Immune stimulatory effect of anti-EpCAM immunotoxin – improved overall survival of metastatic colorectal cancer patients

Abstract

Introduction: In a recent phase I trial in a heterogeneous group of carcinoma patients with advanced disease, we did not observe objective responses by CT at 8 weeks in patients treated with either the anti-EpCAM immunotoxin MOC31PE alone or administered in combination with the immunosuppressor cyclosporin (CsA). We have now assessed overall survival (OS) data for the two groups to reveal potential differences, and to elucidate putative underlying mechanisms.

Material and methods: The OS time of MOC31PE monotherapy (34 patients) and MOC31PE in combination with CsA (23 patients), was assessed. Pre- and post-treatment patient sera were analyzed in a multiplex immunoassay, and the immunogenic effects of MOC31PE were studied in vitro and in a dendritic cell maturation assay.

Results: When the data were analyzed for all treated patients regardless of cancer type, the MOC31PE alone group had a median OS of 12.7 months (95% CI = 5.6–19.8 months) compared to 6.2 months (95% CI = 5.6–6.8 months) (p=.066) for the patients treated with MOC31PE + CsA group. For the subgroup of patients with colorectal cancer, the median OS survival was 16.3 months (95% CI = 5.6–27.0) for the MOC31PE only cohort (n = 15), compared to 6.0 months (CI = 5.8–6.2) (p < .001) for the combination group. The cytokine profile in patient sera and the in vitro immunological studies indicate that MOC31PE induced an immunogenic response leading to T-cell activation; a response that was suppressed in patients treated with MOC31PE + CsA.

Conclusions: The results reveal a promising clinical benefit of anti-EpCAM immunotoxin treatment in patients with advanced disease, an effect apparently explained by a previously unknown immunogenic effect of MOC31PE.

Acknowledgments

The authors are grateful for the assistance from Dr. Hans Christian Aass with cytokine analyses. The authors thank Dr. Kjetil Boye for assistance with SSPS and critical reading.

Author contributors

YA, EMI, GK, SD, and OF designed this study. YA, TMH and EMI did laboratory experimentation, analysis and prepared figures. SD, OE, OF and YA collected patient data and provided clinical interpretations. All authors contributed to and approved the final manuscript.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was supported by The Norwegian Cancer Society, Norwegian Research Council, South-Eastern Norway Regional Health Authority and Norwegian Radium Hospital Legacy.