CD3-mediated activation of tumor-reactive lymphocytes from patients with advanced cancer

Lymphocytes from blood or tumors of patients with advanced cancer did not p roliferate and produced very low levels of tumor necrosis factor and IFN-ga mma when cultured with autologous tumor cells. Proliferation and lymphokine production dramatically increased in the presence of beads conjugated with mAbs to CD3 plus mAbs to CD28 and/or CD40, and the lymphocytes destroyed t he tumor cells. Expression density of CD3 concomitantly increased from low to normal levels. Furthermore, beads providing a CD3 signal tin combination with CD28 or CD28 plus CD40) gave partial protection against the inhibitor y effect of transforming growth factor type pi on lymphocyte proliferation and production of tumor necrosis factor and IFN-gamma, MHC class I-restrict ed cytolytic T cells lysing autologous tumor cells in a 4-h Cr-51 release a ssay were generated when peripheral blood leukocytes were activated in the presence of autologous tumor cells and anti-CD3/CD28 or anti-CD3/CD28/CD40 beads. Experiments performed in a model system using anti-v-pl or anti-V-be ta2 mAbs to activate subsets of 7 cells expressing restricted T cell recept or showed that lymphocytes previously activated by anti-v-p can respond to CD3 stimulation with vigorous proliferation and lymphokine production while retaining their specificity, also in the presence of transforming growth f actor type pi. Our results suggest that T lymphocytes from cancer patients can proliferate and form Th1 type lymphokines in the presence of autologous tumor cell when properly activated, and that antigen released from killed tumor cells and presented by antigen-presenting cells in the cultures facil itates the selective expansion of tumor-directed, CD8(+) cytolytic T cells.