To improve the efficacy of CD3 bispecific antibodies (bsAb) in immunologically “cold” solid tumors, Middelburg et al. used various vaccine formulations (long peptides adjuvanted with imiquimod and IL-2 or CpG, or virus-based) to induce activation and influx of peripheral T cells into tumors. Vaccine-recruited CD8+ T cells served as critical effector cells for subsequently administered CD3 bsAb, and the addition of CD3 bsAb facilitated deeper infiltration of T cells into the tumor center. The combination treatment, even with vaccines that did not contain relevant tumor antigens, induced a broadly inflamed Th1 tumor microenvironment and resulted in improved antitumor activity.
Contributed by Ute Burkhardt
ABSTRACT: CD3 bispecific antibody (CD3 bsAb) therapy is clinically approved for refractory hematological malignancies, but responses in solid tumors have been limited so far. One of the main hurdles in solid tumors is the lack of sufficient T-cell infiltrate. Here, we show that pre-treatment vaccination, even when composed of tumor-unrelated antigens, induces CXCR3-mediated T-cell influx in immunologically 'cold' tumor models in male mice. In the absence of CD3 bsAb, the infiltrate is confined to the tumor invasive margin, whereas subsequent CD3 bsAb administration induces infiltration of activated effector CD8 T cells into the tumor cell nests. This combination therapy installs a broadly inflamed Th1-type tumor microenvironment, resulting in effective tumor eradication. Multiple vaccination formulations, including synthetic long peptides and viruses, empower CD3 bsAb therapy. Our results imply that eliciting tumor infiltration with vaccine-induced tumor-(un)related T cells can greatly improve the efficacy of CD3 bsAbs in solid tumors.
Author Info: (1) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden Univer
Author Info: (1) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (5) Genmab, Utrecht, the Netherlands. (6) Genmab, Utrecht, the Netherlands. (7) Genmab, Utrecht, the Netherlands. (8) Genmab, Utrecht, the Netherlands. (9) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (10) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (11) Department of Medical Imaging, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. (12) Department of Medical Imaging, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. (13) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (17) Genmab, Utrecht, the Netherlands. (18) Genmab, Utrecht, the Netherlands. (19) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. t.van_hall@lumc.nl.
