Augmentation of interleukin-2-induced activation of human melanoma tumor-infiltrating lymphocytes by heteroconjugate antibody.
Heteroconjugate (HC) antibody (anti-CD3 mAb x anti-p97 melanoma mAb) or monomeric anti-CD3 mAb by itself did not induce proliferation of uncultured melanoma tumor-infiltrating lymphocytes (TILs). They also failed to induce IL-2 production in uncultured TILs, although anti-CD3 mAb, but not HC antibody, stimulated IL-2 production in peripheral blood mononuclear cells (PBMCs). Sequential treatment of uncultured TILs from p97-antigen-positive (p97+) melanomas with HC antibody, followed by washing and incubation with interleukin-2 (IL-2), induced significantly higher proliferation than incubation with IL-2 alone. HC antibody pretreatment led to significantly greater results than with anti-CD3 mAb at a 1 ng/ml level in IL-2-induced proliferation of TILs from p97+ melanomas, similar to those with anti-CD3 mAb at a level of 100 ng/ml. HC antibody (1 ng/ml) pretreatment did not enhance IL-2-induced proliferation of either TILs from p97- melanomas or PBMCs, while anti-CD3 mAb enhanced the proliferation of TILs from some p97- melanomas and PBMCs. Regardless of the pretreatment of uncultured TILs with HC antibody or anti-CD3 mAb, IL-2-activated TILs were cytotoxic primarily only to autologous tumor cells, and their phenotypes remained the same. Thus, HC antibody can augment IL-2-induced activation of TILs only from p97+ melanomas, without altering their pattern of cytotoxicity or phenotype. The findings were consistent with observations at the clonal level. In contrast to anti-CD3 mAb, HC pretreatment of uncultured TILs from only p97+ melanoma prior to limiting-dilution analysis increased the number of proliferating TIL clones, including autologous tumor-specific cytotoxic T lymphocyte clones. These results suggest that use of HC antibody in vivo would be more advantageous than anti-CD3 mAb, with regard to augmentation of IL-2-induced TIL activation.
Mansfield
P F
PF
Department of General Surgery, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Rosenblum
M G
MG
Murray
J L
JL
Itoh
K
K
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D017252:CD3 Complex; D007376:Interleukin-2; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell