| Details: |
High Risk Neuroblastoma is the 4 th most common pediatric malignancy and is the most common
extracranial malignancy in children. It accounts for 12% of all childhood cancers and about 70% of
patients present with metastatic disease at diagnosis. The mean 5-year survival is at ~50%, despite
multimodal standard of care therapies. Similarly, pediatric glioblastoma is a leading cause of death in
children and patients have a mean survival of 20 months from diagnosis. Recurrent malignant glioma
has barely seen improvement of lifespan, in the last 30 years, from 4 months to 8 months. A unifying
barrier to immunotherapy success, for both neuroblastoma and glioblastoma, is their cold immune
microenvironment, where very few tumor reactive T cells are found within the tumors. While the
mechanisms of such an immune desert in these tumors are largely unknown, the selectivity of the
blood brain barrier is partly implicated in perpetuating the glioblastoma tumor microenvironment. B7-
H3 is a tumor antigen and is one of the leading clinical candidates for immunotherapeutic targeting, in
neuroblastoma and glioblastoma. I will be discussing our studies exploring a multifaceted approach in
targeting B7-H3 tumor antigen and, overcoming the challenges in immunotherapy for neuroblastoma
and glioblastoma. We have engineered chimeric antigen receptor (CAR) T cells, targeting B7-H3
tumor antigen, for enhanced homing to the cold neuroblastoma tumors and shifting it to a hot tumor
microenvironment. To bypass the selectivity of the blood brain barrier for glioblastoma tumors in the
brain, we have taken the approach of intracranial delivery of the immunotherapies, directly proximal to
the tumors. While these cold tumors harbor very few tumor antigen-specific T cells, due to low
mutational burden of the tumors, the endogenous non-tumor antigen specific T cells could be potential
strategic assets against the tumors – here we used bispecific T cell engagers (BiTE) targeted to the
B7-H3 tumor antigen and CD3 on T cells, to mobilize these bystander T cells against the tumors. To
further enhance the efficacy of these cellular immunotherapies, we have strategically used them in
combination with inhibitory checkpoint blockade, thereby targeting multiple mechanisms to overcome
the canonical barriers to immunotherapeutic success in neuroblastoma and glioblastoma. Our studies
lay a strong foundational groundwork in the next stage of clinical translation, for cellular
immunotherapies in neuroblastoma and glioblastoma. |