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From OncoLog, May 2014, Vol. 59, No. 5

“Sleeping Beauty” Technique Modifies T Cells to Treat B Cell Malignancies

By Zach Bohannan 

A novel technique that helps the patient’s own immune system find and destroy cancer cells could extend remission times for patients with B cell lymphomas and leukemias.

This technique uses a gene transfer approach known as Sleeping Beauty to create chimeric antigen receptors (CARs) for use in adoptive T cell transfer and is being used in clinical trials at The University of Texas MD Anderson Cancer Center.

Adoptive T cell transfer

Adoptive T cell transfer is a powerful innovation for the treatment of lymphoma and leukemia. The theory behind the treatment is that T cells harvested from the patient or a donor can be specifically targeted to cancer cells by altering the T cells’ antigen receptors, which recognize pathogens and cells as foreign or dysfunctional. The modified T cells could effectively eliminate the cancer with minimal risk of side effects.

Photo: Dr. Partow Kebriaei

“Delivering CAR T cells after transplantation targets minimal residual disease in hopes of maintaining remission for people with high-risk B cell malignancies.”

– Dr. Partow Kebriaei
Unmodified native T cells generally do not attack cancer cells, which is one reason cancer cells can survive in a patient. Therefore, to make adoptive T cell transfer successful, doctors must somehow alter the T cells’ antigen receptors to ensure that the cells actively target and kill the patient’s cancer cells. For B cell malignancies, these CARs usually target CD19, a B cell–specific protein.

The traditional method of making CARs is to use viral transfection to modify the T cells’ antigen receptors. After the antigen receptors are modified, the chimeric T cells are cultured with antigen-presenting cells that express CD19. These antigen-presenting cells stimulate the transformed T cells and cause them to proliferate. Unfortunately, the traditional viral method of creating CAR T cells is often expensive.

The Sleeping Beauty method

Recently, however, researchers led by Laurence Cooper, M.D., Ph.D., a professor in the Division of Pediatrics, developed a less expensive, nonviral method of creating CARs for patients. The method is called Sleeping Beauty because it relies on a reconstructed version of a transposon (a DNA sequence that can change its location within the genome) that was present millions of years ago in the last common vertebrate ancestor. The reconstructed transposon system can integrate DNA into the host genome without a viral vector.

In this new system, the doctors identify a tumor-specific antigen or marker, such as CD19, which they use to manufacture a CAR-containing DNA construct specific to a patient’s cancer. The doctors insert that sequence into a Sleeping Beauty–specific DNA plasmid. Then, instead of using viruses to introduce the DNA to the T cells, the doctors use electroporation, which disrupts the T cells’ membranes long enough for the Sleeping Beauty DNA to be taken up by the T cells.

Clinical applications

Adoptive T cell transfer therapy typically is done after standard treatment for lymphoma or leukemia. The patient’s T cells are usually harvested before lymphoma or leukemia treatment begins. Depending on the nature of the patient’s disease, such treatment may include chemotherapy, immunotherapy, and/or targeted drugs and may be followed by a hematopoietic stem cell transplant to help control residual disease.

Photo: Dr. Laurence Cooper

“Many drug companies are not in a financial position to pay attention to pediatric needs.... But we may be able to use CAR T cells as drugs in this group of vulnerable patients.”

– Dr. Laurence Cooper
While these therapies are occurring, the CAR construct is engineered and inserted into the patient’s previously harvested T cells. When the patient’s condition has stabilized after therapy, the patient receives CAR-bearing T cells. Partow Kebriaei, M.D., an associate professor in the Department of Stem Cell Transplantation, said, “Delivering CAR T cells after transplantation targets minimal residual disease in hopes of maintaining remission for people with high-risk B cell malignancies.”

Dr. Kebriaei is the principal investigator for two of the three first-in-human clinical studies at MD Anderson in which patients with B cell malignancies receive Sleeping Beauty–derived CAR T cells after stem cell or umbilical cord blood transplantation. She and her colleagues reported in December at the American Society of Hematology Annual Meeting that CAR T cells had been manufactured for 25 patients and administered to 9 patients: 5 who had acute lymphocytic leukemia and 4 who had non-Hodgkin lymphoma. Although it was too soon to tell whether the CAR T cells would extend remissions, the researchers reported that the treatment was well tolerated.

Looking ahead

Dr. Cooper said MD Anderson researchers and clinicians have started a clinical study in which patients with B cell malignancies receive CAR T cell treatment immediately after chemotherapy. This trial is led by Chitra Hosing, M.D., a professor in the Department of Stem Cell Transplantation and Cellular Therapy.

In all of the current studies of CAR T cells, researchers are observing how long the modified T cells remain in the body. Dr. Kebriaei said that future improvements in the persistence of the CAR T cells may someday allow adoptive T cell transfer to replace stem cell transplantation, which can be associated with significant side effects and cost.

MD Anderson researchers are also hoping to use CAR T cells as another treatment option for pediatric lymphoma patients, who generally have fewer treatment options than adult patients. Dr. Cooper said, “Many drug companies are not in a financial position to pay attention to pediatric needs simply because there’s no return on investment for them. But we may be able to use CAR T cells as drugs in this group of vulnerable patients.”

For more information, contact Dr. Partow Kebriaei at 713-745-0663 or Dr. Laurence Cooper at 713-563-5393.

Other articles in OncoLog, May 2014 issue:

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