CART22 / University of Pennsylvania - LARVOL DELTA

IL-10 Levels Differentially Regulate IFNg Signaling of CART19 and CART22 (ASH 2023) - P1, P1/2 | " Serial serum samples from pts enrolled on two clinical trials of the murine CART19 CTL019 (NCT01626495 & NCT02906371) and CART22 (NCT02650414) were examined...All pts who received CART22 had previously received CD19 directed immunotherapy (CART19 N=16, blinatumomab N=1)... Comparing comprehensive serum proteomic profiling between CART19 and CART22 pts we make several novel observations. First, IL-10 levels are significantly higher in CART22 pts at pre-infusion, suggesting that previous immunotherapy has caused an upregulation of this anti-inflammatory cytokine. Second, we show that IL-10 levels have a differential impact on IFNγ levels in CART19 vs CART22 cells."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD22 • CXCL9 • IFNG • IL10

EZH1/2 Inhibition Improves the Anti-Tumor Efficacy of CAR and TCR T-Cell Based Therapies Against Multiple Liquid and Solid Tumors (ASH 2024) - "We observed that CART22 and CART79b co-cultured with tazemetostat showed enhanced cytotoxicity (72 hs, CART22-taz vs -DMSO p<0.001; CART79b-taz vs -DMSO p<0.01)...Pretreating an array of MM (e.g. RPMI-8226) and AML (e.g. THP-1, KG-1) cell lines with tazemetostat before exposure to anti-BCMA (CARTBCMA) or anti-CD33 CART (CART33) significantly increased killing efficacy at multiple E : T ratio and even with ineffective single-agent CART doses (72 hs; CARTBCMA-taz vs -DMSO p<0.01; CART33-taz vs -DMSO p<0.001)...Furthermore, we show that the novel EZH2/1 inhibitor valemetostat lead to an increased improvement of tumor killing as compared to EZH2i alone. Mechanistically, we demonstrate that EZH1/EZH2 modulation can unlock the full potential of adoptive T-cell immunotherapy."

Clinical • IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Ewing Sarcoma • Hematological Malignancies • Large B Cell Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Adenocarcinoma • Prostate Cancer • Sarcoma • Solid Tumor • CD79B • EZH2 • HER-2

CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy. (PubMed, J Immunother Cancer) - P1 | "The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • CD22

Co-administration of CART22-65s and huCART19 for B-ALL (clinicaltrials.gov) - P1/2 | N=93 | Recruiting | Sponsor: Stephan Grupp MD PhD | Trial completion date: Jan 2026 ➔ Jan 2029 | Trial primary completion date: Jan 2025 ➔ Jan 2027

CAR T-Cell Therapy • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD22

CD22-Targeted CAR-Modified T-Cells Safely Induce Remissions in Children and Young Adults with Relapsed, CD19-Negative B-ALL after Treatment with CD19-Targeted CAR T-Cells (ASH 2022) - P1 | " After fludarabine/cyclophosphamide lymphodepletion, patients (pts) were infused with CART22-65s using a 3-day fractionated dosing scheme with the 2nd/3rd doses held for early signs of cytokine release syndrome (CRS)...Of 17 pts infused (median age, 16 years; range 3-28 years), all had CD19-negative, relapsed disease after prior CD19-directed therapy (CART19, n=16; blinatumomab, n=1); 8 had prior inotuzumab; 9 had prior stem cell transplant (SCT); and 3 had multiple prior SCTs...Other SAEs included: (1) platelet refractoriness and recurrent, severe inflammatory reactions to platelet transfusions in 1 pt that improved with corticosteroids and anakinra; and (2) delayed hemophagocytic lymphohistiocytosis in 1 pt after CART22-65s retreatment that resolved without intervention... CART22-65s induced remissions in 77% of children and young adults with highly refractory, CD19-negative B-ALL, including in 4/5 pts refractory to prior CD22-directed therapy. Manufacturing was..."

CAR T-Cell Therapy • Clinical • IO biomarker • Bone Marrow Transplantation • CNS Disorders • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • Rare Diseases • Transplantation • CD19 • CD22

Dual CAR T-Cell for ALL (SOHO 2022) - P1, P1/2 | "Quantitative PCR data demonstrated that CART22-65s and huCART19 had different peak expansions that correlated with distinct cytokine release syndrome events...Early results have demonstrated manufacturing feasibility and anti-leukemia activity; however, limited dual functionality has been observed in some products. Longer follow-up and additional studies are needed to ascertain remission durability and to further optimize dual-targeted CARs."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD22

Comprehensive Secretome Profiling Elucidates Novel Disease Biology and Identifies Pre-Infusion Candidate Biomarkers to Predict the Development of Severe Cytokine Release Syndrome in Pediatric Patients Receiving CART19 (ASH 2021) - P1, P1/2 | "To obtain a more robust understanding of CRS biology, we performed comprehensive secretome profiling to measure more than 1400 serum analytes on serial serum samples collected from patients treated with the 41BB-containing CTL019 on two clinical trials...The IL-18 signalling axis was dysregulated at peak CRS in severe patients with markedly elevated IL18 and IL18BP, despite prior reports suggesting IL-18 up-regulation is unique to the late CRS seen with CART22 (PMID: 32925169)... With comprehensive secretome profiling we made multiple novel insights into the biology of CRS after CART19 and identified several potentially targetable proteins and pathways that could mitigate severe CRS. Similar secretome profiling in patients who developed neurotoxicity will also be shown. We identified two novel pre-infusion biomarkers that demonstrate significant capacity to predict the development of severe CRS following CART19 infusion."

Biomarker • Clinical • Cytokine release syndrome • IO biomarker • Immunology • Inflammation • Oncology • Pediatrics • Rare Diseases • CD163 • CD19 • CXCL10 • CXCL9 • FLT3 • IFNG • IL10 • IL18BP • IL6 • LAG3 • PD-L1

Co-administration of CART22-65s and huCART19 for B-ALL (clinicaltrials.gov) - P1/2 | N=93 | Recruiting | Sponsor: Stephan Grupp MD PhD | Not yet recruiting ➔ Recruiting

CAR T-Cell Therapy • Enrollment open • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD19 • CD22 • CRP

Co-administration of CART22-65s and huCART19 for B-ALL (clinicaltrials.gov) - P1/2 | N=93 | Not yet recruiting | Sponsor: Stephan Grupp MD PhD

CAR T-Cell Therapy • New P1/2 trial • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD19 • CD22 • CRP

CD22 Redirected Autologous T Cells for ALL (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: University of Pennsylvania; Trial completion date: Dec 2022 ➔ Dec 2037; Trial primary completion date: Dec 2021 ➔ Dec 2037

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • CD22

CART22-65s Co-Administered with huCART19 in Adult Patients with Relapsed or Refractory ALL (ASH 2021) - "Methods : Adult patients with r/r ALL were co-administered two humanized autologous CAR T cell products, one targeted to CD19 (huCART19) and the other to CD22 (CART22-65s) after fludarabine and cyclophosphamide lymphodepletion... Of 13 treated patients (median age 46 (range 28-71)), two had received prior murine CART19 cells, 8 had prior blinatumomab, 8 had prior inotuzumab and 10 had a prior allogeneic stem cell transplant (SCT)...This syndrome was refractory to IL6 and IL1beta inhibition but ultimately responded to ruxolitinib... Co-administration and adaptive dosing of CART22-65s with huCART19 in adult patients with r/r ALL is feasible and effective. The two different products demonstrated differential expansion and persistence kinetics. Despite prior exposure to CD19- and/or CD22-specific immunotherapies, all evaluable patients achieved CR with uMRD; we continue to monitor CAR T cell persistence and its impact on durability of response."

Clinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Inflammation • Leukemia • Oncology • Rare Diseases • Septic Shock • Transplantation • CD22 • IL1B • IL6