First human trial goes well

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In a small trial, researchers have used gene-editing technology for the first time to treat breast, colon, and lung cancer in humans. Image credit: Andrew Brookes/Getty Images.
  • For the first time, researchers have used CRISPR technology to substitute genes in patients’ immune cells to treat cancer.
  • Participants included 16 patients with different solid cancers including breast, colon, and lung cancers.
  • Researchers isolated and cloned T-cell receptors from the patient’s blood capable of recognizing tumor– specific antigens.
  • Following treatment, biopsies showed gene-edited T cells near tumors.

For the first time, researchers have used CRISPR gene-editing technology to substitute a gene in a patient’s immune cells to redirect those cells to fight cancer.

Details of a small human clinical trial using this approach are explored in a paper published in Natureand they were presented on November 10 at the Society for Immunotherapy of Cancer in Boston, MA.

“I consider this a big deal,” he said Dr. Arelis Martir-Negron, not involved in this study. Dr. Martir-Negron is a medical geneticist at Miami Cancer Institute, part of Baptist Health South Florida.

“CRISPR is by itself a newer technology, and the fact that they can do the change and remove at the same time,” said Dr. Martir-Negron. “That is what is amazing because in the past […] it would have been almost impossible to do the two things.”

Dr. Stefanie Mandlchief scientific officer at PACT Pharma and one of the authors of the paper, said Medical News Today that the results of the trial demonstrated early proof of concept. PACT Pharma is a biopharmaceutical company working to develop personalized treatments to eradicate solid tumors.

“We can let the patient’s own immune system tell us how to fight the cancer,” she said. “It is possible to make completely bespoke therapy for every patient with cancer.”

T cells are a type of white blood cell that make up part of the immune system. On the surface of T cells are proteins called the T-cell receptor (TCR).

TCRs can recognize antigens, like bacteria or viruses. Receptors and antigens fit together like a lock and key. That mechanism allows T cells to destroy bacteria or cancer cells.

Yet T cells do not always have a receptor that fits the antigen on a cancer cell. Different cancers have different antigens. Additionally, patients often also lack enough T cells to effectively fight cancer cells.

Chimeric antigen receptor T-cell therapy (CAR-T cell therapy) is a new type of cancer treatment. With CAR-T cell therapy, scientists engineer T cells in the laboratory by adding a gene for a receptor that fits the antigen on cancer cells and kills them. Currently, CAR-T therapy is used to treat blood cancers.

The approach detailed in the paper published in Nature is the first step in developing a similar therapy for treating solid cancers, or all cancers outside of blood-related cancer.

The study, which was conducted with collaborators at nine academic centers, involved 16 patients with different solid cancers, including breast, colon, and lung cancer. “These were patients that all the other therapies [had] failed,” explained Dr. Martir-Negron.

Researchers took blood samples and tumor biopsies from the patients.

“And then we sequence those samples,” Dr. Mandl explained that MNT“to find mutations that are specific for the patient’s cancer.”

Researchers identified 175 unique, cancer-specific immune receptors. They then used an algorithm “to predict and prioritize which of these mutations can actually be recognized by the immune system,” Dr. Mandl said. “Then we pick up [the] three best ones to treat this patient’s tumor.”

The selected TCRs are CRISPR engineered to replace the existing TCR in an immune cell.

“Then we grow those cells to billions of cells in the dish,” Dr. Mandl explained. “And then we give them back to the patient, so now we’re giving a lot of these T cells that are all specific to recognize the patient’s tumor back into the patient, so that they can now find and kill the tumor cells. It’s basically a living drug that you give.”

Prior to patients receiving the CRISPR-engineered immune cells, they received a conditioning chemotherapy treatment to deplete existing immune cells.

“We had to develop platform technologies to allow us to reliably isolate these T cells and the genetic material, the [TCRs], and then also to genetically reprogram that patient’s T cells with these receptors. And we also had to develop the manufacturing process to make these large numbers of these cells, right? […] We have successfully done that in a very short amount of time of less than 5 years, and now we hope we can take this forward to make this a reality for all patients with solid tumors.”

– Dr. Stefanie Mandl

A month after treatment, researchers found the tumors in five participants had not grown. Eleven saw no change.

In each patient biopsied following the infusion, researchers found the CRISPR-edited T cells. “They reached their target,” Dr. Martir-Negron explained to MNT.

The majority of side effects patients experienced, according to Dr. Mandl, were due to the conditioning treatment.

“Every patient carries their own cure in themselves in the form of these T cells,” said Dr. Mandl. “We just have to be able to find them and then make enough of them so they have a chance to kill the cancer.”

The therapy could provide lifelong protection against cancer “because the cells will keep living in your body,” Dr. Mandl noted.

The process from taking the patient’s blood to picking the best TCRs took about 5 months, according to Dr. Mandl.

By automating some processes, Dr. Mandl believes the timetable can be shortened.

“It is a very complicated process that needs further development to simplify logistics and also reduce the cost of treatment and increase efficacy so it can become a reality for all patients with cancer,” she said.

In future research, she told us, scientists may look at what happens when giving patients a larger dose of edited T cells. They may also look at ways to make T cells tougher to attacks from the tumor.

“The tumor microenvironment is very, very hostile,” Dr. Mandl explained. “The tumor tries to do things to basically make the T cells inactive and they can do that in many different ways. But we can also use our single-step gene editing technology to either knock in or knock out additional genes that will make the T cells resilient.”

Dr. Martir-Negron warned patients with solid cancers not to get overly excited about this therapy.

“It’s not something that is ready for prime time,” she said. “It will not change any treatment right away.”

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