Abstract 1177: Pharmacological stimulation of DLL1-Notch signaling as an effective cancer immunotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.1177-1177
• Main Authors: Biktasova, Asel K., Dudimah, Fred D., Uzhachenko, Roman, Arasada, Rajeswara Rao, Tchekneva, Elena E., Carbone, David P., Shanker, Anil, Dikov, Mikhail M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-1177

Our data demonstrated that in cancer, expression of Notch ligands is selectively altered and Notch signaling in the hematopoietic compartment is attenuated and associated with impaired anti-tumor immunity caused by the aberrant T cell differentiation and function. Our important and therapeutically relevant finding is that stimulation of DLL1-mediated Notch signaling by systemic administration of soluble multivalent (clustered) DLL1 efficiently restores Notch signaling in the hematopoietic compartment. Such therapy strongly activates Notch downstream signaling and variably modulates expression of Notch receptors and ligands. Clustered DLL1 treatment results in significant enhancement of tumor antigen-specific T cell immune responses and memory, decreased proportion of regulatory T cells, remarkably increased tumor infiltration by T cells, attenuated tumor vascularization, and suppression of tumor growth. In an inducible model of lung tumor expressing L858R mutant EGFR in lung epithelium, clustered DLL1 elicited robust anti-tumor immune responses in concert with EGFR inhibition by erlotinib and produced remarkably improved progression-free survival. It is also likely that more efficient tumor killing and induction of T cell memory would significantly delay tumor progression/recurrence. Activation of Notch signaling by multivalent DLL1 in a panel of lung cancer cells in vitro did not stimulate cells proliferative of colony-forming potential, but rather demonstrated inhibitory effect in several cases. Pharmacological stimulation of Notch by multivalent DLL1 might represent an efficient strategy for enhancement of anti-tumor immunity and targeting multiple mechanisms of tumor growth. Reagents based on the multivalent forms of Notch ligands can be efficiently utilized for the therapeutic modulation of Notch signaling. Citation Format: Asel K. Biktasova, Fred D. Dudimah, Roman Uzhachenko, Rajeswara Rao Arasada, Elena E. Tchekneva, David P. Carbone, Anil Shanker, Mikhail M. Dikov. Pharmacological stimulation of DLL1-Notch signaling as an effective cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1177. doi:10.1158/1538-7445.AM2014-1177