The impact of tumor-specific mutations on cancer therapy using CAR-T-cells: An approach that harnesses the individual’s own T cells

The ability to make very precise changes in DNA with the aid of a new technology, called CRISPR, has already shown promise for a variety of genetic disorders. But attempts to use CRISPR to treat other diseases have produced some disappointments recently.

“What we’re trying to do is really harness every patient’s tumor-specific mutations,” says Stefanie Mandl, chief scientific officer at Pact Pharma and an author on the study. The company worked with experts from several universities to design personalized therapies.

The researchers used not much in the way of T cells to establish the safety of the approach. “We just need to hit it stronger the next time,” he says.

The response to the therapy was limited because the patients’ cancers were very advanced when they joined the trial, suggests Mandl. Also, later tests revealed that some of the receptors the team chose could find the tumor, but didn’t have potent anticancer effects.

The most complicated therapy that has been tried in the clinic is probably this one, says study co-author Antoni Ribas. We want to create an army out of a patient’s own T cells.

Ribas and his colleagues started by studying the genes from blood and tumours to see if they are different from the ones in the blood. Each person in the trial had to have this done. Ribas says that the cancer-causing genes are not the same as in other diseases. “And although there are some shared mutations, they are the minority.”

Joseph Fraietta is a researcher at the University of Pennsylvania who designs T-cell cancer therapies. In some cases, the entire procedure took more than a year.

And as researchers develop ways to speed up the therapies’ development, the engineered cells will spend less time being cultured outside of the body and could be more active when they are infused. Fraietta predicts that the technology will get better.

They don’t like waiting that long to treat dying kids. They continue with CAR-T-cell trials for solid tumours in order to generate the data that has been presented to them. Jensen says that the field is not there yet but that they are getting close.

But common surface proteins have not been found in solid tumours, says Fraietta. Solid tumours provide barriers to T cells, which have to move through the blood to kill the cancer cells. Tumour cells use up the local supply of vitamins and minerals to fuel their growth and suppress the immune system.

CAR-T treatment of a remissioning child: from a dream come true, to a reality reality come true?

Bartolome was a basketball player in the NBA. It sounded like a science fiction movie. Bartolome thinks that was pretty cool.

For their part, Kopp and Bartolome are thrilled. Kopp’s been in remission for more than two years. “Now I joke that I’m genetically modified, because I have been a Homeopathic all my life,” he says. “But this little vial of cells can change my life? Wow. Just, truly, medical miracle.”

Not everyone is enthusiastic about off-the-shelf CAR T-cell treatments. Some point out that this version of the more generic therapy doesn’t appear to last as long, and may not be as effective, as the original versions, which rely on a patient’s own cells. The main problem we have is that one. It is quicker. It’s convenient because of that. Perhaps less expensive. “Then you have a fundamental issue of persistence, that’s what we’re studying at the National Cancer institute,” says Kochenderfer. That is a fundamental problem that you can’t completely fix, no matter what you do.

Outside wealthy countries, the therapy is rare. In Brazil, haematologist Renato Luiz Guerino Cunha at Oncoclínicas Group in São Paulo was the first in the country to treat someone with CAR-T therapy in 2019. But progress has been slow, he says: he lacks the capacity to rapidly produce large quantities of cells. “In three years, we treated just six patients,” he says. We need to find new technologies for the processing.

Crispr-Improves Cancer Immunotherapy: The Case for Car-T Cells? Commentary on “Effects of Patient Injection on Cancer Cells”

McGuirk says this is the most exciting time in his career. I have always been excited about the work we’ve been doing. But this is unprecedented.”

The scientists that were not involved in the research agree that the chances are better than they could have imagined a decade ago. “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

Using T cells to regulate the expression of leukaemia in human blood isotopes has a long lasting lifetime, says Evan Weber

Bartolome say he’ll never forget the day the doctors told him they couldn’t find a trace of cancer in his body. It 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 a great day. And every day since then I just thank my lucky stars.”

The approach is approved to treat leukaemias and other blood related diseases. But researchers have been pursuing ways to make the treatments safer and more effective, and to expand their use to other diseases.

Other synthetic circuits have been designed to allow precise regulation of CAR expression, by placing it under the control of genetic elements that activate the necessary genes in response to a drug8. So far, however, most of these complicated designs have not yet gone through the safety studies and standardization required for use in people, says Sadelain.

Evan Weber is a cancer physician at the Children’s Hospital of Philadelphia and he says the ability to turn the T cells on and off could help reduce a problem called T-cell exhaustion. Some studies have found that giving T cells a ‘rest period’ can reduce T cell exhaustion and boost their overall effectiveness against tumours3.

To wipe the slate clean: a CAR-T-cell platform for combating the brain cancer of childhood and adolescence

Emily Hood had already beaten the odds. She was 17 years old at the time and had been diagnosed with a rare brain cancer. A year and a half later, she was still alive, which put her in a very fortunate minority. People with her form of brain cancer, known as diffuse intrinsic pontine glioma (DIPG), generally survive for only 8–11 months after diagnosis.

Mackall says that it is not a home run. But it’s an indication of the treatment’s potential — which, as Nicholas Vitanza, a neuro-oncologist at Seattle Children’s Hospital who treated Emily, points out, “is what drives us to make the next generation of CAR-T cells better”.

Researchers say that the trickle-down approach to repurposing therapies for adult cancer doesn’t work. There is an urgent need for new therapeutic approaches that can wipe the cancer slate clean because there are few options available for children whose tumours cannot be contained by surgery, radiation and Chemo.

The targets pursued are not ideal. The antigens are not universally expressed on all cells in a tumours, and only a small cluster of evasive cells can cause a relapse. What’s more, because the target molecules are not essential to cellular survival, tumours can evolve ways of ditching them to become resistant to the cellular immunotherapies.

That echoes the findings of others. In the United Kingdom2 and China3, for example, investigators have evaluated anti-GD2 CAR-T cells in small cohorts of people with relapsed neuroblastoma, a paediatric cancer of the nerve tissue. The therapies passed safety tests, but no child experienced tumour shrinkage in either study.

There are exceptions like Umoja Biopharma in Seattle. The company’s first clinical-stage candidate is a CAR-T-cell platform that takes advantage of a tumour-tagging system developed in the laboratory of one of the co-founders, chemist Phillip Low at Purdue University in West Lafayette, Indiana, to combat bone cancers of childhood and adolescence. A clinical trial for teenagers and young adults started earlier this year. Michael Jensen is the co-chief executive of Umoja Biopharma, and he says that there is an innovation playing out in kids for the first time.

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There are no simple solutions to these problems. “We clearly have a long way to go,” says Mackall. “But we’re now seeing promising signals.”