Reference | 1. Oncoimmunology. 2017 Jun 28;6(8):e1338239. doi: 10.1080/2162402X.2017.1338239.
eCollection 2017.
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EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with
Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor
immunity.
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Albu DI(1), Wang Z(1), Huang KC(1), Wu J(1), Twine N(1), Leacu S(1), Ingersoll
C(1), Parent L(1), Lee W(1), Liu D(1), Wright-Michaud R(1), Kumar N(1), Kuznetsov
G(1), Chen Q(1), Zheng W(1), Nomoto K(2), Woodall-Jappe M(2), Bao X(1).
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Author information: <br>
(1)Andover Innovative Medicines Institute, Eisai Inc., Andover, MA, USA.
(2)Oncology Business Group, Eisai Inc., Woodcliff Lake, NJ, USA.
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Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting
alternatively activated tumor associated macrophages (M2TAM), myeloid-derived
suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising
strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an
arachidonic acid pathway metabolite and mediator of chronic inflammation, has
emerged as a powerful immunosuppressor in the TME through engagement with one or
more of its 4 receptors (EP1-EP4). We have developed E7046, an orally
bioavailable EP4-specific antagonist and show here that E7046 has specific and
potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell
differentiation and activation. E7046 treatment reduced the growth or even
rejected established tumors in vivo in a manner dependent on both myeloid and
CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an
IL-2-diphtheria toxin fusion protein that preferentially kills Tregs,
synergistically disrupted the myeloid and Treg immunosuppressive networks,
resulting in effective and durable anti-tumor immune responses in mouse tumor
models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+
cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic
inflammation phenotype into acute inflammation, shown by substantial induction of
STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic
anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been
reported to diminish intratumoral Tregs. Our studies thus reveal a specific
myeloid cell differentiation-modifying activity by EP4 blockade and a novel
combination of E7046 and E7777 as a means to synergistically mitigate both
myeloid and Treg-derived immunosuppression for cancer treatment in preclinical
models.
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