Abstract
BackgroundRecent 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.MethodsWe 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).ResultsData 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).ConclusionsThe 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 registrationClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687
Highlights
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 in current use
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
The results revealed an overlap between the critical amino acid residues involved in the interactions between the HI19α Single-chain variable fragment (scFv) and the FMC63 scFv with the human CD19 (hCD19) extracellular domain (ECD) (Fig. 1d)
Summary
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. Recent studies indicate that relapse may be due to mutations in CD19 that destroy the cognate epitope recognized by the anti-CD19 single-chain variable fragment (scFv), such as FMC63 clone, rendering the tumor cells invisible to CD19 CAR T cells [9, 10]. In cases such as these, an exploration of CD19 CAR T with scFvs capable of binding to different CD19 epitopes may provide alternative choice for patients with mutations in CD19. We present a single-arm, open-label, non-randomized, prospective pilot study that was conducted to evaluate the safety and efficacy of CNCT19 cells in both children and adult patients with R/R B-ALL
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