Improved Activation toward Primary Colorectal Cancer Cells by Antigen-Specific Targeting Autologous Cytokine-Induced Killer Cells

Claudia Schlimper,Ingo G H Schmidt-Wolf,Andreas A Hombach,Hinrich Abken

doi:10.1155/2012/238924

Abstract

Adoptive therapy of malignant diseases with cytokine-induced killer (CIK) cells showed promise in a number of trials; the activation of CIK cells from cancer patients towards their autologous cancer cells still needs to be improved. Here, we generated CIK cells ex vivo from blood lymphocytes of colorectal cancer patients and engineered those cells with a chimeric antigen receptor (CAR) with an antibody-defined specificity for carcinoembryonic antigen (CEA). CIK cells thereby gained a new specificity as defined by the CAR and showed increase in activation towards CEA+ colon carcinoma cells, but less in presence of CEA− cells, indicated by increased secretion of proinflammatory cytokines. Redirected CIK activation was superior by CAR-mediated CD28-CD3ζ than CD3ζ signaling only. CAR-engineered CIK cells from colon carcinoma patients showed improved activation against their autologous, primary carcinoma cells from biopsies resulting in more efficient tumour cell lysis. We assume that adoptive therapy with CAR-modified CIK cells shows improved selectivity in targeting autologous tumour lesions.

Highlights

A variety of therapeutic options for metastatic colon cancer were evaluated during the last decade, most patients in advanced stages of the disease have no hope for cure by standard therapies
Compared to firstly activated effector T cells, ex vivo generated cytokine-induced killer (CIK) cells have a number of advantages since they exhibit properties different from effector or central memory T cells, that is, CIK cells are activated in an MHC-independent fashion [4, 5], produce proinflammatory cytokines, mainly IFN-γ and IL-4 [6, 7], and exhibit antigen-independent cytolytic activities against a variety of tumour cells
We explored whether activation of CIK cells from colorectal cancer patients toward their autologous tumour cells can be improved by chimeric antigen receptor (CAR)-mediated engagement of target cells

Summary

Introduction

A variety of therapeutic options for metastatic colon cancer were evaluated during the last decade, most patients in advanced stages of the disease have no hope for cure by standard therapies. One of the major pitfalls in the adoptive immunotherapy of cancer is the strikingly low activation of T cells from cancer patients compared to healthy donors due to reduced expression of TCR/CD3 components [2]. The need for alternative effector cells in targeting colorectal carcinoma becomes obvious by the fact that T cells infiltrating colon cancer metastases have reduced CD3ζ chain expression and lack tumour-specific activation [3]. Compared to firstly activated effector T cells, ex vivo generated cytokine-induced killer (CIK) cells have a number of advantages since they exhibit properties different from effector or central memory T cells, that is, CIK cells are activated in an MHC-independent fashion [4, 5], produce proinflammatory cytokines, mainly IFN-γ and IL-4 [6, 7], and exhibit antigen-independent cytolytic activities against a variety of tumour cells. After 2-3 weeks in culture, the majority of cells exhibit a large granular lymphocyte morphology and express both NK and T-cell markers including CD8, CD11a, CD49d, CD56, and NKG2D, while lacking most NK-

Methods

Results

Conclusion