Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice.
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.
Victoria
V
Hillerdal
Mohanraj
M
Ramachandran
Justyna
J
Leja
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University SE-75185 Uppsala, Sweden. magnus.essand@igp.uu.se.
Magnus
M
Essand
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D058851:GPI-Linked Proteins / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D047368:Tumor Burden
D000951:Antigens, Neoplasm; D016207:Cytokines; D058851:GPI-Linked Proteins; D052118:Lysosomal-Associated Membrane Protein 1; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins