Targeting EpCAM (CD326) for immunotherapy in hepatoblastoma

Abstract

Hepatoblastoma (HB) is the most common liver cancer in children. Recurrence of HB after chemotherapy and surgery is frequent among high-risk patients and is associated with chemoresistance. Immunotherapy may improve poor treatment outcomes in HB patients. Cytotoxic leukocytes of the innate and adaptive immune system including different populations of cytotoxic T cells play a major role in fighting developing tumors. In this setting, monoclonal antibodies may be employed to specifically direct immune responses toward tumor cells. We addressed this issue by using humanized antibodies that recognize the cell surface molecule EpCAM (CD326, overexpressed in hepatic tumor cells) to enhance immune responses against HB. EpCAM was constantly expressed on HB cells and its expression was independent of previous therapy based on the DNA-damaging agent cisplatin. Co-culture assays performed with two well-described HB cell lines and tumor tissue cultures demonstrated that tumor cell lysis by γδ T cells can be dramatically augmented by applying EpCAM-specific monoclonal antibodies. These data emphasize the value of antitumor immune responses and encourage adapting immunotherapeutic regimens to improve the outcome of high risk HB.

Biomimetic strategies for targeted nanoparticle delivery

“…Cell adhesion molecules are proteins that cells use to bind other cells or extracellular matrix, and these comprise of immunoglobulins, cadherins, selectins, and integrins as the main subtypes . They are employed by a variety of cells, most notably on blood components, such as platelets and leukocytes, or those comprising endothelial surfaces.…”

“…Cell adhesion molecules are proteins that cells use to bind other cells or extracellular matrix, and these comprise of immunoglobulins, cadherins, selectins, and integrins as the main subtypes. [148][149][150] They are employed by a variety of cells, most notably on blood components, such as platelets and leukocytes, or those comprising endothelial surfaces. Despite their favorable binding characteristics and often sitespecific upregulation, the use of adhesion proteins in their entirety has not been commonly reported, most likely due to the difficulty associated with functionalizing nanoparticles using membrane-bound proteins.…”

Immunotherapy in Cancer Treatment

“…Rituxmab is a nmAB that binds to tumor-associated antigens (TAA) and is associated with antibody dependent cell-mediated cytotoxicity (ADCC) [85] and complement dependent cytotoxicity [86] [87]. Other mABs like catumaxomab are bispecific and can crosslink to two different antigens in a manner that retains the capability of activating immune effector functions to treat malignant ascites in patients with epithelial cell adhesion molecules (EPCAM) tumors with specificity to CD3 [88] [89]. Y-ibritumamabtrixetan and I-tositumamab are mAB coupled with toxins or radionucleotide which can recognize CD20 targets [90] [91].…”

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“…Fourth, naked TAA-specific mAbs that opsonize cancer cells and hence activate antibodydependent cell-mediated cytotoxicity (ADCC) [44,[57][58][59], antibody-dependent cellular phagocytosis [60], and complement-dependent cytotoxicity [61], such as the CD20-specific mAb rituximab, which is currently approved for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma [62,63]. Fifth, so-called "bispecific T-cell engagers" (BiTEs), i.e., chimeric proteins consisting of two single-chain variable fragments from distinct mAbs, one targeting a TAA and one specific for a T-cell surface antigen (e.g., blinatumomab, a CD19-and CD3 BiTE recently approved for the therapy of Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia) [64][65][66][67][68][69].…”