Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes.
The antitumor effect of adoptively transferred tumor-specific cytotoxic T lymphocytes (CTLs) is impaired by the limited capacity of these cells to expand within the tumor microenvironment. Administration of interleukin 2 (IL-2) has been used to overcome this limitation, but the systemic toxicity and the expansion of unwanted cells, including regulatory T cells, limit the clinical value of this strategy. To discover whether transgenic expression of lymphokines by the CTLs themselves might overcome these limitations, we evaluated the effects of transgenic expression of IL-2 and IL-15 in our model of Epstein Barr Virus-specific CTLs (EBV-CTLs). We found that transgenic expression of IL-2 or IL-15 increased the expansion of EBV-CTLs both in vitro and in vivo in a severe combined immunodeficiency disease (SCID) mouse model and enhanced antitumor activity. Although the proliferation of these cytokine genes transduced CTLs remained strictly antigen dependent, clinical application of this approach likely requires the inclusion of a suicide gene to deal with the potential development of T-cell mutants with autonomous growth. We found that the incorporation of an inducible caspase-9 suicide gene allowed efficient elimination of transgenic CTLs after exposure to a chemical inducer of dimerization, thereby increasing the safety and feasibility of the approach.
Quintarelli
Concetta
C
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Vera
Juan F
JF
Savoldo
Barbara
B
Giordano Attianese
Greta M P
GM
Pule
Martin
M
Foster
Aaron E
AE
Heslop
Helen E
HE
Rooney
Cliona M
CM
Brenner
Malcolm K
MK
Dotti
Gianpietro
G
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D041722:Genes, Transgenic, Suicide / Q000502:physiology*; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014161:Transduction, Genetic; D019076:Transgenes
D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2