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DRUG:

HD-CAR-1

i
Other names: HD-CAR-1, 3rd-generation CD19-directed CART, CD19.CAR T, 3G. CD19 CAR T Cells
Associations
Company:
Heidelberg University Hospital
Drug class:
CD19-targeted CAR-T immunotherapy
Related drugs:
Associations
22d
Toxicities and outcome after CD19-directed chimeric antigen receptor T-cell therapy for secondary neurolymphomatosis. (PubMed, Am J Hematol)
We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis...Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier. Toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.
Journal • CAR T-Cell Therapy
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CRP (C-reactive protein)
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HD-CAR-1
3ms
Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study. (PubMed, Leukemia)
HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
P1/2 data • Journal • CAR T-Cell Therapy
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • CCR7 (Chemokine (C-C motif) receptor 7) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
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HD-CAR-1
4ms
HD-CAR-1: Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Cells Expressing a Third-generation CAR (clinicaltrials.gov)
P1/2, N=68, Recruiting, University Hospital Heidelberg | Trial completion date: Apr 2024 --> Dec 2027 | Trial primary completion date: Jan 2024 --> Dec 2026
Trial completion date • Trial primary completion date • Viral vector
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CD19 (CD19 Molecule)
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cyclophosphamide • fludarabine IV • HD-CAR-1
10ms
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma. (PubMed, Nat Med)
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
Journal • CAR T-Cell Therapy
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CD19 (CD19 Molecule)
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CD19 expression • CD19 underexpression
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Yescarta (axicabtagene ciloleucel) • HD-CAR-1
1year
The Ig Superfamily Ligand B7H6 Subjects Activated T Cells to NK Cell Surveillance and Limits CAR T Cell Persistence (ASH 2023)
We then co-injected CD19.CAR T cells and patient-autologous NK cells in leukemia-engrafted mice and observed reduced CAR T cell persistence in the peripheral blood of mice with NK cell co-injection...We therefore analyzed tissue of patients that were treated with nivolumab and ipilimumab (NCT03416244)...We therefore suggest an alternative immune checkpoint that limits T cell expansion and persistence in physiological and cellular engineering contexts. Targeting the B7H6-NKp30 axis may offer a means to modulate T cell immunity across multiple disease entities.
Clinical • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • GZMB (Granzyme B) • NCR3LG1 (Natural Killer Cell Cytotoxicity Receptor 3 Ligand 1)
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Opdivo (nivolumab) • Yervoy (ipilimumab) • HD-CAR-1
1year
3rd-Generation CD19-directed Chimeric Antigen Receptor T-Cells (CARTs) for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) – Status Report of the Ongoing Academic Phase 1/2 Trial (HD-CAR-1) (DGHO 2023)
Successful generation of homebrewed 3 rd generation HD-CAR-1 CARTs was possible for heavily pretreated patients with high-risk CLL and exerted a promising safety and efficacy profile.
P1/2 data • CAR T-Cell Therapy
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TP53 (Tumor protein P53)
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HD-CAR-1
1year
Absence of CD39 on chimeric antigen receptor (CAR) T cells is predictive for response in adult ALL patients (DGHO 2023)
Administration of third-generation HD-CAR-1 CARTs was remarkably safe and of promising efficacy. Responses correlated with MRD clearance and were dose-dependent. Lack of CD39 expression on T cell subsets within the CART product was associated with improved anti-leukemic activity of CARTs.
Clinical
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ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)
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ENTPD1 expression
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HD-CAR-1
over1year
HD-CAR-1: Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Cells Expressing a Third-generation CAR (clinicaltrials.gov)
P1/2, N=68, Recruiting, University Hospital Heidelberg | N=48 --> 68 | Trial completion date: Oct 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Jan 2024
Enrollment change • Trial completion date • Trial primary completion date • Viral vector
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CD19 (CD19 Molecule)
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CD19 expression
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cyclophosphamide • fludarabine IV • HD-CAR-1
over1year
PROTEOMIC PROFILING IDENTIFIES GRANZYME B INHIBITOR SERPIN B9 AS MEDIATOR OF RESISTANCE TO CAR T-CELL AND BISPECIFIC ANTIBODY TREATMENT IN NODAL B-CELL LYMPHOMA (ICML 2023)
We further combined CD19-CAR treatment with clinically relevant drugs and assessed how killing of lymphoma cells and expansion of T-cells was altered...We sought to improve T-cell-mediated cytotoxicity specifically in samples with high SERPINB9 expression and found that immune checkpoint inhibitors and lenalidomide enhanced expansion of CAR T-cells and increased killing of lymphoma cells. In addition, vorinostat and antibody-drug-conjugate polatuzumab vedotin specifically killed lymphoma cells without affecting T-cell expansion... This study is the first to investigate proteomic determinants of response to CD19-CAR and CD19-BsAb in B-NHL. With this approach, we identify tumorigenic Serpin B9 as mediator of resistance and provide combinatorial drug treatments to improve response to CD19-CAR. Collectively, these results may contribute to the targeted advancement of T-cell engaging therapy.
CAR T-Cell Therapy • IO biomarker
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CD19 (CD19 Molecule) • GZMB (Granzyme B) • SERPINB9 (Serpin Family B Member 9)
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CD19 expression
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lenalidomide • Zolinza (vorinostat) • Polivy (polatuzumab vedotin-piiq) • HD-CAR-1
almost2years
THIRD-GENERATION CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS IN ADULT ALL PATIENTS (EBMT 2023)
Refractory and/or relapsed (r/r) adult ALL patients received escalating doses of CD19-directed third-generation CARTs comprising the costimulatory domains CD28 and CD137 (4-1BB) after lymphodepletion with fludarabine and cyclophosphamide. Third-generation HD-CAR-1 CARTs were remarkably safe and of promising efficacy. A specific subset of memory T cells within the CART product could predict response to treatment. Overall, HD-CAR-1 appears to be a promising step towards safe and effective ALL eradication.
Clinical
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CD19 (CD19 Molecule) • TNFRSF9 (TNF Receptor Superfamily Member 9)
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cyclophosphamide • fludarabine IV • HD-CAR-1
almost3years
3RD-GENERATION CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELLS (CARTS) FOR RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) – RESULTS FROM AN ACADEMIC PHASE 1/2 TRIAL (HD-CAR-1) (EBMT 2022)
 HD-CAR-1 is an investigator-initiated trial evaluating efficacy and safety of escalating doses of CD19-directed CARTs comprising CD28 and 4-1BB as costimulatory molecules in patients with advanced B-cell malignancies after fludarabine/cyclophosphamide lymphodepletion.  Homebrewed 3rd generation HD-CAR-1 CART could be successfully generated for heavily pretreated patients with high-risk CLL and exerted a promising safety and efficacy profile.
P1/2 data • CAR T-Cell Therapy
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule)
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cyclophosphamide • fludarabine IV • HD-CAR-1
almost3years
TREATMENT OF ADULT ALL PATIENTS WITH THIRD-GENERATION CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS - RESULTS OF THE HEIDELBERG TRIAL 1 (HD-CAR-1 TRIAL) (EBMT 2022)
 HD-CAR-1 is an investigator-initiated phase I/II trial initiated in September 2018 designed to evaluate escalating doses of third-generation CD19-directed CARTs (1×106 to 2×108 CARTs/m2) comprising the costimulatory domains CD28 and CD137 (4-1BB) after lymphodepletion with fludarabine and cyclophosphamide.  HD-CAR-1 product manufacturing was feasible for all patients enrolled in HD-CAR-1 so far. In adult patients with r/r ALL, third-generation HD-CAR-1 CAR T cells displayed an excellent safety profile as well as high clinical efficiency.
Clinical • IO biomarker
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CD19 (CD19 Molecule) • TNFRSF9 (TNF Receptor Superfamily Member 9)
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cyclophosphamide • fludarabine IV • HD-CAR-1