A5007442676- CAR-T cell therapy research
- Pancreatic and Hepatic Oncology Research
- Neuroblastoma Research and Treatments
- Silicon Carbide Semiconductor Technologies
- Integrated Circuits and Semiconductor Failure Analysis
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer Research and Treatments
Cancer Prevention Institute of California
2025
Stanford Cancer Institute
2025
Massachusetts General Hospital
2024
Harvard University
2022-2024
Dana-Farber/Harvard Cancer Center
2022
Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target expression, escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated cancer-associated fibroblasts (CAF), which may contribute limited efficacy of mesothelin-directed CAR in early-phase clinical trials. To provide more favorable TME for pancreatic ductal adenocarcinoma (PDAC), we an antimesothelin secreted...
BackgroundOutcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed surface and the efficacy of CD22-directed CAR (CAR22) in unknown, which was what we aimed to examine this study.MethodsIn single centre, open-label, dose-escalation phase 1 trial, intravenously administered CAR22 at two dose levels (1 million 3 CAR22-positive T cells per kg bodyweight) adult (aged...
Abstract Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 CD22 (CAR19-22), which was well tolerated associated with high response rates but common. Interleukin-15 (IL15) induces proliferation diverse immune cells can augment lymphocyte trafficking. Here, we...
Abstract Patients with large B-cell lymphoma (LBCL) progressing after anti-CD19 CAR T-cell (CAR19) therapy have poor outcomes. Subsequent shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 CAR19-refractory LBCL patients who received anti-CD22 (CAR22) in a phase 1b trial (NCT04088890). Residual was unquantifiable 17 33 evaluable post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak transgene levels...
<div>Abstract<p>Patients with large B-cell lymphoma that progresses after anti–CD19 chimeric antigen receptor (CAR) T-cell (CAR19) therapy have poor outcomes. Subsequent CAR shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 patients CAR19-refractory who received anti–CD22 (CAR22) in a phase Ib trial (NCT04088890). Residual was unquantifiable 17 33 evaluable post-CAR22 infusion. Single-cell RNA sequencing revealed minimal...
<p>CAR T-cell surveillance methods and time points of the two cohorts</p>
<p>Linear regression analysis of CAR22 transduction efficiency, vector copy number (VCN) and T cell subsets in CD4/CD8 enrichment material product (A) Linear efficiency versus material. (B) the products. (C) VCN (D) products.</p>
<p>Cytopenia within 28 days following CAR22 infusion in early and late groups. (A) The nadir white blood cell count, hemoglobin levela platelet count were comparable between (B) Similar administration of filgrastim given dosage, red transfusion burden groups.</p>
<p>Maximal expansion (CMax) and area under the curve from day 0 to 28 (AUC0-28) of CAR22 post-infusion, as assessed by flow cytometry (A) qPCR (B), in early late groups patients</p>
<p>Comparative analysis of Comparative T cell subsets CD4/CD8 enrichment material during CAR22 manufacturing process. (A) CD4+ and (B) CD8+ cells.</p>
<p>Comparative analysis of CAR22 transduction rate, vector copy number (VCN) and T cell subset in products between patients who experienced disease progression (PD) within 90 days versus more than after CAR19 therapy (A) Patients PD post-CAR19 infusion exhibited lower rates VCN their compared to those days. (B) The was similar the 2 groups.</p>
<p>Comparison of CAR19 transgene level, CAR22 product characteristic and cell kinetics across different co-stimulatory domain</p>
<p>Sensitivity analysis for handling residual CAR19 qPCR data below limit of quantification (LOQ) in leukapheresis material</p>
<p>CD39 expression on CD4+ and CD8+ CAR22, stratified by median levels (High/Low) or using a 20% cutoff, its correlation with CAR22 expansion as measured flow cytometry qPCR, treatment response, survival outcomes. (A) The CD39 level in the product, (> < median) shows no significant difference maximal (CMax) peripheral blood (PB) after infusion. (B) median, area under curve from day 0 to 28 (AUC0-28) post-infusion PB. (C) CMax AUC0-28 qPCR (D) complete response rate,...
<p>CAR22 product release criteria</p>
<p>CAR22 construction</p>
<p>The CAR T-cell maximal expansion (CMax) and area under the curve from day 0 to 28 (AUC0-28) for CAR19 CAR22 following or infusion in same patient. (A) Analysis by flow cytometry. (B) qPCR assay. No statistical comparison was performed due limited number of patients.</p>
<p>Quantifiable CAR19 transgene levels in leukapheresis material and CAR22 products, their correlation with complete response (CR) rate survival outcomes. (A) The CR is similar between patients without quantifiable products. (B) Progression-free (PFS) overall (OS) are material. (C) PFS OS products.</p>
<p>Cohort 2: Patient demographics upon receiving CAR19 or CAR22 therapies</p>
<p>Hemogram analysis prior to leukapheresis for CAR22</p>
<p>Comparative analysis of exhaustion markers expression CD4/CD8 enrichment material during CAR22 manufacturing process Expression markers, including CD39, lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD1), and T-cell immunoglobulin mucin-3 (TIM3), in (A) CD4+ (B) CD8+ T-cells showed no significant difference between the two groups.</p>
<p>Comparison of CRS, ICANS, and IEC-HS between different leukapheresis interval groups, CAR19 transgene level, CAR22 product transduction rate cut off by median</p>
<p>Key reagents and resources</p>
<p>Supplementary Video S2. Meso^FAP CAR T cells on AsPC1</p>
<p>Supplementary Methods</p>