Teaching the Immune System to Have Long-term Memory for Leukemia

Your immune system is designed to protect against foreign invaders such as infections, but you may not realize that it also destroys abnormal cells that your body produces. Researchers suggest that some types of cancer cells, such as acute lymphoblastic childhood leukemia (ALL) that recurs or is resistant to standard therapies, are especially adept at dampening the immune system’s radar.

Alix Seif, MD, MPH, an attending physician in both the Blood and Marrow Transplantation and the Hematologic Malignancies sections at The Children’s Hospital of Philadelphia, is interested in finding ways to teach the immune system to recognize leukemia and give it long-term immune memory to prevent disease relapse.

“Think of the immune system like a border guard,” Dr. Seif said. “These approaches give the border guard a little more power to look inside the body and detect culprits who may be starting an uprising. It makes the immune cells more suspicious of the bad cells.”

Hyundai Hope on Wheels, a national independent nonprofit organization committed to helping kids fight cancer, presented Dr. Seif a research grant at a Handprint Ceremony Sept. 9 to support her innovative scientific investigations. During the event, children receiving cancer treatments at Children’s Hospital dipped their hands in paint and added their colorful symbols of hope to a white car that is covered with children’s handprints from all over the country.

ALL is the most common childhood cancer, usually appearing between the ages of 2 and 4. It has a good track record for successful treatment; however, about 15 to 20 percent of patients with ALL will relapse. It can be extremely difficult for physicians to help this group of children stay in remission using standard chemotherapy. Novel immune therapies are alternative approaches that are generating excitement in the pediatric cancer research community because they are potentially more effective, less toxic, and longer lasting than cell poisons.

Chimeric antigen receptor-armed T cells (CTL019) — formerly known as CART19 — is an immune therapy that made international headlines over the last two years. Researchers from the University of Pennsylvania and Children’s Hospital engineered immune cells, called T cells, to recognize CD19 protein, an antigen that is expressed by a type of tumor common to ALL, and then kill the leukemia. In research studies, children with relapsed or refractory cancer had a complete response 90 percent of the time with CTL019 therapy.

“It feels miraculous to those of us who have cared for these children who otherwise would not have options,” Dr. Seif said. “Unfortunately, it’s not a perfect treatment.”

CTL019 therapy offers incredible benefits in some cases, but in others, the leukemia stops putting CD19 on its surface, taking away the engineered T cells’ target. Another problem is that the T cells may not have a long enough lifespan to completely eliminate the leukemia. Dr. Seif and her study team aim to help solve these treatment challenges by coaching the immune system as a whole to identify and remember several antigens on ALL cells.

“Our approach relies on stimulating multiple immune cells, rather than engineering one type of immune cell, which may open up this type of therapy to other tumor types,” Dr. Seif said. “I could imagine it being used in conjunction with CART19 or as an alternative for children who have tumors without CD19.”

Using a mouse model, Dr. Seif’s research team added foreign proteins from jellyfish and fireflies to leukemia cells to elicit a strong response from the mouse immune system, which cleared the leukemia spontaneously. Next, the researchers introduced leukemia cells minus the foreign proteins, and the mouse immune system again eliminated the leukemia.

“What this tells us is that it’s not just recognizing that one protein,” Dr. Seif said, “which suggests that if the CD19 went away, it could still recognize other features on the leukemia.”

While these study results show that it may be possible to evoke an internal immune response and memory against multiple antigens on the same tumor, a potential roadblock is that the immune systems of children with ALL may be too tolerant of the leukemia cells. Basically, the immune system learns how to differentiate between healthy “self” cells and harmful intruders, so that it does not attack its own body tissue. ALL cells may convince the immune system that they more closely resemble “self” than foreign by sending messages that, “I’m OK, don’t attack me.”

Dr. Seif’s study team is looking at ways to circumvent tolerance and counter ALL’s evasion tactics. They will test drugs already available that could either block the inhibitory signals that ALL gives the immune system or rev up the immune system’s surveillance to promote long-term protection.

“We’re trying to retrain the immune system to do what it should have been doing all along,” Dr. Seif said. “If a precancerous cell slips through, the immune system should be able to recognize it, remember it, and kill it.”