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Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Authors' Affiliations: ¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Center, and ² Division of Bone Marrow Transplant, Department of Medicine, Stanford University, Stanford, California; ³ Cancer Immunotherapy Program and Blood and Bone Marrow Transplant Programs, Roger Williams Medical Center, Providence, Rhode Island; and ⁴ Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California

Requests for reprints: Robert S. Negrin, Center for Clinical Sciences Research Building, Room 2205, 269 West Campus Drive, Stanford, CA 94305. Phone: 650-723-0836; Fax: 650-724-6182; E-mail: negrs{at}Stanford.edu.

Cytokine-induced killer (CIK) cells are ex vivo activated and expanded CD8⁺ natural killer T cells that have been shown to have antitumor activity. This is the first study exploring cell killing of primary ovarian carcinoma cells with and without bispecific antibodies. Primary cancer cells and autologous CIK cells were collected from women with epithelial ovarian cancer. Bispecific antibodies against cancer antigen-125 (BSAbxCA125) and Her2 (BSAbxHer2) were developed using chemical heteroconjugation. On fluorescence-activated cell sorting analysis, the expansion of CIK cells resulted in a significant increase of CD3⁺CD8⁺ and CD3⁺CD56⁺ T cells. With enhancement by bispecific antibodies, the mean percent lysis in a ⁵¹Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 21.7 ± 0.3% to 89.4 ± 2.1% at an E:T ratio of 100:1 (P < 0.001). Anti-NKG2D antibodies attenuated the CIK activity by 56.8% on primary cells (P < 0.001). In a xenograft severe combined immunodeficient mouse model, real-time tumor regression and progression was visualized using a noninvasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8⁺NKG2D⁺ CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 and BSAbxHer2 had significant reduction in tumor burden (P < 0.001 and P < 0.001) and improvement in survival (P = 0.05 and P = 0.006) versus those treated with CIK cells alone. Bispecific antibodies significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis seems to be mediated in part by the NKG2D receptor.

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