CART123 / University of Pennsylvania - LARVOL DELTA

CD123-directed chimeric antigen receptor T-cell (CART123) therapy for relapsed/refractory pediatric acute myeloid leukemia (ASH 2025) - P1 | "LDregimens included fludarabine and cyclophosphamide with (n=3) or without (n=4) azacitidine...Treatment for toxicity includedtocilizumab, steroids and anakinra...Detailed molecular characterization is underway tobetter understand response mechanisms. Future investigation of CART123 will continue dose explorationand evaluate co-therapy with cytokine blockade."

CAR T-Cell Therapy • Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Pediatrics • CD123 • CSF2 • CXCL9 • IFNG • IL3RA • IL6

CAR T Cells Accelerate Disease Progression in AMLs Harboring an Inflammatory Transcriptional Signature (ASH 2024) - P1 | "We recently identified an unexpected mechanism of resistance arising from CART-associated cytokines that suppress apoptosis in AML blasts via JAK/STAT signaling, and showed this resistance mechanism was active in our clinical study of CART targeting CD123 (CART123) on AML blasts (NCT03766126) (Bhagwat et al., 2024). In particular, we find evidence of inflammatory signaling in AML progresses upon exposure to CART, and we have developed a tool that can identify such AMLs in pre-CART samples. This may be used to refine patient selection, or to highlight those patients who will require additional combination therapy, such as ruxolitinib, to improve outcomes with AML-directed CART."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA • STAT5

Cytokine Release Syndrome Results in Reduced AML Killing By CD123 CAR T Cells (ASH 2023) - "Fludarabine and cyclophosphamide were used for lymphodepletion (LD)...Finally, we found that anti-apoptotic effects of cytokines can be prevented, and CART-123 killing of AML can be restored, via ruxolitinib blockade of JAK/STAT signaling in both in vitro and in vivo settings... We conducted a pilot study of CD123-directed CAR T cells (CART-123) in adults with relapsed or refractory AML. The primary objective was safety with a secondary objective of anti-leukemia efficacy. Twenty-two subjects were screened, and 20 were eligible for the trial."

CAR T-Cell Therapy • Cytokine release syndrome • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Infectious Disease • Inflammation • Leukemia • Oncology • Transplantation • CD123 • CD4 • CSF2 • CTLA4 • ENTPD1 • FLT3 • IL3RA • LAG3 • PD-1 • STAT5

Serum-Based Proteomic Analysis of Cytokine Release Syndrome in Pediatric AML Patients Receiving CART123 (ASH 2024) - P1, P1/2 | "Unique protein signatures identified in this study suggest potential lineage specific differences in immune response to CAR-T therapy. Together, these results warrant further exploration to identify clinically targetable regulators of CRS to decrease toxicity and increase efficacy in AML patients, where efficacy has not been observed to the extent of B-cell malignancies."

Clinical • Cytokine release syndrome • IO biomarker • Omic analysis • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Inflammation • Leukemia • Oncology • Pediatrics • ANXA3 • CCL2 • CD123 • CD22 • CLEC4C • CRTAM • CXCL16 • GDF15 • GZMA • GZMB • GZMH • IFNG • IL1RN • IL2 • IL3RA • NOS3 • PTEN • SIGLEC9 • TNFRSF1B • YTHDF3

CD123 Redirected T Cells for AML in Pediatric Subjects (clinicaltrials.gov) - P1 | N=12 | Terminated | Sponsor: University of Pennsylvania | N=18 ➔ 12 | Trial completion date: Jan 2036 ➔ May 2025 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2036 ➔ May 2025; Administrative reasons

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

CART123 + Ruxolitinib in Relapsed/Refractory AML (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: University of Pennsylvania | Not yet recruiting ➔ Recruiting

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

CART123 + Ruxolitinib in Relapsed/Refractory AML (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: University of Pennsylvania

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Lentivirally Redirected CD123 Autologous T Cells in AML (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: University of Pennsylvania | Recruiting ➔ Active, not recruiting | N=12 ➔ 22 | Trial primary completion date: Aug 2024 ➔ Dec 2033

Enrollment change • Enrollment closed • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

CD123 Redirected T Cells for AML in Pediatric Subjects (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: University of Pennsylvania | Active, not recruiting ➔ Recruiting | N=12 ➔ 18

Enrollment change • Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

Lentivirally Redirected CD123 Autologous T Cells in AML (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: University of Pennsylvania | Active, not recruiting ➔ Recruiting

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

Lentivirally Redirected CD123 Autologous T Cells in AML (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: University of Pennsylvania | Trial primary completion date: Aug 2023 ➔ Aug 2024

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML) (ASH 2022) - P1 | "AMELI-01 (NCT04106076) is a phase 1, open-label, dose-escalation trial evaluating the safety, tolerability, expansion, and persistence of UCART123v1.2 given at escalating dose levels after LD with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients (pts) with R/R CD123+ AML...Pts must have received ≥2 cycles of chemotherapy (one with standard dose cytarabine), ≥ 1 cycle of a high/intermediate dose cytarabine containing regimen, ≥ 2 cycles of an HMA combination regimen, or prior allogeneic HSCT... Adding alemtuzumab to the FC regimen was associated with improved LD and significantly higher UCART123v1.2 cell expansion and persistence, which correlated with improved activity and safety, including one pt in the DL2 FCA arm who achieved a durable MRD-negative CR. Overall, these data support the safety and activity of UCART123v1.2 after FCA LD in pts with CD123+ R/R AML."

CAR T-Cell Therapy • Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • CD123 • IFNG • IL10 • IL15 • IL2 • IL6 • TNFA

Lentivirally Redirected CD123 Autologous T Cells in AML (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: University of Pennsylvania | Trial primary completion date: Feb 2023 ➔ Aug 2023

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

CD123 Redirected T Cells for AML in Pediatric Subjects (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: University of Pennsylvania | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

Lentivirally Redirected CD123 Autologous T Cells in AML (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: University of Pennsylvania | Trial primary completion date: Jun 2022 ➔ Dec 2022

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology