CD19-directed CAR-T Cell Therapy for Refractory or Relapsed Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma: a Multicenter Phase I/II Trial.
The goal of this prospective, multicentric, single-arm, phase I/II clinical trial is to evaluate the safety and efficacy of a novel CD19-directed CAR-T cell locally produced in an academic institution in Brazil in patients with refractory or relapsed acute lymphoblastic leukemia or non-Hodgkin lymphoma. Participants will receive a single intravenous infusion of an autologous academic anti-CD19 CAR-T cell and will be followed for 5 years.
100 项与 Autologous CD19-directed CAR-T cells(University of Sao Paulo) 相关的临床结果
100 项与 Autologous CD19-directed CAR-T cells(University of Sao Paulo) 相关的专利（医药）
项与 Autologous CD19-directed CAR-T cells(University of Sao Paulo) 相关的文献（医药）
Timing of Anti-PD-L1 Antibody Initiation Affects Efficacy/Toxicity of CD19 CAR-T Cell Therapy for Large B-Cell Lymphoma.
作者: Alexandre V Hirayama ; Erik L Kimble ; Jocelyn H Wright ; Salvatore Fiorenza ; Jordan Gauthier ; Jenna M Voutsinas ; Qian Vicky Wu ; Cecilia C S Yeung ; Nicolas Gazeau ; Barbara S Pender ; Delaney R Kirchmeier ; Aiko Torkelson ; Abigail Chutnik ; Ryan D Cassaday ; Aude G Chapuis ; Damian J Green ; Hans-Peter Kiem ; Filippo Milano ; Mazyar Shadman ; Brian G Till ; Stanley R Riddell ; David G Maloney ; Cameron J Turtle
Over half of the patients treated with CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be due in part to PD-1/PD-L1-associated CAR-T cell dysfunction. We report data from a phase 1 clinical trial, in which adults with LBCL were treated with autologous CD19 CAR-T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR-T cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome, and inferior efficacy, which was associated with slower accumulation of CAR-T cells and lower concentrations of inflammatory cytokines in blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR-T cell accumulation in blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR-T cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR-T cell kinetics, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR-T cells in blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR-T cell immunotherapy for adults with LBCL.
2022-02-17·Haematologica1区 · 医学
Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 CAR-T in advanced B-cell malignancies.
1区 · 医学
作者: David M Cordas Dos Santos ; Kai Rejeski ; Michael Winkelmann ; Lian Liu ; Paul Trinkner ; Sophie Günther ; Veit L Bücklein ; Viktoria Blumenberg ; Christian Schmidt ; Wolfgang G Kunz ; Michael Von Bergwelt-Baildon ; Sebastian Theurich ; Marion Subklewe
Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is is characterized by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory B-cell malignancies. Patients with grade ≥ 2 CRS presented with a significantly higher median BMI, waist circumference, Waist-to-Height Ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with CRS 0-1° vs CRS ≥ 2°. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥ 2 CRS. Receiver operating characteristic (ROC) analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.
CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: Transforming the Treatment of Relapsed and Refractory Disease.
3区 · 医学
作者: Katherine C Pehlivan ; Brynn B Duncan ; Daniel W Lee
PURPOSE OF REVIEW:
Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T) targeting specific antigens present on acute lymphoblastic leukemia (ALL) blasts have generated promising results in children and adults with relapsed and refractory disease. We review the current evidence for CAR-T cell therapy in ALL, associated toxicities, and efforts to improve durable response to therapy.
CD19-directed CAR-T cells have recently been approved by the FDA for use in children and young adults with ALL and in adults with diffuse large B cell lymphoma (DLBCL) in the relapsed/refractory setting. CD22-directed CAR-T cells have shown efficacy against leukemia as well in a recent clinical trial, representing the first alternative CAR target to approach comparable efficacy to CD19 CAR-T cells. Standardization of toxicity grading and management, strategies to combat significant relapse rates after CAR-T therapy, and applicability of CAR-T cells to treat central nervous system (CNS) disease remain challenges in the field and represent priorities for continued research. CAR-T cells are a feasible, effective, and rapidly evolving therapy for patients with relapsed and refractory B cell malignancies.
100 项与 Autologous CD19-directed CAR-T cells(University of Sao Paulo) 相关的药物交易