- For the first time, researchers have used CRISPR technology to replace genes in patients’ immune cells to treat cancer.
- Participants included 16 patients with various solid types of cancer, including breast, colon, and lung cancers.
- The researchers isolated and cloned T-cell receptors from the patient’s blood, which can recognize tumor-specific antigens.
- Following treatment, biopsies revealed 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 reviewed in an article published in Nature and presented on November 10 at the Society for Immunotherapy of Cancer in Boston, MA.
“I think it’s a big deal,” said Dr. Arelis Martir-Negron, who was not involved in this study. Dr. Martir-Negron is a medical geneticist at Miami Cancer Institute, part of Baptist Health South Florida.
“CRISPR is in itself a newer technology and the fact that they can make and remove the change and removal at the same time,” said Dr. Martir-Negron. “That’s amazing because in the past […] it would have been almost impossible to do the two things.”
Dr. Stefanie Mandl, scientific director of PACT Pharma and one of the authors of the article, told Medical News Today that the results of the study provide 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 we can fight the cancer,” she said. “It is possible to provide a completely tailored therapy for each patient with cancer.”
This is how CAR T-cell therapy works
T cells are a type of white blood cell that are part of the immune system. The surface of T cells contains proteins called T-cell receptors (TCR).
TCRs can recognize antigens such as bacteria or viruses. Receptors and antigens go together like a lock and a key. This mechanism allows T cells to destroy the bacterium or cancer cell.
However, T cells do not always have a receptor that adapts a cancer cell’s antigen. Different types of cancer have different antigens. In addition, patients often also lack enough T cells to effectively combat 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 develop T cells in the laboratory by adding a gene for a receptor that adapts the antigen to cancer cells and kills them. CAR-T therapy is currently used to treat blood cancers.
The approach described in the article published in Nature is the first step towards developing a similar therapy to treat solid cancers or all types of cancer outside of blood cancer.
The study, which was conducted in collaboration with staff from nine academic centers, included 16 patients with various solid types of cancer, including breast, colon, and lung cancers. “These were patients for whom all other treatments had failed,” Dr. Martir-Negron explained.
The researchers took blood samples and tumor biopsies from the patients.
“And then we sequence those samples,” Dr. Mandl explained to MNT, “to find mutations that are specific to the patient’s cancer.”
The researchers identified 175 unique, cancer-specific immune receptors. They then used an algorithm “to predict and prioritize which of these mutations could actually be recognized by the immune system,” said Dr. Mandl. “Then we pick [the] top three to treat that patient’s tumor.”
The selected TCRs were developed by CRISPR-to replace the existing TCR in an immune cell.
“We then grow these cells into billions of cells in the shell,” explained Dr. Mandl. “And then we give them back to the patient, so now we’re putting a lot of these T cells, all of which are specific to recognize the patient’s tumour, back into the patient so they can now find and kill the tumour cells. It’s basically a living drug that you give.”
Before patients received the immune cells developed by CRISPR-, they received conditioning chemotherapy to break down the existing immune cells.
“We needed to develop platform technologies that would enable us to reliably isolate these T cells and the genetic material, the [TCRs], and then also genetically reprogram this patient’s T cells with these receptors. And we also had to develop the manufacturing process to produce this large number of these cells, right? […] We have successfully achieved this in a very short period of less than 5 years, and now we hope that we can push this forward to make this a reality for all patients with solid tumors.”
Potential for lifetime protection
One month after treatment, the researchers found that the tumors had not grown in five participants. Elf saw no change.
In every patient who was biopsied after the infusion, the researchers found the CRISPR-processed T cells. “They achieved their goal,” Dr. Martir-Negron told MNT.
According to Dr. Mandl, most of the side effects experienced by patients were 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 protect against cancer for a lifetime, “because the cells in your body will continue to live,” says Dr. Mandl.
Time-consuming and expensive
The process from taking blood from the patient to choosing the best TCRs took about 5 months, according to Dr. Mandl.
Dr. Mandl believes that by automating some processes, the schedule can be shortened.
“It’s a very complicated process that needs to be further developed to simplify logistics, reduce treatment costs and increase effectiveness so that it can become a reality for all cancer patients,” she said.
In future research, she told us, scientists could study what happens when patients are given a larger dose of processed T cells. They could also look for ways to make T cells more resistant to attacks by the tumor.
“The tumor’s microenvironment is very, very hostile,” explained Dr. Mandl. “The tumor is trying to do things to basically make the T cells inactive, and they can do that in a lot of different ways. But we can also use our single-stage gene editing technology to either turn on or off additional genes that make T cells resilient.”
Dr. Martir-Negron warned patients with solid cancers not to get too excited about this therapy.
“It’s not something that’s ready for prime time,” she said. “It won’t immediately change any treatment.”