TY - JOUR
T1 - Tumor-infiltrating lymphocytes can be activated in situ by using in vivo activants plus F(ab')2 bispecific antibodies
AU - Thibault, Claude
AU - Nelson, Heidi
AU - Chapoval, Andrei I.
PY - 1996
Y1 - 1996
N2 - In vitro-activated T lymphocytes can be retargeted with anti-CD3 x anti-tumor bispecific antibodies (BsAb) to kill tumor cells in vitro and in vivo. The purpose of the present study was to examine the systemic and intra-tumor effects of in vivo T-cell activation with BsAb, staphylococcal enterotoxin B (SEB), and β-glucan in combination with BsAb as a retargeting agent. CL-62 melanoma cells were injected subcutaneously into C3H/HeN mice. Mice were subsequently treated with BsAb alone or with SEB or β-glucan plus BsAb. Fresh splenocytes, lymph-node cells and tumor-infiltrating lymphocytes (TIL) were tested for their proliferative response using incorporation of 2H-thymidine, and for their ability to lyse CL-62 cells in the presence or absence of BsAb in 4-hr 51Chromium release assays. Toxicity of treatments was assessed in a D-galactosamine model. BsAb, alone or combined with β- glucan, had essentially no effect on systemic T-cell cytotoxicity, and essentially no effect on systemic proliferation, unless exogenous IL-2 was provided. At the tumor site, BsAb alone, BsAb plus β-glucan, and SEB plus BsAb all significantly increased BsAb-mediated TIL cytotoxicity. In contrast to the TIL-limited effects of BsAb and of BsAb plus β-glucan, SEB plus BsAb markedly increased both systemic and intra-tumor T-lymphocyte activation. Toxicity correlated with measures of systemic activation, with limited effects from BsAb alone and from β-glucan plus BsAb, and with marked lethality from SEB plus BsAb. Overall, these results suggest moderate intra- tumor activation of TIL, but no measurable systemic activation after in vivo treatment with BsAb or β-glucan plus BsAb. SEB plus BsAb results in complete T-cell activation in both systemic and intra-tumor compartments, but at the expense of increased systemic toxicity. In conclusion, TIL can be activated in situ with different combinations of in vivo activants. In vivo- activated TIL can be retargeted with bispecific antibodies to lyse tumor cells, and may be an alternative to ex vivo T-cell activation and adoptive transfer therapy.
AB - In vitro-activated T lymphocytes can be retargeted with anti-CD3 x anti-tumor bispecific antibodies (BsAb) to kill tumor cells in vitro and in vivo. The purpose of the present study was to examine the systemic and intra-tumor effects of in vivo T-cell activation with BsAb, staphylococcal enterotoxin B (SEB), and β-glucan in combination with BsAb as a retargeting agent. CL-62 melanoma cells were injected subcutaneously into C3H/HeN mice. Mice were subsequently treated with BsAb alone or with SEB or β-glucan plus BsAb. Fresh splenocytes, lymph-node cells and tumor-infiltrating lymphocytes (TIL) were tested for their proliferative response using incorporation of 2H-thymidine, and for their ability to lyse CL-62 cells in the presence or absence of BsAb in 4-hr 51Chromium release assays. Toxicity of treatments was assessed in a D-galactosamine model. BsAb, alone or combined with β- glucan, had essentially no effect on systemic T-cell cytotoxicity, and essentially no effect on systemic proliferation, unless exogenous IL-2 was provided. At the tumor site, BsAb alone, BsAb plus β-glucan, and SEB plus BsAb all significantly increased BsAb-mediated TIL cytotoxicity. In contrast to the TIL-limited effects of BsAb and of BsAb plus β-glucan, SEB plus BsAb markedly increased both systemic and intra-tumor T-lymphocyte activation. Toxicity correlated with measures of systemic activation, with limited effects from BsAb alone and from β-glucan plus BsAb, and with marked lethality from SEB plus BsAb. Overall, these results suggest moderate intra- tumor activation of TIL, but no measurable systemic activation after in vivo treatment with BsAb or β-glucan plus BsAb. SEB plus BsAb results in complete T-cell activation in both systemic and intra-tumor compartments, but at the expense of increased systemic toxicity. In conclusion, TIL can be activated in situ with different combinations of in vivo activants. In vivo- activated TIL can be retargeted with bispecific antibodies to lyse tumor cells, and may be an alternative to ex vivo T-cell activation and adoptive transfer therapy.
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U2 - 10.1002/(SICI)1097-0215(19960717)67:2<232::AID-IJC14>3.3.CO;2-1
DO - 10.1002/(SICI)1097-0215(19960717)67:2<232::AID-IJC14>3.3.CO;2-1
M3 - Article
C2 - 8760593
AN - SCOPUS:0029809014
SN - 0020-7136
VL - 67
SP - 232
EP - 237
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -