&lt;p&gt;Decitabine enhances cytotoxic effect of T cells with an anti-CD19 chimeric antigen receptor in treatment of lymphoma&lt;/p&gt;

Li, Sujun; Xue, Lei; Wang, Min; Qiang, Ping; Xu, Hui; Zhang, Xuhan; Kang, Wenyao; You, Fengming; Xu, Hanying; Wang, Yu; Liu, Xin; Yang, Lin; Wang, Xingbing

doi:10.2147/ott.s198567

Cited by 35 publications

(27 citation statements)

References 34 publications

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“… 32 Another demethylating agent, decitabine, was shown to increase the expression of CD19 on lymphoma cells and enhanced the cytotoxic effect of CAR19 T cells. 35 In our experiments, however, AZA did not up-regulate CD19 cell surface expression in B-ALL cells. Additionally, neither PD-L1/PD-L2 expression in leukemia cells nor PD-1 expression in CAR T cells was affected by pre-treatment of leukemia/hosts with AZA, suggesting that AZA effects were not mediated through the modulation of the inhibitory PD-1 checkpoint.…”

Section: Discussioncontrasting

confidence: 63%

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy

Xu¹,

Tse²,

Yang³

et al. 2021

ITT

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Purpose Despite the success of chimeric antigen receptor (CAR) T cells in clinical studies, a significant proportion of responding patients eventually relapsed, with the latter correlating with low CAR T cell expansion and persistence. Methods and Results Using patient-derived xenograft (PDX) mouse models of CD19 + B cell acute lymphoblastic leukemia (B-ALL), we show that priming leukemia-bearing mice with 5-azacytidine (AZA) enhances CAR T cell therapy. AZA given 1 day prior to CAR T cell infusion delayed leukemia growth and promoted CAR T cell expansion and effector function. Priming leukemia cells with AZA increased CAR T cell/target cell conjugation and target cell killing, promoted CAR T cell divisions and expanded IFNγ + effector T cells in co-cultures with CD19 + leukemia Nalm-6 and Raji cells. Transcriptome analysis revealed activation of diverse immune pathways in leukemia cells isolated from mice treated with AZA. We propose that epigenetic priming with AZA induces transcriptional changes that sensitize tumor cells to subsequent CAR T cell treatment. Among the candidate genes up-regulated by AZA is TNFSF4 which encodes OX40L, one of the strongest T cell co-stimulatory ligands. OX40L binds OX40, the TNF receptor superfamily member highly specific for activated T cells. TNFSF4 is heterogeneously expressed in a panel of pediatric PDXs, and high TNFSF4 expression correlated with increased CAR T cell numbers identified in co-cultures with individual PDXs. High OX40L expression in Nalm-6 cells increased their susceptibility to CAR T cell killing while OX40L blockade reduced leukemia cell killing. Conclusion We propose that treatment with AZA activates OX40L/OX40 co-stimulatory signaling in CAR T cells. Our data suggest that the clinical use of AZA before CAR T cells could be considered.

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Section: Discussioncontrasting

confidence: 63%

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy

Xu¹,

Tse²,

Yang³

et al. 2021

ITT

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“…The results of this clinic trial demonstrate decitabine is modestly safe and active, and has a potential synergistic effect with chemotherapy in obstinate R/R-DLBCL. Along with the deep exploration of lymphoma therapy, DAC increases expression of the surface antigen CD19 on lymphoma cells and potentiates the activity of CAR-T cells towards B-cell malignancies (40). The ORR and CR rates of relapsed/refractory cHL patients who received decitabine plus PD-1 blockade was significantly higher than those who took PD-1 blockade alone.…”

Section: Discussionmentioning

confidence: 99%

Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure

Wang

Chen

et al. 2021

Front. Oncol.

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ObjectiveThe prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment.MethodsTwenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred.ConclusionDecitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03579082.

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“…We demonstrated for the first time that pretreatment with DAC augments activation of CD123 CAR-T cells in vitro and also show an enhanced antileukemia effect in the context of combination treatment in vivo. Consistent with these results, Li et al (20) reported that lymphoma cells were more sensitive to killing by CD19 CAR-T cells following pretreatment with DAC, and that two patients with refractory/relapsed B-cell lymphoma received sequential therapy (DAC followed by CAR-T cells), of whom both achieved CR. Together, these data may indicate the FIGURE 4 | Investigations on the effect of DAC on intrinsic potency and subsets of CAR-T cells.…”

Section: Discussionmentioning

confidence: 59%