epocrates
Podcast Recap | Intention to Treat: Unleashing CRISPR on Cancer
In a well-rounded discussion with patient Alyssa Tapley and her mother Kiona Tapley and Dr. Waseem Qasim, professor of cell and gene therapy at University College London and pediatric immunologist at Great Ormond Street Hospital for Children, host Rachel Gotbaum explored the ups and downs of a common treatment journey for patients with lymphoblastic leukemia and, ultimately, the chance clinical trial and experimental treatment therapy that led to her full recovery. Below are five key highlights from the interview.
Podcast length - 26:25 min.
5 Key Takeaways
1. After more than 6 months of treatment for acute T-cell lymphoblastic leukemia, doctors discovered that patient Alyssa Tapley’s cancer was chemo resistant.
After another failed bone marrow aspirate and worsening leukemia, doctors prescribed Alyssa another round of chemotherapy treatment, this time nelarabine. Unfortunately, this too failed and Alyssa and her mother learned that she needed a bone marrow transplant, which ultimately was also unsuccessful.
In fact, every conventional treatment doctors tried were no match for Alyssa’s aggressive form of leukemia, so doctors began preparing for the worst.
2. Following much concern and consideration, Alyssa ultimately made the decision to join a clinical trial in which she would be given multiple CAR T-cell infusions in the hope that they would “destroy the leukemia.”
Alyssa and her mother were warned that Alyssa might experience a high temperature, low blood pressure, and lower neutrophil counts. While they waited for any signs that the treatment was working, Alyssa and her mother also met with the palliative care team and made plans for hospice care that they hoped they’d never have to use.
After five weeks of infusions, doctors tested Alyssa’s bone marrow and delivered the good news that they could not find any trace of leukemia in her body. At the time of the podcast recording, Alyssa has been in remission for one year.
3. According to Dr. Qasim, the CAR T-cell therapy clinical trial was born of the desire to bring new treatments to children who have little or no remaining options following standard protocols.
“In this particular case, this young lady had a type of leukemia that had arisen in her T lymphocytes. And unfortunately, she’d been through all the standard treatments and a bone marrow transplant, and the disease had come back,” Dr. Qasim explained.
CAR T cells were engineered to detect and kill certain leukemias and have typically been successful in the treatment of B-cell malignancies, but there have been few alternative options for patients with T-cell leukemia. Even still, Dr. Qasim points out a number of hurdles with CAR T therapy, including the challenge of collecting cells from patients who have previously had a lot of chemo and whether those cells will respond to CAR T therapy. Additionally, T cells must be trained to fight other T cells without fighting each other.
Dr. Qasim notes that most CAR T-cell treatments on the market work by taking a patient’s own cells, engineering them, then giving them back. In developing his own CAR T therapy, the doctor proposed a different approach, “Can we take cells from a healthy donor and make a bank of cells that can be then given to multiple recipients? Imagine what that does to the ability to be able to give this to larger numbers of patients."
4. Dr. Qasim’s CAR T-cell therapy employs cell engineering, CRISPR gene editing, and base editing steps to enable cell retrieval from one person followed by delivery to another, while eliminating cell rejection by the new host.
To overcome T-cell leukemia in this way, Dr. Qasim says his research has led to the discovery of three editing steps that are required to remove molecules on the surface of the T cells, enabling their availability and use “off the shelf.”
“We’ve had an interest in gene editing for some time now. And now, most recently, we’ve managed to adopt base editing. And the platform had a major advantage in the way it works to knock out genes without causing double-strand DNA breaks. So, if we’re undertaking three separate edits, this is multiplexed editing, that introduces the risk of translocations between the sites of editing. But as soon as we switch to base editing, we’re making changes to single letters of the DNA code to stop genes being expressed, but we’re not causing a cut. So, this is much gentler on the cells, is very targeted, and we were able to quickly move to a phase 1 study.”
5. So far, two teenage patients, including Alyssa, have had success with Dr. Qasim’s CAR T-cell therapy. During the course of their treatment, Dr. Qasim was able to identify clear evidence that they might be on the road to recovery.
During what was ultimately a successful therapy for two recent patients and trial participants, Dr. Qasim was able to confirm the presence of infused cells, which increased over a period of days to weeks while the leukemia became undetectable. He also observed evidence of the biological activity of the cells, which meant they were not only active but releasing cytokines. In the patient, this activity resulted in a fever, or cytokine release syndrome, which is commonly accepted as a sign that cells are active and doing their job.
This positive activity was not as stable in all patients. Dr. Qasim identified a patient that developed severe complications related to a chest infection and ultimately did not survive.
When asked if both patients in whom his CAR T cell therapy worked as expected could be considered cured, Dr. Qasim was hesitant but hopeful. “I think we are very careful about using the word “cure.” Cure is something that usually we talk about in the rearview mirror after a period of time. These are patients under active follow-up and monitoring. Having said that, the longer we are from the time of the procedure and the longer the patient remains in remission, the more confident we can be about saying there’s going to be a long-term success.
Any views, thoughts, and opinions expressed in this podcast recap are solely that of the host and guests and do not reflect the views, opinions, policies, or position of epocrates and athenahealth.
Source:
(2023, June 22). N Engl J Med. Intention to Treat. Unleashing CRISPR on Cancer. https://www.nejm.org/doi/full/10.1056/NEJMp2303851