiate Immune Responses and Remodel the Tumor Microenvironment in Pediatric Gliomas (SNO 2025) - "In vivo, CD123 CAR T-cells were administered intratumorally as monotherapy or in combination with B7-H3 CAR T-cells. Targeted depletion of CD123+ TAMs enhances B7-H3 CAR T-cell efficacy by mitigating immunosuppressive signaling while preserving beneficial myeloid support. This dual-targeting strategy offers a mechanistically guided approach to overcoming TME-driven resistance in DIPG and other pHGG."

Biomarker • CAR T-Cell Therapy • Clinical • Tumor microenvironment • Brain Cancer • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • CD123 • CD276 • IL3RA

Dual CD123 and B7-H3 CAR T Cells Potentiate Immune Responses and Remodel the Tumor Microenvironment in Pediatric Gliomas (WFNOS 2025) - "In vivo, CD123 CAR T-cells were administered intratumorally as monotherapy or in combination with B7-H3 CAR T-cells. Targeted depletion of CD123+ TAMs enhances B7-H3 CAR T-cell efficacy by mitigating immunosuppressive signaling while preserving beneficial myeloid support. This dual-targeting strategy offers a mechanistically guided approach to overcoming TME-driven resistance in DIPG and other pHGG."

Biomarker • CAR T-Cell Therapy • Clinical • Tumor microenvironment • Brain Cancer • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • CD123 • CD276 • IL3RA

Dual CD123 and B7-H3 CAR T Cells Potentiate Immune Responses and Remodel the Tumor Microenvironment in Pediatric Gliomas (WFNOS 2025) - "In vivo, CD123 CAR T-cells were administered intratumorally as monotherapy or in combination with B7-H3 CAR T-cells. Targeted depletion of CD123+ TAMs enhances B7-H3 CAR T-cell efficacy by mitigating immunosuppressive signaling while preserving beneficial myeloid support. This dual-targeting strategy offers a mechanistically guided approach to overcoming TME-driven resistance in DIPG and other pHGG."

Biomarker • CAR T-Cell Therapy • Clinical • Tumor microenvironment • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • CD123 • CD276 • IL3RA

CD123-CAR T Cells Manufactured in the Presence of Dasatinib Induce High Grade CRS and/or IEC-HS without Improving Efficacy in Pediatric Patients with Recurrent/Refractory Leukemia (ASH 2024) - "We previously reported (Naik et al, Blood 2022, 140 (Supplement 1) : 4584-5) that infusion of CD123-CAR T cells after lymphodepleting chemotherapy with fludarabine and cyclophosphamide was well tolerated, with transient fevers representing grade 1 cytokine release syndrome (CRS) and without dose limiting toxicities...All DL4 patients required multiple doses of immune modulatory agents including tocilizumab, steroids and emapalumab. One patient also received ruxolitinib, anakinra and etanercept without benefit, and died of cardiorespiratory failure...Our findings are in contrast with CAR.dasa T-cell products that target other antigens. While additional mechanistic studies are in progress, our results highlight that dasatinib cannot be considered a universal agent to improve the effector function of CAR T cells for hematological malignancies."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Immunology • Leukemia • Oncology • Pediatrics • Rare Diseases • CASP3 • CASP7 • CD123 • CSF2 • ENTPD1 • HAVCR2 • IFNG • IL10 • IL3RA • IL6 • PD-1 • TNFA

Dual CD123/B7-H3 CAR T Cell Therapy Reprograms the Tumor Microenvironment and Enhances Immunity in DIPG (SITC 2025) - "Endpoints included TAM depletion, TME remodeling, tumor burden, and survival.Results In vitro, M2 macrophages suppressed B7-H3 CAR T cell proliferation, persistence, and cytokine secretion; these effects were reversed by co-treatment with CD123 CAR T cells. Dual targeting of CD123+ TAMs and B7-H3+ tumor cells reprograms the DIPG TME and enhances CAR T-cell function by overcoming immunosuppressive barriers while preserving supportive immune populations. This strategy offers a promising mechanistic approach to improving CAR T therapy in DIPG."

Biomarker • CAR T-Cell Therapy • Tumor microenvironment • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • CD123 • CD276 • IL3RA

CD123-Directed T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: St. Jude Children's Research Hospital | N=56 ➔ 108

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • CD123 • IL3RA

CD123-Directed T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: St. Jude Children's Research Hospital | N=32 ➔ 56 | Trial completion date: Jul 2026 ➔ Jul 2030 | Trial primary completion date: Jul 2025 ➔ Jul 2029

Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • CD123 • IL3RA

High Grade CRS and/or IEC-HS in Pediatric Patients with Recurrent/Refractory Leukemia Receiving CD123-CAR T Cells Manufactured in the Presence of Dasatinib (TCT-ASTCT-CIBMTR 2025) - "All DL4 patients required multiple doses of immune modulatory agents including tocilizumab, steroids and emapalumab. One patient also received ruxolitinib, anakinra and etanercept without benefit, and died of cardiorespiratory failure...Our findings are in contrast with CAR.dasa T-cell products targeting other antigens. Thus, reprogramming CAR T cells with dasatinib cannot be considered a universal approach to improve their antitumor activity."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Immunology • Leukemia • Oncology • Pediatrics • Rare Diseases • CD123 • CSF2 • ENTPD1 • HAVCR2 • IFNG • IL10 • IL3RA • IL6 • PD-1 • TNFA

CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: St. Jude Children's Research Hospital | Active, not recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • CD123 • IL3RA

CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Jul 2025 ➔ May 2026 | Trial primary completion date: Jul 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • CD123 • IL3RA

CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • CD123 • IL3RA

Mouse CD123-CAR T Cells Elicit Robust Anti-AML Activity without HSC Toxicity in Syngeneic Models (ASGCT 2023) - "Our findings reveal that the TME of our immune competent leukemia CAR T cell therapy models recapitulate human disease, showing an increase in dying tumor cells within the bone marrow of mice in the treated group, with a number of other populations (e.g. dendritic cells, regulatory T cells) approximating the tumor-only microenvironment profile.We have developed the first functional mCD123-CAR T cells targeting mouse AML and ALL and have shown their activity in immunocompetent models, with potent anti-leukemic activity in vitro and in vivo with minimal toxicity. Our model will provide insight into the impact of the AML TME on CAR T cell functionality and inform future strategies to improve CAR T cells in the immunosuppressive TME."

CAR T-Cell Therapy • Preclinical • Acute Myelogenous Leukemia • ABL1 • BCR • CD123 • KDM5A • NUP98

Preliminary Results from a Phase 1 Trial Showing Safety and Anti-Leukemic Activity of CD123-CAR T Cells in Pediatric Patients with AML (TCT-ASTCT-CIBMTR 2023) - P1 | "Patients received Fludarabine/Cyclophosphamide prior to a single CAR T cell infusion. Conclusions Our initial clinical experience with CD123-CAR T cells demonstrates feasibility, safety, and evidence of anti-leukemic activity. Upcoming CD123-CAR T cell products will be manufactured with dasatinib to limit T cell differentiation and exhaustion thereby enhancing our CD123-CAR T cell therapy approach."

CAR T-Cell Therapy • Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Oncology • Pediatrics • CD123 • CD20 • CD4 • ENTPD1 • HAVCR2 • PD-1

Safety and Anti-Leukemic Activity of CD123-CAR T Cells in Pediatric Patients with AML: Preliminary Results from a Phase 1 Trial (ASH 2022) - P1 | "Patients received lymphodepleting chemotherapy with Fludarabine and Cyclophosphamide followed by a single CAR T cell infusion. Conclusions Our initial clinical experience with CD123-CAR T cells for pediatric patients with r/r AML demonstrates feasibility, safety, and evidence of anti-leukemic activity. Upcoming CD123-CAR T cell products will be manufactured in the presence of dasatinib to limit T-cell differentiation and exhaustion as we continue to explore our CD123-CAR T cell therapy approach for pediatric r/r AML."

CAR T-Cell Therapy • Clinical • IO biomarker • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Oncology • Pediatrics • Transplantation • CCR7 • CD123 • CD20 • CD8 • ENTPD1 • HAVCR2 • IL15 • IL6 • PD-1

LigandCD70.CAR As a Platform for Dual-Targeting CAR T Cells for Acute Myeloid Leukemia (ASH 2022) - "We evaluated the LigandCD70.CAR in combination with a CLL-1.CAR and a CD123.CAR, as both have shown preclinical efficacy and are currently being tested in clinical trials...The simultaneous targeting of two AML antigens may thus mitigate the risk of antigen-negative relapse. These data indicate that the Ligand70.CAR combined with other AML targeting CARs could be an effective therapeutic option for AML."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Oncology • CD123 • CD27 • CD70

Establishing Immunocompetent Leukemia Models to Investigate the Impact of CAR T Cells on the Immune Microenvironment and Bone Marrow Niche (ASH 2022) - "To date, preclinical evaluation of CD123-CAR T cells have used human xenograft models, which lack a functional immune system...To determine in vivo toxicity of mCD123-CAR T cells, non-tumor bearing C57BL/6 mice were given 200 mg/kg cyclophosphamide (Cy) and one effector T cell infusion generated from transgenic luciferase mice (N=5) and monitored by bioluminescence imaging for 10 days...mCD123-CAR T cells demonstrated potent anti-leukemic activity in vitro and have anti-leukemia activity with minimal to no toxicity in vivo. These findings will provide insight into the impact of the AML TME on CAR T cell functionality, and inform future strategies to improve CAR T cells in the immunosuppressive TME."

CAR T-Cell Therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CD123 • KDM5A • NUP98

Structural Changes in Peptide-Scfv Bispecific Cars Impact T Cell Effector Function Against Acute Myeloid Leukemia (ASH 2022) - "A single infusion of 3x106 GRP78-CAR, CD123-CAR, B7H3-CAR or bispecific 78.123- and 78.B7H3-CAR T cells had potent in vivo anti-AML activity (p<0.05, N=5/group). This has been rarely observed for scFv-scFv bispecific CARs, in which normally one of the scFvs dominate. Thus, peptide-scFv CARs present a promising bispecific CAR design to prevent immune escape for a broad range of malignancies."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • B2M • CD123 • CD276 • CD8 • HSPA5

CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: St. Jude Children's Research Hospital; Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML) (clinicaltrials.gov) - P1; N=32; Not yet recruiting; Sponsor: St. Jude Children's Research Hospital

New P1 trial