Journal
CANCER IMMUNOLOGY RESEARCH
Volume 2, Issue 7, Pages 616-631Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-14-0027
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Funding
- NIH [K23 CA148964-01]
- Johns Hopkins School of Medicine Clinical Scientist Award
- American Society of Clinical Oncology Young Investigator Award
- Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins
- National Pancreas Foundation
- Lefkofsky Family Foundation
- NCI SPORE in Gastrointestinal Cancers [P50 CA062924]
- Lustgarten Foundation
- Sol Goldman Pancreatic Cancer Center
- AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award [09-30-14-LUTZ]
- Dana and Albert Cubby Broccoli Endowed Professorship
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Pancreatic ductal adenocarcinoma (PDAC) is considered a nonimmunogenic neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other nonimmunogenic tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a nonimmunogenic neoplasm into an immunogenic neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naive patients for immune checkpoint and other immunomodulatory therapies.(C) 2014 AACR.
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