Generously funded by DUNN with Cancer

Sheila Singh – McMaster University, ON

Project Title: “Cotargeting Ephrin Receptor Tyrosine Kinases A2 and A3 in Glioblastoma using bispecific CAR-T immunotherapy”

Description of Project:

Glioblastoma (GBM) is the most common malignant primary adult brain tumor and is highly aggressive and resistant to standard therapies. Members of erythropoietin-producing hepatocellular carcinoma receptor (EphR) family are associated with GBM progression and poor patient prognosis. We hypothesize that targeting the EphR family will be an efficacious strategy for GBM treatment. Our previous studies have shown that EphA2 and EphA3 have been implicated in driving brain tumor initiating cells (BTICs) to escape therapy, thus accounting for GBM progression. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in rGBM that was enriched in BTIC marker expression. Knockdown of EPHA2 and EPHA3 in GBM cells together led to increased differentiation and blocked tumorigenic potential, promoting significantly higher survival of mice bearing human GBM tumors. Given our strong track record in developing immunotherapies for GBM, we propose to arm immune cells called T cells with a synthetic protein that binds to both EphA2 and A3, allowing these chimeric antigen receptor (CAR) T cells to recognize EphA2+/EphA3+GBM tumor cells and destroy them. By developing a therapy that specifically targets tumor cells at recurrence, we hope to alleviate disease burden and extend survival of GBM patients.

What receiving this award means:

“We are so grateful to the BTFC and DUNN with Cancer for the many levels of support they provide to the brain cancer research community. BTFC supports new ideas, innovation and transformative thinking about incredibly challenging problems like how to develop new treatments for a highly treatment-resistant brain tumour such as GBM. BTFC funds our trainees in a very challenging funding environment, and they provide them with an incredible community of support to promote their career development. Finally, BTFC supports our patient community, and by connecting patients with researchers, they give patients invaluable hope that science will pave the way to new and better treatments and better outcomes for Canadians with brain tumours. So thank you BTFC, on so many levels, for all that you do and special thank you to DUNN with Cancer for your support in making this award possible.”

Midpoint Update – March 2024

Our project, titled “Co-targeting Ephrin Receptor Tyrosine Kinases A2 and A3 in Glioblastoma using bispecific CAR-T immunotherapy,” seeks to address the formidable challenge posed by glioblastoma (GBM). Rooted in the recognition of intratumoral heterogeneity and potential role of Ephrin receptor (Eph) family in tumourigenesis and driving therapeutic resistance, our proposal sought to develop a novel therapeutic strategy using bispecific Chimeric Antigen Receptor (CAR) T cells against the EphA2 and EphA3 receptors. Over the past few months , we have made significant strides in the realization of our proposed objectives. We have been successful in generating EphA2/A3 CAR-T cells by successful transduction of healthy donor-derived T cells with the EphA2/A3 or EphA3/A2 CAR constructs. Additionally, we have conducted preliminary in vitro cytotoxicity assays against recurrent GBM patient-derived specimen, which has shown extremely promising results for this approach. Our efforts have transitioned towards optimizing the transduction efficiency of CAR-T cells and further testing their efficiency in vitro. Moving forward, we will soon evaluate the in vivo efficacy of the EphA2/3 CAR-T cells in our patient-derived xenograft models. We are appreciative of the invaluable support our partners at the Brain Tumour Foundation of Canada have provided in our pursuit of transformative therapeutic solutions against GBM.