SEP 27, 2017 12:00 PM PDT

Enhancing Checkpoint Blockade in Lymphoma with In Situ Vaccination

Presented at: Cell Biology 2017
Speaker
  • Assistant Professor, Hematology and Medical Oncology Director, Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai
    Biography
      Joshua Brody, MD, is an Assistant Professor in Hematology and Medical Oncology and the Director of the Lymphoma Immunotherapy Program at the Icahn School of Medicine at Mount Sinai in New York City. He is also a member of the Lymphoma Research Foundation's (LRF's) Mantle Cell Lymphoma Consortium (MCLC) and an LRF Career Development Award (CDA) grant recipient.

      He received his MD from State University of New York (SUNY) Stony Brook School of Medicine and his BA in molecular and cellular biology from Harvard University. He completed his residency in Internal Medicine at Yale New Haven Hospital and his fellowship in Medical Oncology at Stanford University School of Medicine. With clinical focus in chronic lymphoid leukemia (CLL), cutaneous lymphomas, follicular lymphoma (FL), mantle cell lymphoma (MCL), and post-transplant lymphoproliferative disorders (PTLD), his lab at Mount Sinai focuses on basic and applied tumor immunology.

    Abstract

    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 (used to increase efficacy) 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 will discuss 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.


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