Benonisson and Altintas et al. developed a bispecific antibody targeting mouse CD3ε and mouse TRP1 and tested it in a fully immunocompetent, syngeneic mouse B16F10 tumor model. The antibody briefly induced systemic T cell activation, which was followed by an infiltration of inflammatory macrophages into the tumor and a subsequent increase in intratumoral CD4+ and CD8+ T cells and NK cells. All treated mice experienced delayed tumor growth, and 50% survived long term. Tumor eradication could be mediated by CD4+ or CD8+ T cells alone, indicating redundancy, but no formation of long-term memory was observed.

Immunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field and multiple tumor-associated antigens (TAA) are evaluated for hematological and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences. Here, we investigated the systemic and intra-tumoral effects of a mouse CD3 bsAb in a fully immune-competent mouse melanoma model. Systemic administration of 0.5 mg/kg antibody induced a brief overall T-cell activation that was selectively sustained in the tumor microenvironment for several days. A fast subsequent influx of inflammatory macrophages into the tumor microenvironment was observed, followed by an increase in the number of CD4+ and CD8+ T cells. Although the capacity to directly kill melanoma cells in vitro was very modest, optimal tumor elimination was observed in vivo, even in the absence of CD8+ T cells, implying a redundancy in T-cell subsets for therapeutic efficacy. Finally, we took advantage of the full immune-competence of our mouse model and tested immune memory induction. Despite a strong initial immunity against melanoma, treatment with the CD3 bsAb did not install protective memory responses. The observed mechanisms of action revealed in this immune-competent mouse model might form a rational basis for combinatorial approaches.

Author Info: (1) Human Genetics, Leiden University Medical Center. (2) Translational Research, Genmab. (3) Medical Oncology, Leiden University Medical Center. (4) Preclinical in vivo Pharmacology, Genmab. (5)

Author Info: (1) Human Genetics, Leiden University Medical Center. (2) Translational Research, Genmab. (3) Medical Oncology, Leiden University Medical Center. (4) Preclinical in vivo Pharmacology, Genmab. (5) Genmab. (6) Translational Research, Genmab (Netherlands). (7) Translational Research, Genmab. (8) Human Genetics, LUMC. (9) Antibody Research & Technologies, Genmab. (10) Medical Oncology, Leiden University Medical Center t.van_hall@lumc.nl.

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