Vidyalakshmi Chandramohan

The lab began with the investigation of toxin-based targeted therapies for brain tumors, which led to the development of the dual specific immunotoxin (IT), D2C7-IT. D2C7-IT is a recombinant antibody fragment derived-IT with a high binding affinity for two of the most common established driver oncogenes of GBM, the wild type epidermal growth factor receptor (EGFRwt) and its mutant EGFR variant III (EGFRvIII). D2C7-IT has demonstrated a potent anti-tumor response in preclinical animal models of brain tumors. After completion of the D2C7-IT preclinical studies in GBM xenograft models, we manufactured good laboratory practice-grade D2C7-IT at Duke University and completed toxicity studies for an FDA-IND application. In an ongoing Phase I dose-escalation/expansion study of D2C7-IT (NCT02303678), we have observed encouraging survival outcomes.

My current research is focused on identifying novel therapeutic targets in the tumor microenvironment to enhance the efficacy of D2C7-IT and investigating predictive biomarkers for D2C7-IT in the clinic.

T-cell specific targeting: One of the projects in the laboratory is focused on targeting immune checkpoint pathways; specifically, the T cell receptors programmed cell death protein 1 (PD-1) and its ligand PD-L1. Historically, GBM is characterized by systemic and local immunosuppression. Hence, to control and eliminate brain tumors, effective tumor cell killing by cytotoxic agents and concurrent induction and maintenance of anti-tumor T cell function by blocking inhibitory receptors on T cells is imperative. By targeting PD-1 or PD-L1 in combination with D2C7-IT, we aim to generate a durable anti-tumor immune response in GBM patients. Based on our preclinical evidence, the Duke Neurosurgery clinical team is evaluating the combination of D2C7-IT+αPD-L1 in a clinical trial for rGBM patients (NCT04160494). In support of the ongoing clinical work, we are conducting comprehensive phenotyping of immune populations in the blood to identify cellular and molecular signatures to predict clinical response to D2C7-IT+αPD-L1 therapy.

Tumor-associated macrophages (TAMs) targeting: TAMs constitute 30-50% of the tumor mass and have been implicated in inhibiting the anti-tumor T cell response in GBM. The second arm of our laboratory focuses on overcoming TAM-mediated immunosuppression and engendering protective T cell responses via CD40 co-stimulation. We hypothesize that by leveraging the dual functionality of CD40 co-stimulation and subsequently eliminating TAM suppression and increasing T cell infiltration, that the anti-tumor efficacy of D2C7-IT can be enhanced, leading to a therapeutic benefit.

Identifying biomarkers for D2C7-IT/D2C7-IT+αPD-L1 therapies: To investigate predictive/prognostic immune signatures associated with D2C7-IT or D2C7-IT+αPD-L1 therapies, we are conducting multiparametric flow cytometry and gene expression analysis of peripheral blood mononuclear cells (PBMCs) from patients enrolled in our Phase 1 D2C7-IT or D2C7-IT+αPD-L1 clinical trials. Identification of predictive biomarkers will aid in the selection of GBM patients who will respond to D2C7-IT or D2C7-IT+αPD-L1 therapies.