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

Abstract

BackgroundAdoptive 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.ResultsAn 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.ConclusionsOur 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.

Spotlight on chimeric antigen receptor engineered T cell research and clinical trials in China

“…The spacers used in China are mainly CH 2 CH 3 , Fc hinge, and CD8 hinge (Deng et al, 2015;Guo et al, 2015;Wang et al, 2013) (Table 1). Recently, it has been reported that CH 2 CH 3 spacer could bind soluble Fc-receptors and cause off-target cell lysis (Almåsbak et al, 2015), and that the mutation or deletion of the CH 2 region could obviate this problem.…”

“…Also, other modifications are also introduced into CAR-T cells, such as CD137 co-stimulatory ligand expression (Zhao et al, 2015), bi-specific antigen recognition targeting prostate specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) (Kloss et al, 2013), and extracelluar matrix degradation with heparanase (Caruana et al, 2015) etc.. Recently, an on-switch CAR paradigm was also developed, which allowed the activation of CAR-T cells to be controlled by small molecules (Wu et al, 2015). Although the next generation strategies help to improve the function of CAR-T cells, they also increase the difficulty of gene modification, and the safety and efficacy of these newly developed constructs have yet to be established in human studies (Chmielewski and Abken, 2015).…”

“…The gene modification methods of CAR-T cells in China are mainly lentivirus , retrovirus transduction (Deng et al, 2015) and plasmid electro-transfection (Table 1). Virus transduction is favorable for inserting the gene of interest into the target cell genome and precipitating continuous expression.…”

Therapeutic strategies for targeting cancer stem cells

“…Preclinical models have been developed as a proof of concept that CARs could also be used to target CSCs. [57] Deng et al, [58] for instance, demonstrated that CAR T cell therapy could inhibit tumor growth of highly metastatic prostate cancer that expresses low levels of EpCAM. Other CSC-targeting adoptive T cell therapies include CAR T cells which bind to a CSCspecific N-glycosylation-dependent epitope of CD133, [59] high-molecular weight melanoma associated antigen or chondroitin sulfate proteoglycan 4-specific CAR T cells that were reported to specifically eliminate melanoma with a CSC phenotype, [60,61] and epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells which target glioma SCs.…”

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…CAR T cells @ C I C E d i z i o n i I n t e r n a z i o n a l i against PSMA (otherwise known as glutamate-carboxypeptidase) can specifically target in vitro such antigen-expressing cells and in vivo kill the tumor cells. In concurrent addition to CAR T cell adoptive immunotherapy,an administration of interleukin-2 (IL-2) may further increase immune responses (29,(48)(49)(50)(51)(52).…”