A multidisciplinary research team at Johns Hopkins Kimmel Cancer Center has identified critical immune system defects that explain why pancreatic cancer remains largely resistant to immunotherapy treatments. The findings, published in Cancer Cell in November 2022, emerge from an ongoing platform trial that has been evaluating immunotherapy approaches in pancreatic cancer patients since 2015.
Platform Trial Reveals Tumor Microenvironment Barriers
The research was led by Dr. Lei Zheng, co-director of the Pancreatic Cancer Precision Medicine Center of Excellence Program, alongside Dr. Elizabeth Jaffee, deputy director of the Johns Hopkins Kimmel Cancer Center, and Dr. Elana Fertig, director of oncology quantitative sciences. The team employed multi-omic strategies to analyze banked biospecimens, examining the genetic alterations, transcriptomes, and protein expression patterns within pancreatic cancer tumor microenvironments.
The platform trial design enables researchers to use generated data to advance immunotherapy development within the same ongoing study, according to Zheng. This approach allows for continuous refinement of treatment strategies based on emerging findings.
Two Critical Immune Defects Identified
The study examined two established immunotherapy approaches: anti-PD-1 checkpoint inhibitors, which block immune checkpoints that cancer cells exploit to evade immune responses, and GVAX, a therapeutic vaccine designed to stimulate patients' immune systems to attack cancer cells. These treatments were studied both individually and in combination.
Despite treatment with these immunotherapies, researchers identified two fundamental problems in pancreatic cancer's characteristically "cold" tumor microenvironment. First, T-cells remain exhausted and insufficiently active even after immunotherapy intervention. Second, infiltrating myeloid cells actively prevent T-cell activation against pancreatic cancer cells.
Neutrophil Hijacking Mechanism Discovered
A particularly significant finding involved the role of neutrophils, immune cells normally created to fight infections. Zheng explained that pancreatic cancer cells hijack these neutrophils, converting them into suppressors of T-cell activation. This hijacking mechanism represents a major component of the myeloid cell dysfunction that undermines immunotherapy effectiveness.
The discovery of this neutrophil reprogramming provides new insight into why pancreatic cancers maintain their immunosuppressive microenvironment despite treatment with current immunotherapy approaches.
New Combination Strategies Under Investigation
Based on these findings, researchers have initiated testing of two novel treatment combinations. The first strategy combines anti-CD137 agonist antibody treatment with anti-PD-1 immunotherapy to enhance T-cell activation. The second approach pairs anti-IL-8 neutrophil-blocking antibody treatment with anti-PD-1 immunotherapy to prevent T-cell inactivation.
These new combination strategies directly target the identified defects: the CD137 agonist aims to overcome T-cell exhaustion, while IL-8 blockade seeks to neutralize the immunosuppressive neutrophil activity.
Clinical Context and Significance
Pancreatic cancer represents one of the most challenging malignancies, with a five-year survival rate of approximately 10%. The disease's resistance to immunotherapy has been a major obstacle in improving patient outcomes, making these mechanistic insights particularly valuable for future therapeutic development.
The platform trial receives support from the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Bristol-Myers Squibb. This collaborative funding structure enables the comprehensive multi-omic analysis required to understand the complex tumor-immune interactions in pancreatic cancer.
The identification of specific immune defects provides a roadmap for developing more effective immunotherapy combinations, potentially transforming treatment approaches for this historically treatment-resistant cancer type.
