PURPOSE: Novel natural killer (NK) cell-directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule-related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell-resistant and autologous leukemia and tumor targets. EXPERIMENTAL DESIGN: In vitro-stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or G(D2)-specific chimeric receptors containing either the T-cell receptor zeta or 2B4 endodomain alone or combined. RESULTS: Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor zeta chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-gamma and tumor necrosis factor-alpha, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. CONCLUSION: These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4zeta-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
PURPOSE: Novel natural killer (NK) cell-directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule-related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell-resistant and autologous leukemia and tumor targets. EXPERIMENTAL DESIGN: In vitro-stimulated NK cells from healthy donors and pediatric leukemiapatients were gene modified with CD19 or G(D2)-specific chimeric receptors containing either the T-cell receptor zeta or 2B4 endodomain alone or combined. RESULTS: Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor zeta chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-gamma and tumor necrosis factor-alpha, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. CONCLUSION: These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4zeta-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
Authors: S Sivori; S Parolini; M Falco; E Marcenaro; R Biassoni; C Bottino; L Moretta; A Moretta Journal: Eur J Immunol Date: 2000-03 Impact factor: 5.532
Authors: L J Burns; D J Weisdorf; T E DeFor; D H Vesole; T L Repka; B R Blazar; S R Burger; A Panoskaltsis-Mortari; C A Keever-Taylor; M-J Zhang; J S Miller Journal: Bone Marrow Transplant Date: 2003-07 Impact factor: 5.483
Authors: Laurence J N Cooper; Max S Topp; Lisa Marie Serrano; Sergio Gonzalez; Wen-Chung Chang; Araceli Naranjo; Christine Wright; Leslie Popplewell; Andrew Raubitschek; Stephen J Forman; Michael C Jensen Journal: Blood Date: 2002-10-10 Impact factor: 22.113
Authors: Kyung-Mi Lee; Megan E McNerney; Susan E Stepp; Porunelloor A Mathew; John D Schatzle; Michael Bennett; Vinay Kumar Journal: J Exp Med Date: 2004-05-03 Impact factor: 14.307