Creating “super soldiers” from specific white blood cells to enhance the anti-tumor response was shown in a series of elegant experiments conducted by Princess Margaret’s researchers.
The research is led by a Ph.D. Candidate Helen Lu Yao, postdoctoral fellow Dr. Emma Bell and chief scientist Dr. Daniel de Carvallo describe a modified epigenetic therapy that can turn immune killer T cells into “super soldiers” by enhancing their ability to kill cancer cells.
Their findings could boost immunotherapy, a new model in cancer treatment that is currently effective for a minority of cancer patients. Some patients respond well to immunotherapy, with their tumors greatly reduced in size, but others only respond partially or not at all. Doctors and scientists around the world are working to understand why immunotherapy helps only some patients.
The research has been published in Molecular cellFebruary 19, 2021.
“Our goal for the future is to use this strategy in conjunction with other immunotherapies to boost anti-tumor immunity,” says Dr. de Carvallo, assistant professor, Department of Medical Biophysics, University of Toronto. “We envision a future clinical trial where we collect T cells from a patient for epigenetic therapy in vitro. This can effectively expand the army of cancer killer cells and create an “army of super soldiers”. These cells can then be re-infused into the patient, to boost their internal immune response to the tumor.
Dr. de Carvallo’s lab for the first time observed an increase in T-cell infiltration in tumors of mice treated with epigenetic therapy. When they removed the T cells, the treatment stopped working, indicating that the T cells were contributing to the treatment’s success.
Intrigued by this finding, the researchers set out to apply the epigenetic DNA modification therapy directly to T cells in the laboratory. They isolated T cells from healthy human donors, as well as from patients with melanoma, breast, ovarian, and colorectal cancer. Their results demonstrated that epigenetic therapy boosted T cells’ ability to kill cancer.
Epigenetics works by adding or removing chemical “markers” to DNA. Much like separable sticky notes, these markers help determine which genes can be turned on or off. Simply, you can alter cell function by using drugs that alter epigenetic markers.
Basically, the researchers found that an available chemotherapy drug removed specific genetic markers that were blocking genes in a subset of the major genes in T cells. Removing these markers turned these genes back on and “turbocharged” the T cells to become more effective killing machines.
Researchers discovered two specific genes that were activated by epigenetic therapy that were responsible for improving T cells in killing cancer cells.
High-dimensional single-cell mass cytometry analyzes – a next-generation technology that identifies single cells and responds to drugs – revealed an increase in the number of granzymatic proteins and perforin, which T cells use to perform the killing function. When unleashed, like a deadly swat team, porphyrin is able to pierce holes in the cell membrane to allow the enzymes to enter an infected or cancerous cell to finish the job of killing it.
“T cells have become a kind of ‘super soldier’, with highly active molecules – with bigger and better weapons – to destroy cancer cells,” Dr. de Carvallo explains, adding that the paper describes in detail the molecular mechanism of how the process occurs.
One of the main innovations in the paper is the use of epigenetic therapy to influence the behavior of genes in the T cell. Most of the research on epigenetic genetic therapies focuses on their effect on cancer cells. However, this paper looks at how our immune cells respond, and gives insight into how anti-tumor activity can be enhanced in our immune systems.
The emerging field of gene therapy seeks to influence genetic activity without actually modifying DNA sequences – making this an exciting treatment avenue for cancer research.
“The genetic manipulation of immune cells for treatment is not experimentally trivial. Clinical application is more complex and costly,” says Dr. de Carvallo. “Our work paves the way for clinical investigations that combine epigenetics with other immunotherapy strategies.
This research was supported by the Canadian Institutes of Health Research (CIHR), the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Ontario Institute for Cancer Research, the Canadian Cancer Society Innovation Award and the Scotiabank Research Chair.
Dr Daniel De Carvallo received research funding from Pfizer and Nektar Treatments. Dr. de Carvalho is the co-founder and shareholder of DNAMx, Inc. Christian Klein is an employee who owns stocks, patents, and property rights in Roche. John Stag is a permanent member of the Scientific Advisory Board and holds a specialist in Superficial Oncology.
About Princess Margaret Cancer Center
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