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T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

ABSTRACT: Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.

SUBMITTER: Parkhurst MR

PROVIDER: S-EPMC3048186 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

Parkhurst Maria R MR Yang James C JC Langan Russell C RC Dudley Mark E ME Nathan Debbie-Ann N DA Feldman Steven A SA Davis Jeremy L JL Morgan Richard A RA Merino Maria J MJ Sherry Richard M RM Hughes Marybeth S MS Kammula Udai S US Phan Giao Q GQ Lim Ramona M RM Wank Stephen A SA Restifo Nicholas P NP Robbins Paul F PF Laurencot Carolyn M CM Rosenberg Steven A SA

Molecular therapy : the journal of the American Society of Gene Therapy 20101214 3

Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was ind ...[more]

PMID: 21157437

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Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction

Project description:BackgroundRecently, a few researches focus on the correlation between postoperative carcinoembryonic antigen (post-CEA) and the outcome of colorectal cancer (CRC), but none investigates the predictive value of post-CEA in a prognostic model. Besides, current recommendations on the frequency of post-CEA surveillance are not individualized and well followed. There is an absence of identification of patients who are more likely to have abnormal post-CEA levels and need more frequent CEA measurements.MethodsConsecutive CRC patients who underwent curative surgery were enrolled and randomly divided into the discovery (n=352) and testing cohort (n=233). Impacts of preoperative CEA (pre-CEA) and post-CEA on prognosis were assessed. Cox regression model was applied to develop prognostic nomograms, which were validated by the concordance index (C-index), calibration curve, and receiver operating characteristic curve (ROC) analysis. And prediction improvement of the nomograms was assessed with net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Logistic regression was used to identify predictive risk factors and construct the prediction model for post-CEA elevation.ResultsPost-CEA independently predicted overall survival (OS) and disease-free survival (DFS), while pre-CEA did not. Post-CEA elevation represented higher risks in patients with normal pre-CEA, compared to those with persistent elevated CEA. The nomograms for OS and DFS were established with body mass index, tumor differentiation, N stage, lymphocyte-to-monocyte ratio, and post-CEA. The nomograms showed good calibration and superior discrimination than pTNM stage, with the C-index of 0.783 and 0.759 in the discovery set and 0.712 and 0.774 in the testing set for OS and DFS, respectively. Comparisons between models using IDI and NRI implied that the nomograms performed better than pTNM stage and the predictive power could be improved with the addition of post-CEA. The prediction model for post-CEA elevation was established with age, platelet-to-lymphocyte ratio, preoperative CA19-9, and pre-CEA. The AUC of the model in the two cohorts was 0.802 and 0.764, respectively.ConclusionsElevated post-CEA was a strong indicator of poor prognosis. The addition of post-CEA significantly enhanced the performance of prognostic nomograms. And the prediction model for post-CEA elevation may help identify patients who ought to reasonably receive more intensive postoperative surveillance of CEA levels.

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T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

Publications

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

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