HD-CAR-1

The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

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.

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, N=68, Recruiting, University Hospital Heidelberg | Trial completion date: Apr 2024 --> Dec 2027 | Trial primary completion date: Jan 2024 --> Dec 2026

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.

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.

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.

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.

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

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.

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.

 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.

 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.