Interleukin-2-transduced lymphocytes grow in an autocrine fashion and remain responsive to antigen.
The maintenance of T lymphocytes in vivo after adoptive transfer for immunotherapy requires the systemic administration of interleukin-2 (IL-2), but prolonged administration of IL-2 is associated with substantial toxicity. The constitutive production of IL-2 by T cells may be an alternative method to prolong T-cell survival and potentially augment antitumor responses. To study the effects of constitutive production of IL-2 on the growth and antigen reactivity of a murine T cell, the sperm-whale myoglobin (SWM) specific T-cell line 14.1 was retrovirally transduced with the cDNA for IL-2. Cells that were transduced with vectors without an internal promoter were able to proliferate in the absence of exogenously added IL-2, and to grow in an autocrine fashion. These vectors used an internal ribosomal entry site (IRES) to allow translation of the neomycin phosphotransferase (neor) gene. In contrast, the cells transduced with an IL-2 vector in which the neor gene was under the transcriptional control of an internal SV-40 promoter failed to proliferate or grow in the absence of exogenously added IL-2. The proliferation of the cells growing without IL-2 could be inhibited with antibodies to the IL-2 receptor or to human IL-2, indicating that they were still IL-2 dependent. Despite their autocrine growth, no tumor formation was observed in syngeneic mice injected subcutaneously with the transduced cells, and the cells retained their antigen reactivity and specificity. These results suggest that autocrine growth of T cells for therapy will not interfere with effector function.
Treisman
J
J
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Hwu
P
P
Minamoto
S
S
Shafer
G E
GE
Cowherd
R
R
Morgan
R A
RA
Rosenberg
S A
SA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000502:physiology; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D018076:DNA, Complementary; D007376:Interleukin-2; D015375:Receptors, Interleukin-2