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Chemokines: can effector cells be redirected to the site of the tumor?

ABSTRACT: Chemokines (ie, chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading to the clinical use of this cytokine family in new treatment approaches for patients with cancer.

SUBMITTER: Dubinett SM

PROVIDER: S-EPMC3076643 | biostudies-literature | 2010 Jul-Aug

REPOSITORIES: biostudies-literature

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Chemokines: can effector cells be redirected to the site of the tumor?

Dubinett Steven M SM Lee Jay M JM Sharma Sherven S Mulé James J JJ

Cancer journal (Sudbury, Mass.) 20100701 4

Chemokines (ie, chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading t ...[more]

PMID: 20693843

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Project description:The main challenge of adoptive therapy with Chimeric Antigen Receptor modified T cells (CAR T) is the application to the field of solid tumors, where the identification of a proper antigen has emerged as one of the major drawbacks to CAR T cell treatment success. CD44 is a glycoprotein involved in cell-cell and cell-matrix interactions. The isoform containing the variant domain 6 of CD44 gene (CD44v6) has been implicated in tumorigenesis, tumor cell invasion and metastasis and represents an attractive target for CAR T cell therapies. Targeting CD44v6 antigen has been shown to control tumor growth in acute myeloid leukemia and multiple myeloma mouse models. While CAR T approach for the treatment of B cell malignancies has shown great success, response rates among patients with solid cancer are less favorable. The purpose of our study was to test the efficacy of CD44v6.CAR T cells, produced in compliance with Good Manufacturing Practice (GMP), in adenocarcinoma tumor models. We generated a bicistronic retroviral vector containing the CD44v6 CAR and the HSV-TK Mut2 suicide gene to enhance the safety of the proposed CAR T cell therapy. CD44v6 transduced CAR T cells were homogeneously positive for ΔLNGFR selection marker, were enriched in T central memory (TCM) and T memory stem cells (TSCM) and displayed a highly activated phenotype. In vitro assays revealed antigen-specific activation and cytotoxicity of human CD44v6.CAR T cells against CD44v6 expressing tumor cell lines. When infused in immunodeficient tumor bearing mice, human CD44v6.CAR T cells were able to reach, infiltrate and proliferate at tumor sites, finally resulting in tumor growth control. Next, we checked if cells produced in compliance with GMP grade standards retained the same antitumor activity of those produced with research grade materials and protocols. Noteworthy, no differences in the potency of the CAR T obtained with the two manufacturing processes were observed. In conclusion, our preclinical results suggest that CD44v6.CAR T based adoptive therapy could be a promising strategy in solid cancer treatment.

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Chemokines: can effector cells be redirected to the site of the tumor?

Publications

Chemokines: can effector cells be redirected to the site of the tumor?

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