Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody

Abstract

BACKGROUND: Novel technologies to redirect T-cell killing against cancer cells are emerging. We hypothesised that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T-cell killing mediated by carcinoembryonic antigen (CEA)/CD3-bispecific T-cell-engaging BiTE antibody (MEDI-565). METHODS: We analysed proliferation and lysis of CEA-positive (CEA þ ) CRC specimens that had survived previous systemic chemotherapy and biologic therapy to determine whether they could be killed by patient T cells engaged by MEDI-565 in vitro. RESULTS: At low concentrations (0.1 -1 ng ml À1 ), MEDI-565 þ T cells caused reduced proliferation and enhanced apoptosis of CEA þ human CRC specimens. High levels of soluble CEA did not impair killing by redirected T cells and there was no increase in resistance to T-cell killing despite multiple rounds of exposure. CONCLUSIONS: This study shows for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies, such as MEDI-565 that result in exposure of tumours to large numbers of T cells, is warranted.

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

“…63 A series of studies with MEDI-565 demonstrated that the BiTE Ò antibody construct could induce patient T cells to kill metastatic CRC specimens derived from patients previously treated with conventional chemotherapy. 64 Herein we extend these initial findings by characterizing the in vitro and in vivo pharmacology of MEDI-565. Key parameters assessed in this report include the BiTE Ò antibody construct's (a) bispecific binding capacity, (b) high potency of T cell killing of CEA-expressing cells, (c) functional effects on T cells, (d) mechanism of action of T cell killing, (e) ability to induce T cell killing of CEA-expressing cells independent of CEA density, of the presence of high levels of soluble CEA, or of the mutational status of tumor cell lines, and (f) capacity to inhibit growth of CEA-expressing tumors in xenograft mouse models.…”

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

“…Other members of the BiTE-family, which are in pre-clinical or clinical studies, are specific for carcino-embryonic antigen (CEA), EpCAM, CD33, HER2/neu, EGFR and the melanoma-specific chondroitin-sulfate proteoglycan (MCSP), also called High Molecular Weight Melanoma Associated Antigen (HMW-MAA) [94][95][96][97][98][99][100]. The MCSP-reactive BiTE was less potent in in vitro cytolysis experiments than expected [94].…”

Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

“…Furthermore, a CD3/EGFR BiTE ® caused acute toxicity in cynomolgus monkeys likely due to EGFR expression in normal tissue [10]. Not surprisingly, most CD3 bispecific proteins currently in clinical trials are targeting receptors whose expression is confined to the hematopoietic lineage (CD19, CD20, CD123) [6,11,12], or receptors with exceptionally high tumor specificity, such as carcinoembryonic antigen (CEA) [13], prostate-specific membrane antigen (PSMA) [14] or MHCI-gp100 complex [15]. Thus, the applicability of T cell redirection with currently available technologies is limited to antigens with extraordinarily high tumor specificity, which impedes the application to many solid tumor types, where no antigens with comparable high specificity are available.…”