In the world of precision oncology, it’s something like the Holy Grail: the ability to genetically fine-tune a cancer patient’s immune cells into weapons that target their specific tumor, without harming healthy tissue.
Now, for the first time in humans, scientists have shown that it is indeed possible. In a small phase 1 clinical trial run by PACT Pharma, researchers edited the genes of 16 patients’ immune cells to work against their cancer, then engineered thousands of cells containing the edited genes and reinserted them into their bodies. The study met its goal of establishing that the therapy was safe and well-tolerated, according to results presented Nov. 10 at the annual Society for Immunotherapy in Cancer Conference in Boston and in a paper published in Nature.
“This is a leap forward in developing a personalized treatment for cancer,” Antoni Ribas, M.D., Ph.D., co-corresponding author, PACT founder and professor of medicine at UCLA, said in a press release. Ribas developed the therapy alongside fellow PACT founders Nobel Laureate David Baltimore, Ph.D., of Cal Tech and Jim Heath, Ph.D. of the Institute for Systems Biology in Seattle.
The treatment combines two types of therapies that have gained traction in recent years: CRISPR/Cas9 gene editing and T cell receptor therapy, or TCR therapy. The former involves the use of an enzyme called Cas9 to cut DNA, allowing scientists to alter it, while TCR therapy modifies a patient’s T cells—a type of immune cell—so they attack the patient’s tumor.
Both techniques are complicated on their own, but this treatment required a new level of complexity. First, to target the cancer without damaging healthy cells, the scientists had to sequence DNA from patient blood and tumor samples to find gene mutations that were exclusive to the tumor. There’s little overlap in these gene mutations between individuals; thus, the sequencing had to be carried out for each individual patient in the study.
“A lot of therapies right now are basically taking the same target and putting it into the patient’s cells. That’s pretty complicated already,” Susan Foy, Ph.D., first author on the study, told Fierce Biotech. “What we’re actually trying to do is first find that target in the patient’s cells. We screen the patients for the cure to their own cancer.”
Next, using T cells isolated from the patients, the researchers designed new T cell receptors that would target cancer cells carrying one of three different mutations they’d selected through sequencing. Things got even hairier here: The researchers used CRISPR to both remove the DNA for an existing T cell receptor and replace it with the DNA for a new one, reprogramming it entirely.
The use of CRISPR to add and remove genes at the same time is new modality for a clinical application, Foy noted.
“Up to this point, CRISPR has basically been used to take out different genes,” she said.
For each patient, the researchers then manufactured T cells containing up to three different T cell receptors. After the patients completed a course of chemotherapy, the cells were infused. Analysis confirmed that the T cells were circulating in the patients’ bodies and that they were clustering around their tumors. Most patients didn’t experience any side effects that could be attributed to the edited T cells. In the few that did, their symptoms were mild and quickly resolved.
While the trial wasn’t meant to establish efficacy or effective dosing levels, the researchers were heartened to see that growth stalled in five of the patients’ tumors. Another subject even saw their lung tumors shrink.
“We do believe that those results are due to our cells causing tumor regression in that patient,” Foy said. “So we’re starting to see early signs that the therapy is working.”
All the patients in the trial had some type of solid tumor, including tumors in the breast, colon and lung. While treatments that involve genetically engineered T cells, such as CAR T cell therapy, tend to perform well in blood cancers, they’re less efficacious in patients with solid tumors. That’s because tumors put up a lot of barriers that prevent the immune system from eradicating the cancer, like creating a hostile microenvironment that renders T cells and other immune cells useless.
Now that the team has hints that the therapy can work, they’ll try to make it more efficacious. Besides simply infusing higher doses of the cells, they’ll also work on improving the editing efficiency. Using CRISPR to knock out a new T cell receptor in one fell swoop is still a new technique, and it’s not at 100% yet, Foy noted.
“We still end up with some wild type cells or some cells that didn’t insert the T cell receptor that we tried to insert,” she said. When the team started out, their success rate was around 10%. Now it’s up to 40%.
“We hope to improve that to a much higher percentage,” Foy added.
The results unlock the next step in clinical research for PACT with a second phase 1 trial slated to begin next year. Meanwhile, PACT recently diverted some of its staff to a new, unnamed business venture. The company’s most recent fundraising effort raised $75 million in a series C, led by Vida Ventures.