Adoptive T Cell Therapy of Viral Infection and Cancer [Elektronisk resurs] Ex vivo Expansion of Cytomegalovirus- and Prostate Antigen-specific T Cells

• The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (T H ) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system. To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65 495-503 peptide, a recombinant adenovirus coding for pp65, in vitro transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8 + T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4 + T H cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and T H cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells ex vivo from virtually all stem cell donors for adoptive T cell transfer. I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8 + T cells even when starting from undetectable frequencies (<0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8 + T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer. 

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Immunology in the medical area  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska och farmaceutiska grundvetenskaper  (hsv)

Immunologi inom det medicinska området  (hsv)

MEDICINE  (svep)

Microbiology, immunology, infectious diseases  (svep)

Immunology  (svep)

MEDICIN  (svep)

Mikrobiologi, immunologi, infektionssjukdomar  (svep)

Immunologi  (svep)

Genre

government publication  (marcgt)

Indexterm och SAB-rubrik

Immunology

Immunotherapy

Adoptive T cell therapy

Dendritic cell

T cell

Tetramer

Cytomegalovirus

Transplantation

pp65

Prostate cancer

TARP

Prostate antigens

Immunologi