Oncologists have achieved some immune system responses in patients with pancreatic cancers using various combinations of vaccines and immune checkpoint inhibitor drugs, but it's not always clear which therapy is inducing what type of response. To help drive further study, investigators from the Johns Hopkins Kimmel Cancer Center have made public a free, web-based atlas of mass cytometry profiles from patients with metastatic pancreatic cancers. The work was partly supported by the National Institutes of Health.
The atlas contains information from 260 cytometry profiles (of markers on immune cells) from blood samples from 64 patients who participated in three clinical trials of two pancreatic cancer vaccines and two checkpoint inhibitors in different permutations, explains Won Jin Ho, M.D., an 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.
"We have a platform for immune profiling based on 40-plus protein level markers to understand immune system responses," Ho says. "We also study patients before and after treatment so that we can understand longitudinal responses, or how cancer treatments induce changes in the immune system."
A description of the atlas was published in the Jan. 12 issue of Cancer Immunology Research, a publication of the American Association for Cancer Research. The resource, available online through SciServer at sciserver.org/datasets/biomed/cytof_atlas, houses fully annotated cytometry data from three trials. Enabled by collaboration with the Institute for Data Intensive Engineering and Science at Johns Hopkins, the atlas' user interface and built-in tools simplify comparisons of cell types and expression levels. Researchers plan to add to the atlas over time, including information from tumor tissue analyses, Ho says.
"Pancreatic cancer is such a lethal disease, which was our motivation to make this public," Ho says. The five-year survival rate is just 13%, according to the Pancreatic Cancer Action Network. "Our group has done a lot of investigational immunotherapy trials. These are early-phase trials of smaller groups of patients but have been very informative, even if the clinical outcomes have not met what we wanted."
Researchers applied new cytometry techniques to blood samples collected in previously completed trials to build the atlas, to help inform development of new therapies. Dimitrios Sidiropoulos, Ph.D., a computational cancer immunologist at Johns Hopkins, co-led the cross-trial integration of the data, finding immune signatures in blood that are distinct to specific immunotherapies and that can be projected onto tumor tissues, demonstrating the utility of the atlas. "What we're hoping is that scientists can go to this repository, explore the data and generate hypotheses to carry out new studies," says Ho.
Ho and colleagues have made additional data available from their studies: Raw protein expression data are shared in files available on zenodo (doi.org/10.5281/zenodo.13937090). Analysis code is available on the GitHub repository (github.com/wjhlab/Immunotherapy-Atlas).
In the same issue of the journal, Ho and colleagues also reported results of a new phase II study of 57 patients with metastatic pancreatic cancer whose disease progressed while on chemotherapy. The trial, led by Dung Le, M.D., the Bloomberg~Kimmel Professor of Cancer Immunotherapy, and Katie Bever, M.D., an assistant professor of oncology, randomized patients to one of two treatment groups: the vaccine CRS-207 plus the immunotherapies anti-PD1 nivolumab and anti-CTLA4 ipilimumab, with or without the vaccine GVAX, during six 21-day cycles.
While response rates were not significantly different between the groups, in-depth immunologic studies co-led by Amanda Huff, Ph.D., an assistant professor of oncology, observed that the vaccine-based regimens could generate T-cell clones specific to the antigen mesothelin and the mutation KRAS, and that those clones infiltrated the tumors. These findings, communicated as companion publications, are complementary in determining the effects of key immunotherapeutic agents. Adding anti-CTLA4 to the immunotherapy backbone significantly increases the infiltration of antigen-experienced T cells and "is going to be an important part of future immunotherapy backbones," Ho says.
Co-authors of the atlas study were Dimitrios N. Sidiropoulos, Zhehao Zhang, Jennifer N. Durham, Soren Charmsaz, Nicole E. Gross, Jae W. Lee, Yanyi Sun, Susheel Perikala, Joseph A. Tandurella, Dmitrijs Lvovs, Arik Mitschang, Gerard Lemson, Sarah M. Shin, Alexei G. Hernandez, Sarah Mitchell, James M. Leatherman, Ludmila Danilova, Hao Wang, Elana J. Fertig, Elizabeth M. Jaffee, Katherine M. Bever and Dung T. Le of Johns Hopkins.
The work was supported by a grant from the Lustgarten Foundation for Pancreatic Cancer Research; the National Institutes of Health (grants P01-CA247886-01A1, U01CA212007 and U01CA253403); the National Cancer Institute (grants R50 CA243627, F31CA268724-01, R21CA264004 and S10OD034407); SU2C/AACR grant DT-14-14; the Emerson Cancer Research Fund; an Allegheny Health Network grant; the JHU Discovery Award; and SPORE GI P50CA062924-24A1.
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