Macrophage profiles to improve immunotherapy
Using macrophage cytokine production and epigenetics to predict and control immune response
Macrophages are phagocytic cells of the innate immune system that have a unique plasticity. They dynamically and rapidly switch between promoting and suppressing immune responses. They are often the first cells encountered by drugs and other therapies. The activities of macrophages are therefore a major influence on a patient’s response to immunotherapy, including therapies with chimeric antigen receptor (CAR) T cells.
The EDIT lab (for Engineering and Designing Immunotherapies), led by Dr. Heather Gustafson, is developing novel technology platforms focused on macrophages and their functions, particularly their release of cytokines. These short-lived small proteins direct the immune response, for example toward inflammation or anti-inflammation, by activating signalling cascades that alter gene expression in target cells.
In collaboration with a pediatric clinical trial, Dr. Gustafson and colleagues are using cytokine assays, large-scale proteomics, and machine learning to identify patient cytokine profiles associated with benefits or toxicity from T-cell immunotherapy. The profiles could lead to biomarkers for response to treatment, including tools to predict the risk of serious adverse events. The EDIT team is developing a mouse model to validate the profiles and see how they change with therapy, including checkpoint inhibitors. They will use the mice to test the effects of other treatments including modulators of cytokines, inflammasomes, epigenetic alterations, and metabolic changes.
The EDIT lab has an additional approach to profiling patient responses. Research suggests that vaccinations or disease exposures may alter the activities of macrophages through epigenetic reprogramming. For example, a more open chromatin configuration at cytokine-related genes may change cytokine release from macrophages in response to pathogens or therapy. The team is profiling patient epigenomes using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to identify epigenetic targets and cellular programs involved in tumorigenesis, relapse, and therapeutic toxicity. Using the results, they are developing a PCR assay to predict which patients are at risk of severe toxicity to guide immunotherapy.
Based on available samples, the EDIT lab began with macrophage profiles associated with CAR T responses. However, the technology has broad applications in multiple diseases including cancer, particularly predicting relapse. The profiles also have potential to predict and direct treatment for autoimmune diseases. Profiling could be useful in measuring or predicting severe drug reactions or poor outcomes such as a cytokine storm in influenza or COVID-19.
Dr. Gustafson has expertise in engineering small peptide therapeutics and drug delivery systems to regulate macrophages. She is interested in partnerships that use the EDIT lab’s knowledge and technical expertise to advance macrophage-focused predictive models and therapies.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Sponsored research agreement
- Collaborative research opportunity
- Consultation agreement
- Gustafson HH, Pun SH. Instructing macrophages to fight cancer. Nat Biomed Eng 2018. 2(8):559-561. doi: 10.1038/s41551-018-0276-0.
- Gustafson HH, Olshefsky A, Sylvestre M, Sellers DL, Pun SH. Current state of in vivo panning technologies: Designing specificity and affinity into the future of drug targeting. Adv Drug Deliv Rev 2018. 130:39-49. doi: 10.1016/j.addr.2018.06.015.
- Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv Drug Deliv Rev 2017. 114:206-221. doi: 10.1016/j.addr.2017.04.010.
- Ngambenjawong C, Gustafson HH, Pineda JM, Kacherovsky NA, Cieslewicz M, Pun SH. Serum stability and affinity optimization of an M2 macrophage-targeting peptide (M2pep). Theranostics 2016. 6(9):1403-14. doi: 10.7150/thno.15394.
- Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H. Nanoparticle Uptake: The Phagocyte Problem. Nano Today 2015 10(4):487-510. doi: 10.1016/j.nantod.2015.06.006
- Herd H, Daum N, Jones AT, Huwer H, Ghandehari H, Lehr CM. Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano 2013. 7 (3), 1961-1973 doi: 10.1021/nn304439f
- Moos PJ, Honeggar M, Malugin A, Herd H, Thiagarajan G, Ghandehari H. Transcriptional responses of human aortic endothelial cells to nanoconstructs used in biomedical applications. Mol Pharm 2013. 10 (8): 3242-3252 doi: 10.1021/mp400285u
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