Vallera et al. bioengineered CAM1615HER2, a tri-specific killer engager (TriKE) consisting of an antibody fragment recognizing CD16 and a scFv recognizing HER2, linked by a human IL-15 molecule. In vitro, CAM1615HER2 enhanced NK cell expansion; increased degranulation and IFNγ production in response to HER2+ target cells; and increased NK cell-mediated killing of a variety of HER2+ cancer cell lines and ovarian cancer spheroids. When using NK cells taken from patient tumors (vs. healthy donor PBMCs), these effects were less pronounced. In a xenograft mouse model, CAM1615HER2 mediated tumor control and increased survival.
Contributed by Lauren Hitchings
ABSTRACT: Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKE(TM)) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.
Author Info: (1) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455, USA. (2) Masonic C
Author Info: (1) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455, USA. (2) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455, USA. (3) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (4) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (5) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN 55455, USA. (6) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (7) Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
