June 2022: According to the findings of a study that was just recently published by Stanford Medicine in mice, a cancer treatment that makes use of a patient’s own genetically modified immune cells in order to attack cancer cells is safer and more effective when it can be toggled on and off by an oral medication.
The first treatment, which is now commonly referred to as CAR-T cell therapy, has shown remarkable success in combating a variety of blood cancers. However, due to the fact that some patients have an immune reaction to the engineered cells that is potentially fatal, CAR-T therapy is typically reserved for use only after other treatments have been explored first.
It has also had a lower rate of success in treating patients who have solid tumours, such as those found in cancers of the brain and bone. Researchers believe that this is due to the fact that CAR-T cells are susceptible to receiving an excessive amount of signalling, which causes them to become exhausted before they can eradicate solid tumours. In addition, in contrast to blood cancers, it is difficult to identify molecular targets on solid tumours. These molecular targets must be present only on cancer cells and not on normal tissue in order to be effective treatment options.
The researchers at Stanford came up with a modified CAR-T cell therapy that they call SNIP CAR-T. This therapy is activated by taking an oral medication for hepatitis that the Food and Drug Administration has already given the green light for use in humans. (The SNIP CAR-T cells are inactive if the drug is not administered.)
Those patients who are at risk of having an adverse reaction to the genetically modified cells are protected by a failsafe mechanism called the ability to use medication to modulate the activity level of the cells after they have been reinfused into the patient. The researchers also discovered that the modified CAR-T cells were significantly more effective at combating solid cancers in laboratory mice. They theorise that this might be the case because the cells experienced brief and repeated periods of rest while the daily medication was being metabolised in the bodies of the animals.
Crystal Mackall, MD, the Ernest and Amelia Gallo Family Professor as well as a professor of paediatrics and of medicine, stated that they had developed a “remote-controlled” CAR-T therapy that could be customised for each individual patient. “These genetically modified CAR-T cells are not only safer, but they are also more powerful and versatile than the CAR-T cells that were originally developed. It’s a pretty high-tech system all things considered.”
Mackall is the study’s senior author and it was published online on April 27 in the journal Cell. The primary author of the study is Louai Labanieh, who is a graduate student.
According to Labanieh, “I was surprised by the degree to which the SNIP CAR-T cells were better than conventional CAR-T therapy.” “SNIP CAR-T cells completely cured mice with solid tumours in the bone and nervous system,” in contrast to the conventional CAR-T treatment, which was a complete failure.
Because the FDA has already given its blessing to the oral medication that stimulates the activity of the SNIP CAR-T cells, the researchers are optimistic that they will be able to begin clinical trials in people who have solid tumours within the next 24 months.
Putting immune cells to work
CAR-T cells are immune cells called T cells that are collected from a patient and genetically engineered in a laboratory to recognise and attack cancer cells with a specific molecule on their surfaces. These cells are then used to make CAR-T cells. CAR-T cells can then be used to treat patients. After that, the antigens are reintroduced into the patient in order to fight the disease. When the receptor on the CAR-T cell binds to the target on the cancer cell, it kicks off a chain reaction inside the CAR-T cell that sends a signal to the cell to kill the cancer cell.
The Food and Drug Administration (FDA) granted initial approval for the use of CAR-T cell therapy in 2017 for the treatment of acute lymphoblastic leukaemia in children and young adults. Since then, it has also been approved for use in adults who suffer from a variety of other forms of blood cancer, such as multiple myeloma and a few distinct kinds of lymphoma. CAR-T cells that recognise other molecules or two molecular targets instead of one are currently being tested by researchers. The original form of the therapy targets a molecule on the surface of the cancer cells called CD19.
Labanieh’s goal was to design a CAR-T system that, once the cells had been transplanted back into the patient, could be easily monitored and adjusted. He did this by introducing a viral protein known as a protease into the CAR-T cells. The CAR-T receptor, which is located on the cytoplasmic side of the cell membrane, is cleaved by this protease, which in turn blocks the signalling cascade that initiates the killing activity of the cells. The protease can be rendered inactive by using the medication grazoprevir, which is authorised for use in the treatment of hepatitis C. The cells are dormant when the drug is not present, but as soon as it is there, they become active and start eliminating cancer cells from the body.
In the absence of grazoprevir, Labanieh and his colleagues demonstrated that SNIP CAR-T cells become inactive in laboratory mice. On the other hand, the protease was able to be inhibited and the SNIP CAR-T cells were able to become activated when grazoprevir was administered to the mice orally. In a mouse model of CAR-T-induced lethal toxicity, mice that were treated with SNIP CAR-T cells were able to recover after grazoprevir treatment was discontinued. This demonstrated that the system has the potential to act as a safer alternative for patients than conventional CAR-T therapy.
According to Labanieh, “previous efforts to create drug-regulatable CAR-T cells have yielded systems that are either very finicky or leaky.” This is the very first time that we have been able to fine-tune their activity to such a specific degree.
In addition, Mackall stated that “when the SNIP CAR-T system with full dose grazoprevir is on, it is on full power.” “And once the grazoprevir is gone, there is no more treatment. This is extremely important for patients who are suffering from toxicity. We have the ability to stop the cells from reproducing, which would buy the patient some time to get better. The majority of the other safety switches are intended to either eliminate the CAR-T cells entirely or switch them off permanently. It’s possible that the patient will make it through the treatment, but they won’t be cured of their cancer.
Treatment of solid tumors
When the researchers tested the ability of the SNIP CAR-T cells to fight solid cancers in the mice, they found that they were much more effective than conventional CAR-T therapy. In many cases, the researchers were able to cure mice that had a cancer of the brain known as medulloblastoma or a cancer of the bone known as osteosarcoma.
Unexpectedly, they also discovered that adjusting the dose of grazoprevir made the CAR-T cells more discriminating, directing their killing activity toward cancer cells with high levels of a target molecule while sparing normal tissue with lower levels of the same molecule. This was an important discovery because it explains how the CAR-T cells were able to distinguish between cancer cells and normal tissue. According to the researchers, the capability of engineering CAR-T cells to recognise target molecules that are also present on healthy cells has the potential to significantly improve one’s ability to combat human solid tumours.
Mackall characterised this possibility as “a really attractive possibility.” “If we are able to lower the activity of the SNIP CAR-T cells simply by adjusting the dose of grazoprevir, then we will be able to very precisely individualise the therapy for each patient. This will either prevent toxicity or drive the CAR-T cells to kill cancer cells rather than normal tissue. We believe that this treatment for cancer is of the next generation and will revolutionise the CAR-T cell field.
Other authors from Stanford include Robbie Majzner, MD, an assistant professor of paediatrics; postdoctoral scholars Dorota Klysz and Sean Yamada-Hunter, PhD; a senior research scientist named Elena Sotillo, PhD; life sciences researchers Chris Fisher, Kaithlen Pacheco, Meena Malipatlolla, Johanna Theruvath, and Peng Xu, MD, PhD; Jose Vilches-Moure, DVM, PhD,
This study was made possible with funding from the National Institutes of Health (grants U54 CA232568-01, DP2 CA272092, and U01CA260852), the National Science Foundation, Stand Up 2 Cancer, the Parker Institute for Cancer Immunotherapy, Lyell Immunopharma, the Virginia and D.K. Ludwig Fund for Cancer Research, the Cancer Research Institute, German Cancer Aid, and others.
In connection with the study, Labanieh, Mackall, Majzner, and Lin are all listed as co-inventors on a patent. Mackall is one of the co-founders of three companies that are currently working on developing CAR-T-based therapies. These companies are Lyell Immunopharma, Syncopation Life Sciences, and Link Cell Therapies. Labanieh is a consultant for Syncopation Life Sciences in addition to being a cofounder of the company. Labanieh, Majzner, Sotillo, and Weber are all consultants for Lyell Immunopharma as well as shareholders in the company.
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