Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia

Abstract

Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

“…Chimeric antigen receptor T cells (CART) emerges as a promising therapeutic approach for adoptive immunotherapy of cancer in recent years. The most impressive responses have been achieved in patients with refractory or relapsed B acute lymphoblastic leukemia (B-ALL) by CART cells targeting CD19 [1][2][3], which provides a potential curative option for patients who are refractory to standard treatments. However, approximately 30-50% of patients experienced leukemia relapse, the majority within one year after CART cells therapy [4].…”

Detection of CAR‐T19 cells in peripheral blood and cerebrospinal fluid: An assay applicable to routine diagnostic laboratories

“…A main benefit of the assay is its applicability to any CAR-T19 therapy: different from anti-construct specific mAbs (for example the anti-FMC63 mAb), the recombinant CD19 protein may bind to any CD19-binding CAR-T-cell (Ghorashian et al, 2019). This is relevant given that alternatives to FMC63-based CAR-T19 therapies are being sought (Brudno et al, 2016;Ghorashian et al, 2019;Gu et al, 2020). In addition, our assay may be adapted to monitor any CAR construct therapy if the relevant ligand can be sourced as a suitable, fluorochromeconjugated protein.…”

Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Relapse/Refractory B-ALL Patients After Chimeric Antigen Receptor T Cell Therapy: A Systematic Review and Meta-analysis

“…In recent years, the booming of CAR-T cell therapy has given hope to patients with R/R B-ALL with a complete remission(CR) of 70-90% [2,7, 8]. CAR-T cell therapy induces high initial remission rates but no evidence indicates it can improve disease free survival(DFS) and 40-50% patients usually relapse within one year [9,10]. Patients who achieve CR after CAR-T cell therapy often come across a dilemma when some of them are advised to undergo transplantation.…”