T-cell stimulating vaccines empower CD3 bispecific antibody therapy in solid tumors

Jim Middelburg, Marjolein Sluijter, Gaby Schaap, Büşra Göynük, Katy Lloyd, Vitalijs Ovcinnikovs, Gijs G. Zom, Renoud J. Marijnissen, Christianne Groeneveldt, Lisa Griffioen, Gerwin G. W. Sandker, Sandra Heskamp, Sjoerd H. Burg, Tsolere Arakelian, Ferry Ossendorp, Ramon Arens, Janine Schuurman, Kristel Kemper and Thorbald Hall ()
Additional contact information
Jim Middelburg: Leiden University Medical Center
Marjolein Sluijter: Leiden University Medical Center
Gaby Schaap: Leiden University Medical Center
Büşra Göynük: Leiden University Medical Center
Katy Lloyd: Genmab
Vitalijs Ovcinnikovs: Genmab
Gijs G. Zom: Genmab
Renoud J. Marijnissen: Genmab
Christianne Groeneveldt: Leiden University Medical Center
Lisa Griffioen: Leiden University Medical Center
Gerwin G. W. Sandker: Radboud Institute for Molecular Life Sciences
Sandra Heskamp: Radboud Institute for Molecular Life Sciences
Sjoerd H. Burg: Leiden University Medical Center
Tsolere Arakelian: Leiden University Medical Center
Ferry Ossendorp: Leiden University Medical Center
Ramon Arens: Leiden University Medical Center
Janine Schuurman: Genmab
Kristel Kemper: Genmab
Thorbald Hall: Leiden University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44308-6

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