Eliminating Brain Tumors with an Immunotoxin

TO IMPROVE THE SURVIVAL OF PATIENTS with brain tumors, Vidya Chandramohan, Ph.D., focuses on developing bacterial toxin-based therapies for glioblastoma. Glioblastoma-targeting immunotoxins were made by fusing the D2C7 antibody that binds to proteins on most brain tumor cells and Pseudomonas bacterial toxin. The D2C7 immunotoxin was developed 30 years ago in the laboratory of Darell D. Bigner, MD, Ph.D. The D2C7 immunotoxin targets and kills tumor cells and simultaneously induces a robust immune response against the original tumor. Chandramohan and her team manufactured a clinical batch of the D2C7 immunotoxin, and all the preclinical toxicity studies were completed for Duke's FDA investigational new drug (IND) application. An ongoing D2C7 immunotoxin clinical trial has demonstrated encouraging results in patients with recurrent glioblastoma.

As a continuation of the D2C7 immunotoxin work, Chandramohan, an associate professor in the Departments of Neurosurgery and Pathology, and her team are testing combination immunotherapies that would boost the immune response induced by the D2C7 immunotoxin induced tumor cell killing. Their most crucial lab discoveries in the past five years include improved tumor cell killing and survival with D2C7 immunotoxin and T cell activating anti-PD-L1 antibody and enhanced tumor cell killing and survival with D2C7 immunotoxin and T cell and macrophage activating anti-CD40 antibody. Macrophage and T cells are two major immune cell types that play a significant role in tumor cell killing and memory response, preventing tumor recurrence. The seminal preclinical work by Chandramohan and her team has been translated into two clinical trials in patients with recurrent glioblastoma.

Future studies in the Chandramohan laboratory will focus on mechanistic studies to understand how D2C7 immunotoxin and anti-PD-L1 and D2C7 immunotoxin and anti-CD40 combination therapies improve survival and develop biomarkers that could predict clinical response to the two combination therapies. The development, preclinical testing, and clinical production and testing would not be possible without the continued support from Angels Among Us.