PD-L1 Bispecific & CXCL10 Armored CARs for Diffuse Midline Gliomas

ASPIRE Award (2023-Present)

Jim Olson, MD, PhD; Surojit Sarkar, PhD, Seattle Children's Research Institute

Jim Olson, MD, PhD

Surojit Sarkar, PhD

Diffuse midline gliomas (DMGs) are fatal tumors that arise in the brainstem of children and adolescents. Tragically, patients diagnosed with DMG typically survive for only 9-12 months, and their quality of life during this period is often severely compromised. Numerous clinical trials aiming to find effective treatments for DMG have unfortunately failed to demonstrate substantial benefits. However, a recent study to evaluate chimeric antigen receptor (CAR) T cells that target the surface protein B7-H3 demonstrated that the therapy was well tolerated, and induced stable disease for 12 months in one patient with recurrent DMG. B7-H3 is an immune checkpoint protein that is highly expressed during embryonic development but only at low levels after thereafter, and is found in some pediatric cancers, including DMG. Despite these promising initial results, the use of CAR T cells targeting B7-H3 remains limited due to several challenges. These obstacles include antigen heterogeneity and escape, CAR T cell exhaustion, and the overall scarcity of immune cells in the tumor microenvironment. In the case of DMG, B7-H3 is not present on all cancer cells within each patient’s tumor, and upregulation of the immune checkpoint protein PD-L1 can induce CAR T cell exhaustion, so the current generation of B7-H3 CAR T cells is not expected to be curative.

To overcome these barriers, Jim Olson and Surjit Sarkar have devised a plan to further enhance the B7-H3-directed CAR T cells. Their approach involves engineering these cells to secrete a bispecific T cell engager (BiTE) that targets PD-L1 on tumor cells and CD3 on T cells. The BiTE acts by creating an immune synapse, converting the tumor cells’ defense mechanism into a vulnerability, allowing for enhanced tumor cell killing. In addition, the CAR T cells will be engineered to secrete the chemokine CXCL10, which recruits endogenous immune cells into the tumor microenvironment to assist in tumor eradication. The effectiveness of these modified CAR T cells will be evaluated in both murine models and patient-derived orthotopic xenograft models. By overcoming the limitations of current CAR T cell therapies for DMG, Olson and Sarkar will develop this new treatment option with the eventual goal of establishing a clinical trial to target this devastating disease. This innovative strategy holds promise for transforming the treatment landscape of DMGs and offering hope to patients and their families who currently face a dire prognosis.