Co-Investigators:
Stanford University: Carolyn Bertozzi, PhD, Ansuman Satpathy, MD, PhD, Irving Weissman, MD, Robbie Majzner, MD
University College London: Karen Page, DPhil, Karin Straathof, PhD, Marc-Olivier Coppens, PhD, Sergio Quezada, PhD, Kevin Litchfield, PhD
Children’s National Hospital: Conrad Russell Cruz, MD, PhD, Patrick Hanley, PhD, Amy Hont, MD, AeRang Kim MD, PhD, Holly Meany, MD, Anqing Zhang, PhD, Nitin Agrawal, PhD
The Children’s Hospital of Philadelphia: John Maris, MD, Mark Yarmarkovic, PhD, Nik Sgourakis, PhD, Patrick Grohar, MD, PhD
Cardiff University: Andrew Sewell, PhD
The Institute of Cancer Research: Terence Rabbitts, PhD
INSERM: Emmanuel Donnadieu, PhD
Cure rates for the majority of pediatric cancers improved incrementally in the later decades of the 20th century, based largely upon empiric adoptions of chemotherapeutics. However, progress has stalled for most pediatric solid malignancies over the last twenty years, with improvements achieved at the cost of significant treatment-related toxicity. While treatment for adult tumors have witnessed several new advances, as seen in immune checkpoint blockade and targeted small molecules, these are largely ineffective in pediatric cases and there remains an urgent need to develop new strategies to serve these patients.
One area which has seen remarkable success in both adult and pediatric cancer is engineered T-cell therapies. This therapeutic modality can achieve durable responses in refractory lymphoid cancers without long-term toxicity. However, expanding these treatments to solid tumors is formidable and has not seen similar success. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). These issues are compounded in pediatric tumors, which have a decreased mutational burden than adult tumors and have more limited preclinical models.
Now, the NexTGen team led by Martin Pule and Catherine Bollard will take these challenges head on. The team hypothesizes that by coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. This work will initially focus on pediatric sarcomas and brain tumors. Over the course of the project, they will combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T-cell function utilizing state of the art mass spectroscopy and chip cytometry. Protein engineering methods will be employed to engineer CAR-T receptors to target tumor cells and modulate the TME, and relevant tumor models such as immune patient derived xenografts will expand the preclinical models for pediatric tumors.
Crucially, the data generated in these studies will inform the opening of three early phase clinical studies for the treatment of high-risk pediatric sarcomas and brain tumors. These clinical studies will help answer questions related to next generation T-cell therapy development that can only be answered in human studies and will inform the ongoing work in real time.
The vision of the NexTGen team is that CAR T-cell therapy for childhood solid childhood cancers will become frontline within a decade, improving cure rates and mitigating current standard of care toxicity. The innovative and disruptive approaches being used by the team is what is needed to make this a reality and achieve robust and durable treatment responses in this setting. By bringing together a critical mass of diverse researchers with a focus on bench-to-bedside and clinical development, this work will overcome current challenges and begin to realize the promise of expanding T-Cell therapies for all.
published research
Papadaki GF, Woodward CH, Young MC, Winters TJ, Burslem GM, Sgourakis NG. A Chicken Tapasin ortholog can chaperone empty HLA-B∗37:01 molecules independent of other peptide-loading components. J Biol Chem. 2023.
Gupta S, Nerli S, Kutti Kandy S, Mersky GL, Sgourakis NG. HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes. Nat Commun. 2023.
McShan AC, Flores-Solis D, Sun Y, Garfinkle SE, Toor JS, Young MC, Sgourakis NG. Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition. Nat Commun. 2023.
Chin MHW, Reid B, Lachina V, Acton SE, Coppens MO. Bioinspired 3D microprinted cell scaffolds: Integration of graph theory to recapitulate complex network wiring in lymph nodes. Biotechnol J. 2023.
Sun Y, Florio TJ, Gupta S, Young MC, Marshall QF, Garfinkle SE, Papadaki GF, Truong HV, Mycek E, Li P, Farrel A, Church NL, Jabar S, Beasley MD, Kiefel BR, Yarmarkovich M, Mallik L, Maris JM, Sgourakis NG. Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion. Sci Immunol. 2023.