Palmeri et al. fused an agonistic anti-4-1BB Ab and the collagen-binding domain of LAIR1 (ɑ4-1BB-LAIR). However, treating mouse tumor models with ɑ4-1BB-LAIR i.t. plus an Ab specific for tumor-expressed antigen i.p. (combTx) had modest impact. CombTx plus depletion of all CD4+ T or just Treg cells led to high cure rates to primary tumor inoculation, but not tumor rechallenge. FTY720 treatment revealed that CD4+ T cell depletion enabled de novo CD8+ T cell priming in the TdLN, and combTx supported their cytotoxic programming in the TME. Adding anti-CTLA-4 to combTx led to high cure rates to primary tumors, and resistance to tumor rechallenge.
Contributed by Paula Hochman
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 _4-1BB agonist (_4-1BB-LAIR), which consists of a _4-1BB 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 _CD4 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 _4-1BB-LAIR. The combination of TA99 and _4-1BB-LAIR with a clinically approved _CTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of _CTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (3) Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. (4) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (8) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. (9) Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. (10) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. wittrup@mit.edu. Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. wittrup@mit.edu. Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. wittrup@mit.edu.
