Date/Time
Date(s) - 25/05/2021
1:30 pm - 2:30 pm

Title:                     Local sustained delivery of antibody therapeutics from injectablehydrogels for the treatment of glioblastoma

Date:                    Tuesday, May 25, 2021

Time:                    1:30 p.m.   

Zoom:                    available from macchem@mcmaster.ca                               

Host:                    Dr. Ryan Wylie 

Abstract:                    

Modern production techniques and new therapeutic targets hasresulted in the development of different antibody-based treatment modalities,increasing the repertoire of viable drug candidates. The clinical successof immune checkpoint inhibitors (ICIs) has generated great interest inantibody-based drugs as cancer immunotherapeutics.  

The lack of treatment options for glioblastoma, the most malignantglioma, has expedited the investigation of antibody immunotherapeutics forglioblastoma. However, glioblastoma’s low tumor mutational burden (TMB) andimmunosuppressive tumor immune microenvironment (TIME) render ICI monotherapiesineffective. Furthermore, physiological barriers (blood-brain barrier) impededrug localization, requiring high systemic doses that result in severeimmunological side effects. To address these limitations, we demonstrate thebenefit of: (1) local sustained release of antibody immunotherapeutics toincrease the duration and magnitude of anti-cancer response and, (2)combination therapies to further promote immune cell mediated killing ofglioblastoma.

With the goal of creating an implant for the local infusion ofimmunotherapeutics (LIIT), herein, I describe the development of an injectablehydrogel that incorporates an affinity based drug delivery system (DDS). Usingwell known affinity interactions, a three component DDS referred to ascompetitive affinity release (CAR) released a bioactive antibody for >100d.CAR was then modified to a new system called displacement affinity release(DAR), for the delivery of minimally modified antibody. An in situ gelling,injectable, low-fouling poly(carboxybetaine) hydrogel was fabricated for thelocalization of the DDS.

The DDS hydrogel combination was used to deliver a dual antigen Tcell engager (DATE) targeting CD133 positive glioblastoma cells in 3D embeddedspheroid cultures and a patient derived xenograft model. Controlled release ofCD133 targeting DATE increased survival benefit within the xenograft model.Within the 3D embedded spheroid model, the combination therapy of DATE with an?PD-1 ICI increased and sustained cytotoxic effects. 

Here I developed a platform technology for the local infusion ofimmunotherapeutics (LIIT), amenable to any antibody cancer immunotherapeutics.This project demonstrates how local infusion with immunostimulatory drugs canincrease the magnitude and duration of anti-cancer immunotherapy inglioblastoma where physiological barriers impede drug accumulation.