Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
2014 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, 30- p.Article in journal (Refereed) Published
Abstract [en]

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 zeta 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)-gamma 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.

Place, publisher, year, edition, pages
2014. Vol. 14, 30- p.
Keyword [en]
CAR T cells, PSCA, Genetic engineering, Prostate cancer, Adoptive transfer
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-218943DOI: 10.1186/1471-2407-14-30ISI: 000330050700001OAI: oai:DiVA.org:uu-218943DiVA: diva2:699388
Available from: 2014-02-27 Created: 2014-02-20 Last updated: 2017-12-05Bibliographically approved
In thesis
1. The Multiple Faces of Genetically-Modified T Cells: Potential Applications in Therapy
Open this publication in new window or tab >>The Multiple Faces of Genetically-Modified T Cells: Potential Applications in Therapy
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this PhD thesis the potential of T-cells as therapy for disease are explored. The applications of genetically modified T-cells for treatment of cancer and autoimmune disease; the functionality and optimal activation of T-cells are discussed.

Successful treatment of cancer with T-cell receptor (TCR)-modified T-cells was first reported in 2006, and is based on recognition of a specific peptide by the TCR in the context of the MHC molecule. As antigen presentation in tumors is often defective and to avoid MHC-restriction, chimeric antigen receptors (CAR) molecules containing an antibody part for recognition of cell surface antigens and TCR and co-receptor signaling domains have been developed. Activated T-cells mount an efficient immune response resulting in the killing of the cancer cell and initiating T-cell proliferation. The rationale for using genetically modified T-cells instead of isolating tumor infiltrating lymphocytes from the tumor and expanding them (TIL therapy) is that it is often very difficult to obtain viable lymphocytes that are able to expand enough in order to use them for therapy.

This thesis explores the possibility of using prostate-specific antigens to target T-cells towards prostate cancer. The prostate has many unique tissue antigens but most patients with metastatic prostate cancer have undergone prostatectomy and consequently have “prostate antigen” expression only in cancer cells. We targeted the prostate antigens TARP and PSCA with a HLA-A2 restricted TCR and a CAR respectively. In both cases the tumor-specific T-cells were able to generate potent proliferative and cytotoxic responses in vitro. The PSCA CAR-modified T-cells delayed subcutaneous tumor growth in vivo. It is evident from our in vivo experiments that the PSCA CAR T-cells were unable to completely cure the mice. Therefore, we aimed to improve the quality of the transferred T-cells and their resistance to the immunosuppressive tumor microenvironment. Stimulation with allogeneic lymphocyte-licensed DCs improved the resistance to oxidative stress and antitumor activity of the T-cells.

We further investigated the potential of genetically modified regulatory T-cells (Tregs) to suppress effector cells in an antigen-specific manner. Using a strong TCR we hypothesize that the phenotype of the TCR-transduced Tregs may be affected by antigen activation of those cells. We found that the engineered Tregs produced cytokines consistent with Th1, Th2 and Treg phenotypes.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1032
Keyword
cancer immunotherapy, genetically engineered T cells, chimeric antigen receptor, T cell receptor, antigen-specific T cells, immunotherapy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Immunology; Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-232850 (URN)978-91-554-9050-8 (ISBN)
Public defence
2014-11-15, Rudbecksalen, Dag Hammarsjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-24 Created: 2014-09-25 Last updated: 2015-01-23

Open Access in DiVA

fulltext(517 kB)184 downloads
File information
File name FULLTEXT01.pdfFile size 517 kBChecksum SHA-512
3eceeb2e4108a5e72af03923c4a040128c69974feebcbf534362380c0817301b845f30f357c8f7471645e04af0753ee62fbd2194c5367de1e8480f3e581ce36a
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Hillerdal, VictoriaRamachandran, MohanrajLeja, JustynaEssand, Magnus
By organisation
Clinical Immunology
In the same journal
BMC Cancer
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 184 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 803 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf