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.
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+) 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(-1)), MEDI-565+ T cells caused reduced proliferation and enhanced apoptosis of CEA+ 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.
Osada
T
T
Department of Surgery, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA.
Hsu
D
D
Hammond
S
S
Hobeika
A
A
Devi
G
G
Clay
T M
TM
Lyerly
H K
HK
Morse
M A
MA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000502:physiology; D053804:Granzymes / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D018033:Antibodies, Bispecific; D017252:CD3 Complex; D002272:Carcinoembryonic Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009944:Organoplatinum Compounds; D019014:fas Receptor; D000077150:Oxaliplatin; D053804:Granzymes