Bispecific Antibody Therapeutics for Neuroblastoma and Diffuse Midline Glioma

PROJECT SUMMARY/ABSTRACT Clearly identified barriers have undermined the promise of immunotherapy for pediatric patients with solid or brain tumors. Most of these tumors lack genetic mutations that encode immunogenic proteins. Bispecific T cell engagers (BTEs) have potential to overcome this barrier by connecting cancer cells to endogenous host T

cells, bypassing T cell receptor-MHC I interactions to induce T cell expansion and T cell-mediated cancer cell death. Additional barriers in solid tumors are addressed in this application. Barrier #1 is the paucity of endogenous T cells in many pediatric solid and brain tumors. Aim 1 seeks to enhance T cell trafficking into

solid or brain tumors via two complementary strategies that involve self-disassembling polymeric chemokines. The significance of Aim 1 is that a solution for promoting T cell infiltration into pediatric solid tumors will enable BTE options for non-resectable or metastatic solid and brain tumors, potentially converting incurable

cancers to curable. Barrier #2, unique to brain tumor patients, is the blood brain barrier, which precludes many immunotherapeutics from entering the brain. Aim 2 was motivated by the unexpected result in our lab that a novel BTE that we engineered is driving significantly improved survival in a patient-derived mouse model of

diffuse midline glioma (DMG, aka DIPG) despite a relatively intact blood brain barrier. We seek to understand why this BTE is able to access the tumor and extend survival. We also seek to further optimize the BTE and test it in a variety of DMG models. The significance of Aim 2 is that DMG patients have an average life

expectancy of 12 months, and this molecule represents an immunotherapeutic option that does not require cellular engineering. Barrier #3 immunotherapy is that the CD3-binding components of most BTEs that have advanced to clinical development bind to CD3 on T cells via high-affinity CD3 binding domains that 1) trigger

excessive cytokine release, which causes life-threatening cytokine release syndrome (CRS) in some patients, 2) accelerates T cell exhaustion, and 3) drives BTE sequestration in liver and spleen. Aim 3 seeks to discover novel CD3 binding proteins (e.g., fully human antibodies or single chain binders) that can induce cancer cell

death with fewer liabilities. Such CD3 binders have been discovered by others but are locked in industry with no access provided to pediatric cancer researchers. The significance of Aim 3 is that our candidates could be substituted into Pediatric Immunotherapy Network BTEs to increase the likelihood that the resulting molecules

will be safer, more effective (because higher maximally tolerated doses might be expected if CRS risk is reduced), and more efficiently developed. Several protein therapeutics discovered in our lab are advancing in clinical development. We are ideally poised to overcome one or more of these barriers to help the community

provide effective “off-the-shelf” immunotherapy for children with immunologically “cold” solid or brain tumors. While independent, the Aims have potential to work synergistically with each other and with discoveries made by our colleagues in the Pediatric Immunotherapy Network.