Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial

Abstract

Background Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). Methods Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. Results For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. Conclusion In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504.

The Progress and Prospects of Immune Cell Therapy for the Treatment of Cancer

“…In an investigator-initiated trial, HD-CAR-1, a third-generation CAR-T therapy, was evaluated in adult patients with relapsed/refractory ALL. At the end of the 90-day study period, 80% of patients achieved complete remission (CR) 80 . Furthermore, recent studies demonstrate that CAR-T cells equipped with both 4-1BB and CD28 co-stimulatory domains enhance the T cell memory phenotype, exhibiting better proliferation and cytokine release levels compared with those with only one co-stimulatory molecule 64 , 81 .…”

Programmable synthetic receptors: the next-generation of cell and gene therapies

“…3b ). Although potential benefits including prolonged persistence and increased antitumor efficacy have been demonstrated both in vitro and in vivo, 130 – 137 some clinical results did not prove a significant superiority of 3 G CAR T cells to the 2 G CAR T cells. 138 – 140 As the available data was obtained from relatively small and heterogenic samples, it is still too early to draw a conclusion, and further large-scale studies are required to fully evaluate their feasibility.…”

Third-generation CD19.CAR-T cell-containing combination therapy in Scl70+ systemic sclerosis

“…We generated CD19.CAR-T-cells in our Good Manufactory Practice facility by transducing autologous T-lymphocytes retrovirally with a CAR containing intracellular coactivating domains of CD3ζ, CD28 and 41BB. 5 Mycophenolate/nintedanib was stopped before leukapheresis and lymphodepletion chemotherapy (500 mg/m 2 cyclophos-phamide+30 mg/m 2 fludarabine on days −4 to -3, −2). 5 On day −3, fever and elevated C reactive protein (CRP) occurred, requiring an empirical antibiotic therapy.…”

“…5 Mycophenolate/nintedanib was stopped before leukapheresis and lymphodepletion chemotherapy (500 mg/m 2 cyclophos-phamide+30 mg/m 2 fludarabine on days −4 to -3, −2). 5 On day −3, fever and elevated C reactive protein (CRP) occurred, requiring an empirical antibiotic therapy. On day 0 (October 2022), the patient received 400×10 6 (5×10 6 /kg of body weight) CD19.CAR-T-cells (figure 1B).…”