Abstract 621MO
Background
Patients with acute lymphoblastic leukemia (ALL) or relapsed/refractory (r/r) large B-cell lymphoma (LBCL) often progress rapidly, and current manufacture process of chimeric antigen receptor (CAR) T cells takes too long and resulting products are less optimal for in vivo expansion and function. The “DASH CAR-T” manufacturing process we developed enabled production of CAR-T cells of naïve phenotypes within 48 hours. We examined the efficacy of DASH CAR-T cells in a murine model and laid the foundation for novel clinical trials for patients with ALL or r/r B-ALL.
Methods
DASH CAR-T process consisted of 24-hour T-cell activation and subsequent 24-hour transduction with a gamma-retrovirus vector encoding a second generation anti-CD19 CAR. The cell surface marker expression and in vitro function were accessed by flow cytometry analysis. NOG (NOD/Shi-scid/IL-2Rγnull) mouse (n=5) mice bearing Nalm6-luciferase lymphoma were treated with a graded number of control T cells that activated but not transduced (1×106) or transduced with anti-BCMA conventional CAR (1×106), anti-CD19 conventional CAR-T cells (1or 5×106), or anti-CD19 DASH CAR-T cells (1×106). Human CD45+ T cells in peripheral blood (PB) was determined by flow cytometry. Tumor burden was imaged using in vitro imaging system and survival of mice were recorded.
Results
DASH CAR-T cells were mainly “naïve” T cells (CD45RO-/CCR7+). Adoptive transfer of 1×106 DASH CAR-T cells showed an extensive expansion (increased 156 fold) in vivo at day 21, whereas 5×106 conventional CAR-T cells actually contracted (decreased 77 fold) in mice. This extraordinary CAR-T expansion led to a significantly better therapeutic effect and prolonged survival. Untreated mice, mice treated with control T cells, or 4 out of 5 mice treated with anti-BCMA CAR were dead at day 28 after cell infusion. Strikingly, 4 out 5 mice treated with one million anti-CD19 DASH CAR-T cells survived beyond 60 days. In contrast, 1 or 2 out of 5 mice treated with one million or 5 million anti-CD19 CAR-T cells survived.
Conclusions
DASH CAR-T cells manufactured in two days expanded significantly better in vivo and more effective than conventional CAR-T cells. Clinical trials are planned to use DASH CAR-T platform to rapidly generate CAR-T cells to treat patients with ALL or r/r B-ALL.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Hrain Biotechnology Co., Ltd.
Funding
Hrain Biotechnology Co., Ltd.
Disclosure
H. Wang: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. S. Tsao: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. Q. Xiong: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. M. Gu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. C. Fu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. X. Li: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. M. Zhang: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. N. Li: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd. H. Hu: Financial Interests, Personal, Full or part-time Employment: Hrain Biotechnology Co., Ltd.
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