Yale doctor creates new weapons to kill cancer

Dr. Samuel G. Katz, assistant professor of pathology at the Yale School of Medicine, edits individual genes to cill cancer. He is supported by the Alliance for Cancer Gene Therapy.

Dr. Samuel G. Katz, assistant professor of pathology at the Yale School of Medicine, edits individual genes to cill cancer. He is supported by the Alliance for Cancer Gene Therapy.

The battle against cancer is increasingly being fought on the genetic level, and Dr. Samuel Katz is aiding the body’s immune system by creating safer, more effective weapons.

His research is focused on treating cancers of the blood, such as multiple myeloma, Hodgkin’s lymphoma and acute myeloid leukemia, but his technique could eventually be used against solid tumors as well, including cancers of the breast, ovary, pancreas and colon.

Most gene therapy uses genetically modified DNA in the body’s T lymphocytes — a type of white blood cell that is an integral part of the body’s immune system — to find, attack and kill cancer cells.

“Because T cells have this ability to kill, people have modified the system,” said Katz, an assistant professor of pathology at the Yale School of Medicine. “They’ve put a gene into the T cell, which is called a CAR,” for chimeric antigen receptor.

The patient’s own T cells are modified with the new gene, then returned to the body, where they recognize a molecule on the cancer cell’s surface, called an antigen, and destroy the cell.

Using modified DNA, the U.S. Food and Drug Administration this year approved CAR-T therapy for B-acute lymphoblastic leukemia and non-Hodgkin B-cell lymphomas, the first gene therapies available in the United States.

However, inserting a gene into a patient’s DNA — the gene is transported into the cell by a virus — changes the genome, and that can be risky.

“The virus is messing … with your genetic code. It’s changing the words in the book,” Katz said.

He said a gene could be inserted in such a way as to enhance the expression of another gene — one that controls cellular growth, for example. There have been cases in which gene therapy has caused cancer.

Instead, Katz introduces a new gene into the cell in the form of RNA, a molecule in the cell’s cytoplasm (the DNA that forms the body’s genome is located in the nucleus). The genome isn’t altered, eliminating the potential for unrelated genes to be affected.

“When you use the DNA approach, that DNA gets incorporated into your genome, whereas the RNA doesn’t change your genome at all,” Katz said. “It has some safety considerations.”

There are several other advantages of using RNA, Katz said. It takes far less time to modify the patient’s T cells: two days vs. up to several weeks. RNA degrades over time, so “we really can control how much to give and for what length of time we give it,” he said. CAR-T cells not only kill cancerous B cells — another lymphocyte that is part of the immune system — but they “can and do attack the normal B cells,” Katz said. Since the RNA degrades within a week, “then the B cells can come back,” he said.

Another advantage is that the process will modify up to 90 percent of the body’s T cells — there are several types of T cells in the body — whereas the DNA method modifies 10 percent or less.

Modifying DNA also comes with side effects. One, cytokine release syndrome, which has a variety of symptoms, from fever, fatigue, muscle and joint pain and loss of appetite, can at times be fatal.

Also, RNA can be genetically modified in multiple ways so “you can add in additional genes at the same time,” Katz said, giving the CAR-T cells “beneficial properties, like helping the T cell survive, helping the T cell to get to the right place, limit the T cell to not have off-target effects.”

The gene inserted into the patient’s T cells creates a receptor on the cell that will be attracted to an antigen on cancerous B cells. “In this case, the CAR is designed to go after the C19 antigen,” Katz said. “That’s present on a lot of B-cell leukemias and lymphomas.”

While the DNA technique uses a virus to “infect” the T cell with the new gene, the process with RNA is different.

“We get it into the cells using a technique called electroporation,” Katz said. “It opens up the cell a little bit and then the RNA can get in and then the cell membrane repairs itself.”

Electroporation consists of putting two electrically charged metal plates into a solution containing T cells and RNA. A current is formed “and that pushes the RNA into the patient’s cells,” he said.

Katz’s research is supported by a $250,000 grant from the Alliance for Cancer Gene Therapy of Stamford. John Walter, president and CEO, said the alliance has supported Katz’s work “for a couple of years. We view his work as novel and innovative and obviously are hopeful that his work will lead towards new developments in the evolution of CAR-T therapy innovations.”

Walter said the alliance has financially supported gene therapy research “throughout the United States and Canada.