Promising Findings on CRISPR Cancer Therapy Are Finally Emerging

Genetic engineers are designing “the most complex treatment ever” using the genetic scissors technique CRISPR: custom-made, genome-edited immune system cells to attack tumors.

A small human trial has shown that researchers can use CRISPR gene editing to modify immune cells to recognize mutated proteins specific to a person's tumors. These cells can then be safely released into the body to find and destroy their targets.

Combining Gene Editing and Cellular Immunotherapy

This is the first attempt to combine two new treatment approaches in cancer research: gene editing to create personalized treatments and engineering immune cells called T cells to better target tumors. The approach was tested in 16 people with solid tumors (arising in organs or tissues), including breast and colon tumors.

Study coauthor Antoni Ribas, a cancer researcher and physician at the University of California, Los Angeles, says, “It is probably the most complex therapy ever tried in the clinic,” he says. “We are trying to build an army from a patient's own T cells.”

The results were published on November 10, 2022, in Nature and presented the same day at the Society for Immunotherapy of Cancer meeting in Boston, Massachusetts.

Truly Personalized Treatments

In summary, this new procedure was performed in 3 steps:

1. Ribas and colleagues began by looking for tumor-specific mutations absent from the blood by performing DNA sequencing on blood samples and tumor biopsies. This procedure had to be carried out separately for each patient. Ribas says, “The mutations are different in every cancer.” “And although there are some shared mutations, shared mutations were in the minority.”
2. The researchers then used algorithms to predict which mutations might trigger a response from T cells, a type of white blood cell that patrols the body looking for abnormal cells. Stephanie Mandl, chief scientific officer at PACT Pharma in South San Francisco, California, and the study's lead author, says, “If [T cells] see something that is not normal, they kill it.” However, if we are seeing a patient with cancer, it means that at some point the immune system failed to recognize or control the cancer and the tumor grew.
3. After a series of analyses to confirm their preliminary findings and predictions and design proteins called T cell receptors that could recognize tumor mutations, the researchers took blood samples from each participant and used CRISPR genome editing to insert the custom receptors into T cells. Each participant then received low-dose chemotherapy to reduce the number of immune cells already present in their body, and the engineered T cells were infused into the patients.

Joseph Fraietta, who designs T cell cancer therapies at the University of Pennsylvania in Philadelphia, says, “This is an extremely complex manufacturing process.” In some cases, the entire procedure took more than a year.

Each of the 16 participants received T cells engineered for up to three different targets (genetic mutations). The edited cells were subsequently found circulating in their blood and were present at higher concentrations near tumors than unedited cells. One month after treatment, five participants had stable disease, meaning their tumors had not grown. Only two people experienced side effects that may have resulted from the activity of the edited T cells.

Ribas says that although the treatment's effectiveness was low, the researchers used relatively small doses of T cells to establish the safety of the approach. “Next time, we need to hit harder,” he says.

As the researchers develop ways to accelerate the development of these therapies, the engineered cells will spend less time being cultured outside the body and may be more active when infused. Fraietta says, “The technology is going to get better and better.”

A Solid Start

CAR T cells are engineered T cells approved for treating certain blood and lymph cancers, but solid tumors pose a particular challenge. CAR T cells are effective only against proteins expressed on the surface of tumor cells. These proteins can be found in many blood and lymph cancers, meaning there is no need to design new T cell receptors for every person with cancer.

However, Fraietta says that solid tumors do not have shared surface proteins. Solid tumors also create physical barriers for T cells, which must circulate in the blood, travel to the tumor and then infiltrate it to kill cancer cells. Tumor cells sometimes suppress immune responses both by releasing chemicals that suppress immunity and by using the local nutrient supply to fuel their rapid growth.

Fraietta says, “The environment around a tumor is like a sewer.” “T cells become less functional as soon as they enter this area.”

With this initial human trial evidence in hand, Mandl and colleagues hope to engineer T cells not only to recognize cancer mutations but also to be more active near a tumor. Mandl says there are several potential ways to strengthen T cells, for example by eliminating receptors that respond to immunosuppressive signals or changing their metabolism so that they can more easily find an energy source in the tumor environment.

Avery Posey, who studies cell and gene therapies for cancer at the University of Pennsylvania in Philadelphia, says such elaborate designs may be possible thanks to recent technological advances in using CRISPR to edit T cells: “It has become incredibly efficient. Over the next decade, we will see very sophisticated ways of engineering immune cells.”