Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM

BMC Immunology

Yu-Qian Zhang¹  Shuren Zhang¹  Wenbo Ma¹  Yanhong Wu¹  Zhenling Deng¹ 

[1] Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China

关键词: Prostate cancer;    EpCAM;    Cancer stem cell;    Chimeric antigen receptor;    Adoptive T-cell transfer;   

Others  :  1123261
DOI  :  10.1186/s12865-014-0064-x

【 摘 要 】

Background

Adoptive transfer of tumor infiltrating or circulating lymphocytes transduced with tumor antigen receptors has been examined in various clinical trials to treat human cancers. The tumor antigens targeted by transferred lymphocytes affects the efficacy of this therapeutic approach. Because cancer stem cells (CSCs) play an important role in tumor growth and metastasis, we hypothesized that adoptive transfer of T cells targeting a CSC antigen could result in dramatic anti-tumor effects.

Results

An EpCAM-specific chimeric antigen receptor (CAR) was constructed to transduce human peripheral blood lymphocytes (PBLs) and thereby enable them to target the CSC marker EpCAM. To investigate the therapeutic capabilities of PBLs expressing EpCAM-specific CARs, we used two different tumor models, PC3, the human prostate cancer cell line, which has low expression levels of EpCAM, and PC3M, a highly metastatic clone of PC3 that has high expression levels of EpCAM. We demonstrate that CAR-expressing PBLs can kill PC3M tumor cells in vitro and in vivo. Despite the low expression of EpCAM on PC3 cells, CAR-expressing PBLs significantly inhibited tumor growth and prolonged mouse survival in a PC3 metastasis model, probably by targeting the highly proliferative and metastatic population of cancer cells.

Conclusions

Our data demonstrate that PBLs expressing with EpCAM-specific CARs have significant anti-tumor activity against prostate cancer. Therefore, the adoptive transfer of T cells targeting EpCAM could have great potential as a cancer treatment.

【 授权许可】

   
2015 Deng et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al.: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005, 23(10):2346-57.
• [2]Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME: Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008, 8(4):299-308.
• [3]June CH: Adoptive T cell therapy for cancer in the clinic. J Clin Investig 2007, 117(6):1466-76.
• [4]Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al.: Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006, 314(5796):126-9.
• [5]Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, et al.: Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 2007, 15(4):825-33.
• [6]Visvader JE, Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008, 8(10):755-68.
• [7]Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003, 100(7):3983-8.
• [8]Gires O, Klein CA, Baeuerle PA: On the abundance of EpCAM on cancer stem cells. Nat Rev Cancer 2009, 9(2):143. author reply 143
• [9]Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al.: Identification of pancreatic cancer stem cells. Cancer Res 2007, 67(3):1030-7.
• [10]O'Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445(7123):106-10.
• [11]Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al.: Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445(7123):111-5.
• [12]Ni J, Cozzi PJ, Duan W, Shigdar S, Graham PH, John KH, et al.: Role of the EpCAM (CD326) in prostate cancer metastasis and progression. Cancer Metastasis Rev 2012, 31(3–4):779-91.
• [13]Ni J, Cozzi P, Hao J, Beretov J, Chang L, Duan W, et al.: Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell Biol 2013, 45(12):2736-48.
• [14]Grosse-Hovest L, Hartlapp I, Marwan W, Brem G, Rammensee HG, Jung G: A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killing. Eur J Immunol 2003, 33(5):1334-40.
• [15]Zheng Z, Chinnasamy N, Morgan RA: Protein L: a novel reagent for the detection of Chimeric Antigen Receptor (CAR) expression by flow cytometry. J Transl Med 2012, 10:29. BioMed Central Full Text
• [16]Kochenderfer JN, Feldman SA, Zhao Y, Xu H, Black MA, Morgan RA, et al.: Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 2009, 32(7):689-702.
• [17]Sherman LA, Chattopadhyay S: The molecular basis of allorecognition. Annu Rev Immunol 1993, 11:385-402.
• [18]Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse effect following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010, 18:843-51.
• [19]Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al.: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012, 119:2709-20.
• [20]Zhang YQ, Tsai YC, Monie A, Wu TC, Hung CF: Enhancing the therapeutic effect against ovarian cancer through a combination of viral oncolysis and antigen-specific immunotherapy. Mol Ther 2010, 18(4):692-9.