CD20 is an effective immunotherapy target for CD20+ B-cell malignant cells. Monoclonal antibody, especially rituximab, has been a conventional strategy in the treatment of B-cell malignancies such as non-Hodgkin's lymphoma. However, treatment with monoclonal antibodies has not been enough to overcome the refractory/relapse problems. Chimeric antigen receptor engineered T (CAR-T) cells have exhibited excellent therapeutic effect on lymphocytic leukemia in recent years. In this study, a CD20-specific CAR was constructed and the cytotoxic efficacy of CD20 CAR-T cells on B-cell malignant cells was evaluated by CD107a degranulation, pro-inflammation cytokine production, and true lytic ability in vitro and in vivo. It was found that CD20 CAR-T cells possessed stronger cytotoxic ability against CD20 highly expressed cells. Furthermore, when histone deacetylase inhibitor was used to enhance the expression of CD20 antigen on the surface of B-cell malignant cells via inducing acetylation of H3K9 on CD20 promoter site, it revealed that the cytotoxicity of CD20 CAR-T cells against histone deacetylase inhibitor–treated B-cell malignant cells was significantly enhanced.
Get full access to this article
View all access options for this article.
References
1.
TeelingJL, MackusWJ, WiegmanLJ, et al.The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol, 2006; 177:362–371.
2.
TomitaA. Genetic and epigenetic modulation of CD20 expression in b-cell malignancies: molecular mechanisms and significance to rituximab resistance. J Clin Exp Hematop, 2016; 56:89–99.
3.
NadlerLM, RitzJ, HardyR, et al.A unique cell surface antigen identifying lymphoid malignancies of B cell origin. J Clin Invest, 1981; 67:134–140.
4.
DeAngeloDJ. The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program, 2015; 2015:400–405.
5.
MossnerE, BrunkerP, MoserS, et al.Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood, 2010; 115:4393–4402.
6.
GoedeV, FischerK, BuschR, et al.Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med, 2014; 370:1101–1110.
7.
TillBG, JensenMC, WangJ, et al.CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4–1BB domains: pilot clinical trial results. Blood, 2012; 119:3940–3950.
8.
BuddeLE, BergerC, LinY, et al.Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS One, 2013; 8:e82742.
9.
WangY, ZhangWY, HanQW, et al.Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol, 2014; 155:160–175.
10.
LockD, Mockel-TenbrinckN, DrechselK, et al.Automated manufacturing of potent CD20-directed chimeric antigen receptor T cells for clinical use. Hum Gene Ther, 2017; 28:914–925.
AnN, TaoZ, LiS, et al.Construction of a new anti-CD19 chimeric antigen receptor and the anti-leukemia function study of the transduced T cells. Oncotarget, 2016; 7:10638–10649.
13.
ZhangT, BarberA, SentmanCL. Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res, 2007; 67:11029–11036.
14.
NakazawaY, MatsudaK, KurataT, et al.Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia. J Hematol Oncol, 2016; 9:27.
15.
GrossG, WaksT, EshharZ. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 1989; 86:10024–10028.
16.
HaynesNM, TrapaniJA, TengMW, et al.Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation. J Immunol, 2002; 169:5780–5786.
17.
BeechamEJ, MaQ, RipleyR, et al.Coupling CD28 co-stimulation to immunoglobulin T-cell receptor molecules: the dynamics of T-cell proliferation and death. J Immunother, 2000; 23:631–642.
18.
SavoldoB, RamosCA, LiuE, et al.CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest, 2011; 121:1822–1826.
19.
ChmielewskiM, HombachA, HeuserC, et al.T cell activation by antibody-like immunoreceptors: increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decreases selectivity. J Immunol, 2004; 173:7647–7653.
20.
TurattiF, FiginiM, BalladoreE, et al.Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction. J Immunother, 2007; 30:684–693.
21.
WilkieS, PiccoG, FosterJ, et al.Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol, 2008; 180:4901–4909.
22.
HombachAA, SchildgenV, HeuserC, et al.T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol, 2007; 178:4650–4657.
23.
ShimizuR, KikuchiJ, WadaT, et al.HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells. Leukemia, 2010; 24:1760–1768.
24.
YangXJ, SetoE. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol, 2008; 9:206–218.
25.
JiangT, WangF, HuL, et al.Chidamide and decitabine can synergistically induce apoptosis of Hodgkin lymphoma cells by up-regulating the expression of PU.1 and KLF4. Oncotarget, 2017; 8:77586–77594.
26.
XiongD, XuY, LiuH, et al.Efficient inhibition of human B-cell lymphoma xenografts with an anti-CD20 x anti-CD3 bispecific diabody. Cancer Lett, 2002; 177:29–39.
27.
AnN, TaoZ, LiS, et al.Construction of a new anti-CD19 chimeric antigen receptor and the anti-leukemia function study of the transduced T cells. Oncotarget, 2016.
28.
XuY, LiaoR, LiN, et al.Phosphorylation of Tip60 by p38alpha regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. Oncotarget, 2014; 5:12555–12572.
29.
LiS, TaoZ, XuY, et al.CD33-specific chimeric antigen receptor T cells with different co-stimulators showed potent anti-leukemia efficacy and different phenotype. Hum Gene Ther, 2018; 29:626–639.
30.
WangY, XuY, LiS, et al.Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. J Hematol Oncol, 2018; 11:60.
31.
XuY, DongX, QiP, et al.Sox2 Communicates With Tregs Through CCL1 To Promote The Stemness Property Of Breast Cancer Cells. Stem Cells, 2017.
32.
SongE, SuC, FuJ, et al.Selenium supplementation shows protective effects against patulin-induced brain damage in mice via increases in GSH-related enzyme activity and expression. Life Sci, 2014; 109:37–43.
33.
XuY, ZhangS, NiuH, et al.STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer. Sci Rep, 2015; 5:11754.
34.
BettsMR, BrenchleyJM, PriceDA, et al.Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods, 2003; 281:65–78.
35.
CaloE, WysockaJ. Modification of enhancer chromatin: what, how, and why?. Mol Cell, 2013; 49:825–837.
36.
ChaseML, ArmandP. Minimal residual disease in non-Hodgkin lymphoma - current applications and future directions. Br J Haematol, 2017.
37.
HerreraAF, ArmandP. Minimal Residual Disease Assessment in Lymphoma: Methods and Applications. J Clin Oncol, 2017; 35:3877–3887.
38.
PrevodnikVK, LavrencakJ, HorvatM, et al.The predictive significance of CD20 expression in B-cell lymphomas. Diagn Pathol, 2011; 6:33.
39.
ChoiCH, ParkYH, LimJH, et al.Prognostic Implication of Semi-quantitative Immunohistochemical Assessment of CD20 Expression in Diffuse Large B-Cell Lymphoma. J Pathol Transl Med, 2016; 50:96–103.
40.
FryeR, MyersM, AxelrodKC, et al.Romidepsin: a new drug for the treatment of cutaneous T-cell lymphoma. Clin J Oncol Nurs, 2012; 16:195–204.
41.
BaldanF, MioC, LavaroneE, et al.Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells. Oncol Rep, 2015; 33:2199–2206.
42.
QinL, LaiY, ZhaoR, et al.Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells. J Hematol Oncol, 2017; 10:68.
43.
EshharZ. Tumor-specific T-bodies: towards clinical application. Cancer Immunol Immunother, 1997; 45:131–136.
44.
PanjwaniMK, SmithJB, SchutskyK, et al.Feasibility and safety of RNA-transfected CD20-specific chimeric antigen receptor T cells in dogs with spontaneous B cell lymphoma. Mol Ther, 2016; 24:1602–1614.
45.
GargettT, BrownMP. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol, 2014; 5:235.
46.
MarshallMJE, StopforthRJ, CraggMS. Therapeutic antibodies: what have we learnt from targeting CD20 and where are we going?. Front Immunol, 2017; 8:1245.
47.
LachowiezC, DeodharA, KozinE, et al.Obinutuzumab is effective in chronic lymphocytic leukemia and rheumatoid arthritis after rituximab failure: a case report. Am J Case Rep, 2017; 18:516–519.
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
