Watch this video to learn about a novel approach to improving checkpoint blockade therapy in cancer under investigation in early-phase trials by Joshua Brody, MD, and colleagues at the Icahn School of Medicine at Mount Sinai.
Enhancing Checkpoint Blockade in Lymphoma with In Situ Vaccination
Checkpoint blockade therapy for cancer has had tremendous impact on clinical outcomes, yet only a subset of patients respond. Recent studies show that response to checkpoint blockade does not always correlate with tumor-associated antigen (TAA) load and so must be determined by factors beyond mutational burden. This suggests that checkpoint blockade is limited by suboptimal cross-presentation of TAA by activated dendritic cells (DC) and will be potentiated by recruitment, loading and activation of cross-presenting DC at the tumor site.
To test this hypothesis, an early-phase trial (NCT01976585) in low-grade lymphoma was carried out testing a unique in situ vaccine (ISV) combining: 1) fms-like tyrosine kinase 3 ligand (FLT3L) to recruit DC, 2) radiotherapy to load FLT3L-mobilized DC with TAA, and 3) toll-like receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. Strikingly, Brody and colleagues found partial and complete systemic tumor regressions at distant, untreated tumors. They also found specific elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic anti-tumor immune response.
This data prompted a new trial in which anti-PD1 monoclonal antibody (mAb) and ISV are combined with a novel immune-monitoring approach involving co-administration of "surrogate antigens (Ag)" at the ISV site. The approach is being applied to multiple cancer types, including breast, head and neck, melanoma and sarcoma.
In this webinar, Brody discusses these studies, including the key role mass cytometry played in defining the effects of treatment on the intratumoral and systemic immune repertoire with high resolution and in profiling the distinct checkpoint/co-activator molecules on TAA-specific, surrogate-Ag-specific and bulk CD8 T cells.
Michelle Poulin, PhD, Fluidigm Field Applications Scientist, gives a brief overview of mass cytometry, the high-parameter, single-cell technology used by Brody in his research.
Mass cytometry, or cytometry by time-of-flight, the basis of Fluidigm® CyTOF® technology, uniquely enables high-dimensional single-cell proteomic analysis for systems-level discovery and comprehensive functional profiling applications. This brief overview will describe the basic principles and workflow of the technology, including recent advancements.
Joshua Brody, MD
Assistant Professor, Hematology and Medical Oncology
Director, Lymphoma Immunotherapy Program
Icahn School of Medicine at Mount Sinai
New York, NY
Michelle Poulin, PhD
Field Applications Scientist
South San Francisco, CA
For Research Use Only. Not for use in diagnostic procedures.