T cell receptor (TCR) gene therapy to treat melanoma: lessons from clinical and preclinical studies.
BACKGROUND
Adoptive T cell therapy (ACT) with tumour infiltrating lymphocytes is currently the best treatment option for metastatic melanoma. Despite its clinical successes, ACT has limitations in availability and generation of therapeutic T cells for a larger group of patients. Introduction of tumour-specific T cell receptors into T cells, termed TCR gene therapy, can provide an alternative for ACT that is more widely applicable and might be extended to other types of cancer.


METHODS
The current status of TCR gene therapy studies including clinical challenges, such as on-target toxicity, compromised anti-tumour T cell responses, compromised T cell persistence and potential immunogenicity of receptor transgenes. Strategies to address these challenges are covered.


RESULTS
A listing and discussion of strategies that aim at improving the efficacy and safety of TCR gene therapy. Such strategies address antigen choice, TCR mis-pairing, functional avidity and persistence of T cells, immune responses towards receptor transgenes, and combination of ACT with other therapies.


CONCLUSIONS
To ensure further clinical development of TCR gene therapy, it is necessary to choose safe T cell target antigens, and implement (combinations of) strategies that enhance the correct pairing of TCR transgenes and the functional avidity and persistence of T cells.
Erasmus MC-Daniel den Hoed Cancer Center, Laboratory of Experimental Tumor immunology, Rotterdam, The Netherlands.
Miriam
M
Coccoris
Trudy
T
Straetemans
Coen
C
Govers
Cor
C
Lamers
Stefan
S
Sleijfer
Reno
R
Debets
D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes
D011948:Receptors, Antigen, T-Cell