title: Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy.
abstract: A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer.
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology , Cambridge, Massachusetts 02139, United States.|Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
authors.forename: Vineethkrishna
authors.initials: V
authors.lastname: Chandrasekar
authors.affiliation: India Innovation Research Center and Invictus Oncology , New Delhi 110092, India.
authors.forename: Prithvi Raj
authors.initials: PR
authors.lastname: Pandey
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology , Cambridge, Massachusetts 02139, United States.|Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.|Dana Farber Cancer Institute , Boston, Massachusetts 02115, United States.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
keywords: cancer; immune checkpoint inhibitors; supramolecular therapeutics; targeted therapy