Pancreatic cancer remains one of the deadliest forms of cancer, with alarmingly low survival rates. But what if we could unlock the secrets of the immune system to fight back more effectively? That's precisely what researchers at Johns Hopkins are striving for, and they've just released a powerful new tool to help the entire scientific community join the fight.
The Johns Hopkins Kimmel Cancer Center has unveiled a groundbreaking, freely accessible, web-based atlas detailing immunotherapy responses in patients battling metastatic pancreatic cancer. This atlas acts as a comprehensive map, charting the complex interactions between various immunotherapies and the immune system's response within these patients. This resource, partially funded by the National Institutes of Health, aims to accelerate research and development of more effective treatments by providing a wealth of data to researchers worldwide.
Dr. Won Jin Ho, Associate Professor of Oncology at the Johns Hopkins University School of Medicine and Associate Director of the Johns Hopkins Kimmel Cancer Center’s Convergence Institute, explains that the atlas compiles information from a staggering 260 cytometry profiles. These profiles represent markers found on immune cells extracted from blood samples of 64 patients. These patients participated in three distinct clinical trials that explored different combinations of two pancreatic cancer vaccines and two checkpoint inhibitor drugs. In essence, the atlas provides a detailed snapshot of how the immune system reacts to these various treatment approaches.
"We've created a platform for immune profiling, utilizing over 40 protein-level markers, to gain a profound understanding of immune system responses," Dr. Ho states. "Crucially, we study patients both before and after treatment. This allows us to track longitudinal responses – observing how cancer treatments induce changes, sometimes subtle, sometimes dramatic, within the immune system over time." This longitudinal data is invaluable for understanding the dynamics of immunotherapy and identifying potential biomarkers for treatment success or failure. And this is the part most people miss: following the changes over time, not just a single snapshot, is key to understanding how these therapies work.
The details of this atlas are published in the January 12th issue of Cancer Immunology Research, a journal of the American Association for Cancer Research. You can access this incredible resource online through SciServer at sciserver.org/datasets/biomed/cytof_atlas. The atlas boasts fully annotated cytometry data from all three clinical trials. Thanks to a collaborative effort with the Institute for Data Intensive Engineering and Science at Johns Hopkins, the user interface is incredibly intuitive, with built-in tools that simplify the comparison of cell types and protein expression levels. The team plans to continuously update the atlas, incorporating new data, including analyses of tumor tissue.
Despite advancements in cancer treatment, pancreatic cancer remains incredibly challenging to treat. "Pancreatic cancer is such a lethal disease, which was our motivation to make this public," Dr. Ho emphasizes. The statistics are sobering: the five-year survival rate is a mere 13%, according to the Pancreatic Cancer Action Network. "Our group has conducted numerous investigational immunotherapy trials. These are early-phase trials involving smaller groups of patients, but they've proven to be highly informative, even when the clinical outcomes haven't fully met our expectations." This highlights the importance of learning from every trial, regardless of its immediate success.
The creation of this atlas involved employing cutting-edge cytometry techniques on blood samples collected from previously completed trials. The goal is to provide researchers with the insights needed to develop more effective therapies. Dr. Dimitrios Sidiropoulos, a computational cancer immunologist at Johns Hopkins, co-led the cross-trial integration of the data. His work revealed distinct immune signatures in the blood that are specific to certain immunotherapies. These signatures can even be projected onto tumor tissues, demonstrating the powerful utility of the atlas. "Our hope is that scientists will utilize this repository to explore the data, formulate hypotheses, and initiate groundbreaking new studies," Dr. Ho explains.
To further enhance accessibility and transparency, Dr. Ho and his team have also made raw protein expression data available on zenodo (doi.org/10.5281/zenodo.13937090) and analysis code on the GitHub repository (github.com/wjhlab/Immunotherapy-Atlas).
In a related study published in the same issue of the journal, Dr. Ho and his colleagues reported the findings of a new phase II clinical trial involving 57 patients with metastatic pancreatic cancer whose disease had progressed despite chemotherapy. The trial, led by Dr. Dung Le, the Bloomberg~Kimmel Professor of Cancer Immunotherapy, and Dr. Katie Bever, an assistant professor of oncology, divided patients into two treatment groups. One group received the vaccine CRS-207 plus the immunotherapies anti-PD1 nivolumab and anti-CTLA4 ipilimumab, either with or without the vaccine GVAX, over six 21-day cycles.
While the overall response rates weren't significantly different between the two groups, in-depth immunologic studies, co-led by Dr. Amanda Huff, an assistant professor of oncology, revealed that the vaccine-based regimens could generate T-cell clones specifically targeting the antigen mesothelin and the mutation KRAS. These T-cell clones were also found to infiltrate the tumors. These findings, presented as companion publications, are complementary in determining the effects of key immunotherapeutic agents. The researchers found that adding anti-CTLA4 to the immunotherapy backbone significantly increased the infiltration of antigen-experienced T cells. Dr. Ho believes this "is going to be an important part of future immunotherapy backbones." But here's where it gets controversial: some researchers question whether the added toxicity of anti-CTLA4 outweighs its benefits in all patients.
This collaborative effort involved numerous researchers from Johns Hopkins, highlighting the multi-faceted approach needed to tackle such a complex disease.
The atlas development and clinical trials were supported by grants from various organizations, including the Lustgarten Foundation for Pancreatic Cancer Research, the National Institutes of Health, the National Cancer Institute, SU2C/AACR, and several other foundations and awards.
Dr. Ho reports receiving patent royalties and speaking/travel honoraria from various biotechnology and pharmaceutical companies. Other researchers involved in the studies also reported potential conflicts of interest, which are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. This transparency is crucial for maintaining the integrity of the research.
This new atlas represents a significant step forward in the fight against pancreatic cancer. By sharing this wealth of data and insights with the global scientific community, Johns Hopkins is fostering collaboration and accelerating the development of new and more effective treatments. But the ultimate question remains: how can we best utilize this new resource to translate these findings into tangible benefits for patients? What specific hypotheses should researchers prioritize, and how can we ensure that these findings are rapidly translated into clinical practice? Share your thoughts and opinions in the comments below!
