First human trial going 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 replace genes in patients’ immune cells to treat cancer.
  • The participants included 16 patients with various solid cancers, including breast, colon and lung cancer.
  • Researchers isolated and cloned T cell receptors from the patient’s blood that were able to recognize tumor-specific antigens.
  • After treatment, biopsies showed gene-edited T cells near tumors.

For the first time, researchers have used CRISPR gene-editing technology to replace 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 examined in a paper published in Natureand they were presented Nov. 10 at the Society for Immunotherapy of Cancer in Boston, MA.

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

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

Dr. Stefanie Mandl, Chief Scientific Officer at PACT Pharma and one of the paper’s authors, explained Medical News Today that the results of the trial demonstrated an 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 tailor a therapy completely to each patient with cancer.”

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

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

Yet T cells do not always have a receptor that matches the antigen on a cancer cell. Different cancers have different antigens. In addition, patients often also lack enough T cells to effectively fight the 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 manipulate T cells in the lab by adding a gene for a receptor that fits the antigen onto cancer cells and kills them. Currently, CAR-T therapy is used to treat blood cancers.

The approach described in the paper published in Nature is the first step in the development of a similar therapy for the treatment of solid cancers, or all cancers except blood-related cancer.

The study, which was conducted with staff from nine academic centers, involved 16 patients with a variety of solid cancers, including breast, colon and lung cancer. “These were patients who had all other therapies [had] failed,” explains Dr. Martir-Negron.

Researchers took blood samples and tumor biopsies from the patients.

“And then we sequence those samples,” Dr. Mandl out MNT“to find mutations specific to 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,” said Dr. Mandl. “Then we pick up [the] three best to treat this patient’s tumor.”

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

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

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

“We had to develop platform technologies that would allow us to reliably isolate these T cells and the genetic material [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 done that successfully in a very short time of less than 5 years, and now we hope we can continue to make this a reality for all patients with solid tumors.”

– Dr. Stefanie Mandl

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

In every patient who had a biopsy after the infusion, the researchers found the CRISPR-edited T cells. “They accomplished their goal,” explained Dr. Martir Negron MNT.

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

“Each patient carries their own remedy in the form of these T cells,” said Dr. Mandl. “We just need 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 in your body continue to live,” Dr. Mandl up.

The process from drawing the patient’s blood to choosing the best TCRs, according to Dr. Mandl about 5 months.

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

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

In future research, she told us, scientists could look at what happens when patients are given a larger dose of processed T cells. They may also look at ways to make T cells more difficult for the tumor to attack.

“The tumor microenvironment is very, very hostile,” Dr. Mandl out. “The tumor is trying to do things to essentially 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 turn additional genes on or off that make the T cells resilient.”

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

“It’s not something ready for prime time,” she said. “It won’t immediately change a treatment.”

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