TY - JOUR
T1 - Interleukin-2-transduced lymphocytes grow in an autocrine fashion and remain responsive to antigen
AU - Treisman, Jonathan
AU - Hwu, Patrick
AU - Minamoto, Seijiro
AU - Shafer, Gwen E.
AU - Cowherd, Robert
AU - Morgan, Richard A.
AU - Rosenberg, Steven A.
PY - 1995/1/1
Y1 - 1995/1/1
N2 - 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 (neo(r)) gene. In contrast, the cells transduced with an IL-2 vector in which the neo(r) 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.
AB - 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 (neo(r)) gene. In contrast, the cells transduced with an IL-2 vector in which the neo(r) 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.
UR - http://www.scopus.com/inward/record.url?scp=0028813149&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028813149&partnerID=8YFLogxK
U2 - 10.1182/blood.v85.1.139.bloodjournal851139
DO - 10.1182/blood.v85.1.139.bloodjournal851139
M3 - Article
C2 - 7803791
AN - SCOPUS:0028813149
SN - 0006-4971
VL - 85
SP - 139
EP - 145
JO - Blood
JF - Blood
IS - 1
ER -