CD19-Directed Chimeric Antigen Receptor CD19 Redirected Autologous T Cells (CART19) for Orphan Indications of Pediatric B Cell Acute Lymphoblastic Leukemia (B ALL)

This is an open-label, four-cohort, phase 2 study to determine the efficacy of CART19 in pediatric and young adult patientswith hypodiploid (Cohort A) or t(17;19) B-ALL (Cohort B), infants with very high risk KMT2A B-ALL (Cohort C), and in patients with central nervous system (CNS) relapse who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) (Cohort D).

Start Date12 Mar 2020

Sponsor / Collaborator

The Children's Hospital of Philadelphia

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100 Clinical Results associated with Murine CART19(University of Pennsylvania)

100 Translational Medicine associated with Murine CART19(University of Pennsylvania)

100 Patents (Medical) associated with Murine CART19(University of Pennsylvania)

Literatures (Medical) associated with Murine CART19(University of Pennsylvania)

18 Jan 2024·Blood

CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS

Article

Author: Girsch, James H. ; Yun, Kun ; Ilieva, Kristina ; Stewart, Carli M. ; Patra-Kneuer, Maria ; Bezerra, Evandro D. ; Kay, Neil E. ; Nevala, Wendy K. ; Heitmüller, Christina ; Ruff, Michael W. ; Nowakowski, Grzegorz S. ; Hefazi, Mehrdad ; Sakemura, R. Leo ; Kankeu Fonkoua, Lionel Aurelien ; Can, Ismail ; Mai, Long K. ; Steidl, Stefan ; Sirpilla, Olivia L. ; Horvei, Paulina ; Manriquez Roman, Claudia ; Parikh, Sameer A. ; Kimball, Brooke L. ; Ogbodo, Ekene J. ; Siegler, Elizabeth L. ; Kenderian, Saad S. ; Adada, Mohamad M. ; Schanzer, Jürgen ; Endell, Jan ; Ding, Wei ; Huynh, Truc N. ; Augsberger, Christian

AbstractIn the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.

07 Apr 2022·BloodQ1 · MEDICINE

Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy

Q1 · MEDICINE

Article

Author: Grupp, Stephan A. ; Baniewicz, Diane ; Leahy, Allison Barz ; Myers, Regina ; Liu, Hongyan ; Rheingold, Susan R. ; Barrett, David M. ; Patino, Maria ; Newman, Haley ; Hunger, Stephen P. ; Devine, Kaitlin J. ; Li, Yimei ; Maude, Shannon L. ; DiNofia, Amanda ; Callahan, Colleen ; Wray, Lisa

AbstractChimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

01 Jun 2020·JACC: CardioOncologyQ2 · MEDICINE

Cardiovascular Effects of CAR T Cell Therapy

Q2 · MEDICINE

ArticleOA

Author: Frey, Noelle V ; Lefebvre, Bénédicte ; Kang, Yu ; Scherrer-Crosbie, Marielle ; Smith, Amanda M ; Carver, Joseph R

BACKGROUNDAnti-CD19 chimeric antigen receptor (CAR) T cell (CART19) therapy holds great promise in the treatment of hematological malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CART19 therapy.OBJECTIVESWe aimed to define the occurrence of major cardiovascular events (MACE) in adult patients treated with CART19 cells and assess the relationships between clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes.METHODSBaseline clinical, laboratory and echocardiographic parameters were collected in 145 adult patients undergoing CART19 cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis.RESULTSThirty-one patients had MACE (41 events) at a median time of 11 days (Q1-Q3:6-151 days) after CART19 cell infusion. The median follow-up period was 456 days (Q1-Q3: 128-1214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (Q1-Q3: 1-8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53% respectively. The KM estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and Grade 3 or 4 CRS were independently associated with MACE.CONCLUSIONPatients treated with CART19 are at an increased risk of MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.

100 Deals associated with Murine CART19(University of Pennsylvania)

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