CD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs

Joseph R. Palmeri, Brianna M. Lax, Joshua M. Peters, Lauren Duhamel, Jordan A. Stinson, Luciano Santollani, Emi A. Lutz, William Pinney, Bryan D. Bryson and K. Dane Wittrup ()
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Joseph R. Palmeri: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Brianna M. Lax: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Joshua M. Peters: Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
Lauren Duhamel: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Jordan A. Stinson: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Luciano Santollani: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Emi A. Lutz: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
William Pinney: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)
Bryan D. Bryson: Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
K. Dane Wittrup: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-45625-0

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