Discovery of cell surface protein may lead to CAR-T for inflammatory diseases
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Cellular senescence has both positive and negative effects in the body.
The process can lead to tumor suppression and plays a key role in wound healing. However, it also can cause inflammation that results in long-term tissue damage and contributes to chronic diseases, such as liver fibrosis, lung cancer and osteoarthritis.
A study published in Nature detailed the discovery of a urokinase-type plasminogen activator receptor (uPAR), a protein on the surface of cells that is present during senescence.
Healio spoke with two of the study’s authors from Memorial Sloan Kettering Cancer Center — Scott W. Lowe, PhD, chair of the center’s cancer biology and genetics program and an investigator with Howard Hughes Medical Institute, and Michel Sadelain, MD, PhD, director of the Center for Cell Engineering — who plan to move their preclinical research forward and use uPAR as a target for modified chimeric antigen receptor T cells.
Question: Can you describe the rationale for your research approach?
Answer: Cellular senescence is a potent antiproliferative program that also promotes inflammation. Normally, senescence plays a role in tissue wound-healing responses and acts as a barrier to tumorigenesis. However, in the presence of chronic damage, senescent cells accumulate, and a range of studies indicate these cells contribute to tissue decline. Studies in mice suggest that elimination of senescent cells can ameliorate symptoms linked to a range of tissue damage pathologies, including fibrosis. Consequently, there have been substantial efforts to identify therapeutics that can eliminate senescent cells from tissues. The term senolytics has been used to describe these approaches.
Most efforts to identify senolytic therapies have focused on small molecules and primarily repurposed cancer drugs. Although they have shown promise in some settings, these therapies are not particularly potent and have toxicities. Our study was designed to test an alternative approach — whether CAR T-cell therapy could be adapted for use as senolytics. CAR T-cell therapy has been remarkably successful at treating certain leukemias, but it has not been widely considered outside of cancer. Nevertheless, we hypothesized that if a cell surface marker could be identified that was relatively specific for senescent cells, then CAR T cells might be senolytic. Indeed, our study provides proof of principle that this could be the case.
Q: What are the key takeaways from this research?
A: First, uPAR is a molecule that is upregulated on senescent cells but not expressed in vital tissues. Second, CAR T cells targeting uPAR are effective senolytics — ie, they can eliminate senescent cells from tissue. CAR T cells targeting uPAR can ameliorate symptoms of fibrosis in mice. Next, although treatment-related toxicities exist, there is an effective therapeutic window. Finally, the criteria needed for effective CAR T-cell therapy in senescence-related pathologies are different than for cancer indications.
Q: How might CAR-T for senescence-related diseases differ from its application to hematologic malignancies?
A: Whereas the design, manufacturing and administration of senolytic CAR T cells share many features with the CAR T cells used in oncology, senolytic CAR T cells differ in their required potency and persistence. Senolytic CAR T cells will not confront hostile tumor microenvironments but rather a milieu shaped by senescence-associated secretory phenotypes. They do not need to recruit endogenous T cells to overcome their target, as is required for oncolytic T cells, at least in some settings. Senolytic CAR T cells also likely do not need to eliminate every target cell down to the last cell, as ideally would be achieved by tumor-targeted T cells. We believe that extensive CAR T-cell persistence is not necessary and that CAR T cells could be administered once, or iteratively, to “wash out” the senescent cell pool.
Q: What are the next steps in applying your preclinical data to future research?
A: We plan to further study the mechanism of action of senolytic CAR T cells, as well as their therapeutic potential in the context of aging, selected inflammatory disorders and cancer. We will also evaluate alternate CAR targets and their respective efficacy and toxicity profiles.
Q: What are the potential implications of your research if translated into clinical applications?
A: Senescent cells contribute to numerous pathologies, and it is therefore tantalizing to imagine their potential to treat or prevent an array of conditions. Senolytic CAR T cells may also be useful in oncology, in combination with senescence-inducing regimens.
For more information:
Scott W. Lowe, PhD, can be reached at lowes@mskcc.org.
Michel Sadelain, MD, PhD, can be reached at m-sadelain@ski.mskcc.org.
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