Cancer Immunity Therapy: Identifying each patient’s cancer receptors and unlocking them into each patient’s bloodstream using C to T base editing
Cancer can arise when the cells acquire genetic defects. Every cancer is driven by a unique set of mutations, and each person has immune cells with receptors that can recognize these mutations and differentiate cancer cells from normal ones. Patients are less likely to have enough immune cells with the appropriate receptors in order to fight their cancer. This Phase 1 trial showed how to identify each patient’s receptors, put them into immune cells without them, and grow more of them. Then, the bolstered immune cells were unleashed into each patient’s bloodstream to attack their tumor.
The Chief Scientific Officer at Pact Pharma and an author on the study says that they are trying to harness every patient’s tumor-specific mutations. The company worked with experts from the University of California, Los Angeles, the California Institute of Technology, and the nonprofit Institute for Systems Biology in Seattle to design the personalized therapies.
The experimental base editing therapy was eligible for a trial, because there were no other treatment options left. Qasim and his team collected T cells from a healthy donor and used base editing to make four separate changes—all C to T base conversions—to the cells. The edits allowed the donor T cells to slip past the body’s defenses, recognize a certain receptor on leukemia cells, and kill the cancer. Doctors at Great Ormond Street Institute of Child Health, part of University College London, then infused the edited cells into Alyssa’s bloodstream. After he received the edited cells, Alyssa experienced an inflammation called cytokine release syndrome, a common side effect with cancer immunotherapy. It can be life-threatening in certain patients but it was mild and she recovered quickly. A month after her infusion, her cancer was in remission, and she continues to do well. “We’ve confirmed the disease levels are still undetectable,” Qasim says. He presented the preliminary results at a meeting in New Orleans. The findings have not yet been published.
Mandl thinks the response to therapy was limited because the patients had already advanced tumors. Also, later tests revealed that some of the receptors the team chose could find the tumor, but didn’t have potent anticancer effects.
Bruce Levine, a professor of cancer gene therapy at the University of Pennsylvania, says the ability to rapidly identify patients’ unique cancer receptors and generate tailored treatments using them is impressive. Picking the right ones that kill cancer cells will be a challenge. The fact that you can get those T cells into a tumor is something else. If they get there and don’t do anything, that’s disappointing.
The researchers used a computer program to estimate the odds of the T cells provoking a response from other cells. According to the study’s lead author, if T cells see something that doesn’t look normal, they kill it. The immune system lost its fight in patients with cancer, and the tumours grew.
“This is a tremendously complicated manufacturing process,” says Joseph Fraietta, who designs T-cell cancer therapies at the University of Pennsylvania in Philadelphia. The procedure took more than a year in some cases.
Cells engineered to be more active when infused into the body could spend less time being cultured outside of the body as researchers develop ways to speed the development of therapies. “The technology will get better and better,” says Fraietta.
Solid tumours are a challenge for engineered T cells since they are resistant to CAR T cells. The CAR T cells can only be effective against the cancer-causing components of the cell. Such proteins can be found across many blood and lymph cancers, which means there is no need to design new T-cell receptors for each person with cancer.
But common surface proteins have not been found in solid tumours, says Fraietta. Solid tumours give physical barriers to the T cells, which must travel through the blood to kill the cancer cells. Tumour cells also sometimes suppress immune responses, both by releasing immune-suppressing chemical signals and by using up the local supply of nutrients to fuel their rapid growth.
The patient will receive the edited cells to find and destroy T-cells, the news release from University College London said.
The patient, a 13-year-old named Alyssa, was diagnosed with a rare and aggressive type of cancer called T-cell leukemia in May 2021. An important part of the immune system, T cells normally protect the body from infection. They grow too fast in T-cell leukemia. She had a bone marrow transplant and was treated with antibiotics, but her cancer returned.
After receiving treatments for her cancer, she ended up with the only remaining option available to her–parol care.
The first person in the world to be given base edited immune cells was admitted to the Great Ormond Street Hospital for Children in London in May.
“Once I do it, people will know what they need to do, one way or another, so doing this will help people – of course I’m going to do it,” she said in a hospital news release.
The findings of Alyssa’s case were presented at the American Society of Hematology’s annual meeting, and the team at Great Ormond Street hopes to enroll at least 10 more patients to trial the therapy.
The story of Bartolome and Kochenderfer: off-the-shelf CAR-T for cancer patients with aggressive immune cells
Base editing is more precise and less likely to cause unwanted effects on the chromosomes and thus less likely to cause side effects.
“This is quite remarkable, although it is still a preliminary result, which needs to be monitored and confirmed over the next few months,” said Dr. Robert Chiesa, a consultant in bone marrow transplant and CAR T-cell therapy at Great Ormond Street, in the statement.
Bartolome was also a former NBA basketball player. It sounded like something out of a science fiction movie. I thought that was pretty cool,” Bartolome says.
Today, after getting the experimental treatment more than a year ago, both remain in remission, raising hopes the gene-editing technique may offer new hope to at least some cancer patients. On Monday, Kopp’s doctor presented at a research conference the latest encouraging data on 32 patients. NPR got exclusive access to tell the stories of Bartolome and Kopp.
Some researchers aren’t as excited about the off-the-shelf CAR T-cell treatments. This version of the generic therapy doesn’t seem to last as long, and it may be less effective than the original versions, which depend on a patient’s own cells. “That’s similar to the main problem we have here.” It is faster. It is more convenient logistically. Perhaps less expensive. “Then there is a fundamental issue of persistence which is what I am doing,” says Dr. James Kochenderfer who is working at the National Cancer Institute. “No matter what you do, it won’t be enough to overcome that fundamental problem.”
The approach tested on Kopp and Bartolome is known as “off-the-shelf” CAR-T. It’s made in huge batches that would be ready right away for any patient, rather than having to wait weeks or even months for bespoke CAR T-cells made for each patient from their own cells. These off-the-shelf therapies could help patients whose own immune cells are too damaged, or are too sick to wait. Patients with aggressive diseases do not have time on their side. And so some patients will become too sick to receive the therapy, or die before the therapy can be generated in the laboratory,” McGuirk says.
Car-t cell immunotherapy: Where have we come from? Where do we stand, where do we are, and where are we going?
McGuirk says this is the most wonderful time in his entire career. I have always been excited by the work we’ve been doing. But this is unprecedented.”
“The prospects are much brighter than anyone could have dreamed of 10 years ago,” agrees Fyodor Urnov, a gene-editing scientist at the University of California, Berkeley, who was not involved in the research. “This field is progressing remarkably fast.”
McGuirk and others acknowledge that more research is needed involving more patients to figure out just how well the off-the-shelf approach works, how long it lasts, and how to make the cells last longer and work better.
“When you consider the overwhelming number of these patients would have died, that’s a big advance,” McGuirk says. “None of us are satisfied with that. We need to do better. For example, he says, some of the shortcomings might be overcome by giving patients more than one infusion.
Source: https://www.npr.org/sections/health-shots/2022/12/13/1140384354/crispr-improves-cancer-immunotherapy-car-t-cell
Remembering the day his doctors told him he could no longer do anything cancer-like in his body, and that’s what they told him
Bartolome will always remember the day his doctors told him there was no trace of cancer in his body. That was more than a year ago. “It was a life-changing event. And I was bubbling up inside, that’s for sure,” he says. That was an amazing day. And every day since then I just thank my lucky stars.”