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2076 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

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Swati Naik, MBBS1, Madden Renee, MD2*, Aimee C. Talleur, MD2, Rebecca Epperly, MD2, Timothy Lockey, PhD3*, Jennyfer Bran, MD4*, Liqing Tian5*, Ying Li6*, Dinesh Keerthi2*, Alexandra Boyd7*, Amanda Lipsitt4*, Jeffrey E. Rubnitz, MD, PhD8, Jeffery M Klco, MD, PhD9, Barry Shulkin, MD10*, Sarah Schell5*, Polly Adams7*, Jeoungeun John Park4*, Janice Riberdy, PhD11*, Na Shang4*, Jaquelyn T. Zoine, PhD5, Raghuvaran Shanmugam12*, Chris Nevitt, PhD2*, Unmesha Thanekar7*, Jennifer Wallace4*, Elaine Harstead4*, Scott Perry7*, Catherine Willis5*, Jean-Yves Metais, Ph.D.2*, Deanna M. Langfitt, PhD13*, Sheng Zhou, PhD14, Salem M. Akel, PhD15*, Caitlin Zebley, MD, PhD6*, Jeremy Chase Crawford, PhD12*, Benjamin Youngblood, PhD16*, Paul G. Thomas, PhD12*, Frank Fazio5*, Brandon M Triplett, MD2*, Stephen Gottschalk, MD2 and Mireya Paulina Velasquez, MD2

1Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TX
2Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
3Department of Therapeutics Production and Quality, St. Jude Children's Research Hospital, Memphis, TN
4ST. JUDE CHILDREN'S RESEARCH HOSPITAL, Memphis, TX
5St. Jude Children's Research Hospital, Memphis, TN
6Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN
7St Jude Children's Research Hospital, Memphis, TN
8Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
9Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
10Department of Diagnostic Imaging, St. Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, TN
11Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
12Department of Host Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN
13Department of Bone Marrow Transplant and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
14Experimental Cellular Therapeutics Laboratory, St. Jude Children's Research Hospital, Memphis, TN
15St. Jude Children’s Research Hospital, Memphis, TN
16St Jude Children's Research Hospital, Memphis

Background

We are conducting a Phase 1 clinical study to evaluate the safety and efficacy of escalating doses of autologous CD123-CAR T cells for pediatric patients with r/r CD123-positive AML or ALL. 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. We observed anti-AML activity as evidenced by responses in two out of six infused patients albeit with limited CAR T-cell expansion. Mechanistic studies revealed that CD123-CAR T cells were predominantly effector memory and expressed markers associated with T cell exhaustion (TIM3, PD1 or CD39). This phenotype was completely reversed by generating CD123-CAR T cells in the presence of dasatinib (CD123-CAR.dasa T cells), a multikinase inhibitor known to transiently inhibit CAR signaling. Based on these findings, we modified the CD123-CAR T cell production for our protocol and now report on an extended comparison of CD123-CAR and CD123-CAR.dasa T cells and on the clinical course of patients who were infused with CD123-CAR.dasa T cells.

Methods and Results

Single cell RNA seq analysis revealed that CD123-CAR.dasa T cells had upregulated IFNa signaling pathways in comparison to CD123-CAR T cells. In addition, they were in a less differentiated state as judged by a methylation-based multipotency index, exhibited preferential oxphos metabolism, and had increased apoptosis after initial antigen exposure as evidenced by caspase 3/7 activity.

Six patients (5 AML, 1 ALL) were infused with CD123-CAR.dasa T cells on dose level (DL) 3 (3x106/kg) or 4 (1x107/kg). All patients developed high-grade fevers within 3 hours of infusion. All 3 patients on DL3 developed grade 2 CRS that responded to a single dose of tocilizumab. On DL4, all 3 patients presented with grade 4-5 CRS with evidence of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). 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. Autopsy results were consistent with CRS and no evidence of on target/off cancer toxicity. Patients post CD123-CAR.dasa T-cell infusion had significantly higher levels of circulating chemokines and cytokines, including IFNg, GMCSF, IL10, IL6 and TNFa, in comparison to patients who had received CD123-CAR T cells. Peak expansion of CD123-CAR.dasa T cells, as judged by qPCR analysis, was higher in comparison to CD123-CAR T cells. However, this did not translate into improved anti-leukemia activity as no patients had a response.

Conclusions

CD123-CAR T cells generated in the presence of dasatinib induced high grade CRS and/or IEC-HS without improved anti-leukemia activity. 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.

Disclosures: Rubnitz: Biomea Fusion, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thomas: Cytoagents: Membership on an entity's Board of Directors or advisory committees; Shennon Bio: Membership on an entity's Board of Directors or advisory committees; PACT Pharma: Consultancy, Other: travel support; Sanofi: Consultancy, Other: travel support ; JNJ: Consultancy, Other: travel support; Pfizer: Consultancy, Other: travel support; Immunoscape: Membership on an entity's Board of Directors or advisory committees; 10X genomics: Consultancy, Other: travel support; Merck: Consultancy, Other: travel support; Illumina: Consultancy, Other: travel support. Gottschalk: Immatics: Other: DSMB; Be Biopharma: Consultancy; CARGO: Consultancy; T cell and/or gene therapy for cancer: Other: Patent and patent applications.

*signifies non-member of ASH