Treating cancer is complex as each tumor differs greatly from another. This is due to their genetic makeups. Similarly, each patient responds differently to treatments. This uniqueness stimulates the development of personalized treatment.
One of the most promising personal treatments is immunotherapy, where scientists utilize the defending nature of a person’s immune system and engineer immune cells to kill tumor cells.
UW-Madison scientists from different departments are working together to find a more efficient and precise way of modifying T cells in the immune system to cure cancers.
“It is a really exciting time in the idea of putting synthetic genetic sequences into human bodies, specifically into T cells,” said Krishanu Saha, a biomedical engineering professor at UW-Madison. “All of the technology and genetic works we are doing could have a pretty large impact if applied to treatments of leukemia and other cancers.”
T cells are a type of white blood cells that naturally recognize and kill viruses, while the engineered T cells carry specific chimeric antigen receptor sequences in their genome to recognize and kill different cancer cells.
In theory, this treatment is as simple as three steps: draw a tube of blood, modify T cells in the blood and put cells back into the body. However, the existing method of using a virus to introduce CAR sequences into T cells is not so precise; the sequences are added to multiple spots on the genome, Saha explained.
There are 15,000 spots on the genome that CAR sequences could potentially integrate into, which concerns the FDA because some important genes could be mutated due to the integration, Saha said. For instance, other tumors might grow if tumor-suppressing genes were affected.
Personalized treatment is a young field, but with new genome editing technologies like CRISPR Cas9 and whole genome sequencing, this treatment holds a lot of promises in the future, Saha expressed.
“The CRISPR technique, in contrast, can do a very targeted integration, meaning that you are able to put the synthetic sequence into one spot in the genome,” Saha said.
CRISPR is an advanced genetic engineering technique that essentially contains two parts: guide DNA and a DNA cutting protein. Saha said he designed guide DNA to lead proteins to cut at specific spots on the genome before integrating CAR sequences at that spot.
Cooperating with David Beebe, another biomedical engineering professor at UW-Madison, Saha assayed functions of different CAR T cells in terms of killing cancer cells precisely.
The most effective CAR T cells would be transferred into mice models to cure mouse cancers, Saha said. These experiments were conducted with Christian Capitini, a pediatric professor at UW-Madison.
According to Capitini, CAR T cells have shown some promising future in treating relapsed acute lymphoblastic leukemia, or ALL, in clinical trials. Capitini recently opened the second phase of a clinical trial to treat children with ALL at UW-Madison.
The first phase of clinical trial took place in Philadelphia in 2014 and 90 percent of children had remissions 30 days after infusing CAR T cells. The second phase is taking place in nine medical institutions across the U.S. to observe remission rates after six months of infusion, Capitini explained.
Compared to traditional cancer therapies, personalized therapies are fairly noninvasive, only some blood samples are needed so patients seem excited about the progress and are willing to participate in clinical trials of personalized treatments, Reid Alisch, an assistant professor in psychiatry department at UW-Madison, said.
Besides, after marrow transplantation, the only standard therapy left for relapsed leukemia is chemotherapy, which patients had experienced a lot, Capitini said.
“This is at least something different. Also, it’s a personalized medicine because it’s using your own body cells, and there’s a little appeal about that,” Capitini explained.
Capitini said that severe side effects on the heart and brain were observed in clinical trials, including symptoms like fever, seizures and unconsciousness, but these symptoms are reversible and usually patients recover without additional treatments.
“Children tend to tolerate side effects better than adults, partly because they don’t have chronic diabetes like adults do. Even though they are sick, their organs are healthier and they can handle [CAR T cell treatment] better,” Capitini said.
But Saha and Capitini agreed that the toxicity of CAR T cells is still unclear, and the research goal is to understand the functions and reasons of toxicity of CAR T cells based on different responses observed on each patient.
