Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice.

Abstract

BACKGROUND:

Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer.

METHODS:

We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student's t-test), proliferation (paired Student's t-test), CD107a expression (paired Student's t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves).

RESULTS:

PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice.

CONCLUSIONS:

Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer.

• Authors: Victoria Hillerdal, Mohanraj Ramachandran, Justyna Leja, Magnus Essand
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 30 (Jan 18 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 24438073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cytokines
• GPI-Linked Proteins
• Lysosomal-Associated Membrane Protein 1
• Neoplasm Proteins
• PSCA protein, human
• Receptors, Antigen, T-Cell
• Recombinant Fusion Proteins

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Cell Degranulation
• Cell Line, Tumor
• Cell Proliferation
• Coculture Techniques
• Cytokines (metabolism)
• Cytotoxicity, Immunologic
• GPI-Linked Proteins (immunology)
• Genetic Therapy (methods)
• Humans
• Immunotherapy, Adoptive (methods)
• Lysosomal-Associated Membrane Protein 1 (metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Proteins (immunology)
• Prostatic Neoplasms (genetics, immunology, metabolism, pathology, therapy)
• Receptors, Antigen, T-Cell (biosynthesis, genetics)
• Recombinant Fusion Proteins (biosynthesis)
• T-Lymphocytes (immunology, metabolism, transplantation)
• Time Factors
• Transduction, Genetic
• Transfection
• Tumor Burden