Background: Targeted CD19 CAR-T therapy makes great progress in r/r B-NHL with 50% CR. However, another half of patients relapses from a short duration of response or refractory to CAR-T therapy. Antigen escape and heterogeneity of antigen expression are the key mechanisms of anti-CD19 CAR-T therapy failure. A single CAR targeting CD19 and CD22 simultaneously may overcome such obstacles.
Methods: T cells transduced with CD19/CD22 dual targeted CAR lentiviral vectors were infused in patients with R/R B-NHL with CD19 or CD22 positive under fludarabine- and cyclophosphamide-based lymphodepletion. The post-infusion responses, toxicities, and cytokine profiling in enrolled patients were observed and monitored. Cytokine arrays contains 45 different kinds of cytokines related to function of immune cell. Cytokine arrays was performed at the day of CAR-T infusion, day 1-3 after CAR-T infusion, peak of cytokine release syndrome (CRS) according to clinical status and recovery day from CRS
Results: Baseline characteristics are listed in Table 1. We enrolled 17 patients with r/r B-NHL.(Figure J) The median transduction efficiency of CD19/CD22 CAR-T was 48%. In vitro cytotoxicity assays were conducted and showed prominent anti-lymphoma activities with CD19/CD22 CAR-T. The patients received CD19/CD22 CAR-T infusion at doses of 4.9-9.4×10^6/kg. 11 (64.7%) and 6 (35.3%) patients achieved complete response (CR) and partial response (PR) 1 month after CAR-T infusion. With the median follow-up of 244 days, 1-year overall survival (OS) and 1-year progression free survival (PFS) were estimated at 70.7% and 48.4%, respectively. Among patients who achieved CR 1-year OS and 1-year PFS were estimated at 100% and 83.3%.(Figure I) In this trial, all 17 patients experienced CRS. Grade 1, 2, and 3 cytokine release syndrome occurred in 4 (23.5%), 12 (70.6%), and 1 (5.9%) patients respectively. Cytokine arrays showed MIP-3β increase at day 1-3 after CAR-T infusion. CD40 ligand, MIP-1β, GROβ, EGF, PDGF-AB/BB, RANTES, IL-8, TRAIL decrease and PD-L1/B7-H1, MIP-1α, GM-CSF, IL-1ra, IL-3, IL-5, MIP-3β, MCP-1, IP-10 increase were observed at CRS peak. (Figure A, B, C, D) In subgroup analysis, we found patients who achieved CR with lower level of CD40 ligand, FGF basic at day 1-3, and GM-CSF, IP-10 at recovery day than PR patients.(Figure E, F, G, H)
Conclusions: CD19/CD22 dual targeted CAR-T is a promising solution for improving response and prolonging PFS for r/r B-NHL patients with less than grade 3 CRS adverse events. Cytokine profiling showed CD40 ligand, MIP-1β, GROβ, EGF, PDGF-AB/BB, RANTES, IL-8, TRAIL decrease and PD-L1/B7-H1, MIP-1α, GM-CSF, IL-1ra, IL-3, IL-5, MIP-3β, MCP-1, IP-10 increase during CRS. MIP-3β may be a biomarker of early phase of CRS. Lower level of CD40 ligand, FGF basic at early phase of CRS and lower level of GM-CSF, IP-10 when recovery from CRS may be related to good response.
[Fig. A-D CRS cytokines | Fig. E-H prognosis related cytokine | Fig. I survival | Fig H workflow]
|prior lines of therapy||3||DLBCL||Burkitt||lymphoblastic lymphoma|
Clinical Trial Registry: ChiCTR1800015575
Disclosure: Nothing to declare