May 2014

Blocking Paths to Resistance to T Cell Therapy

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Tremendous interest in immunotherapy approaches to cancer treatment is building, as researchers look for new ways to train patients’ own immune system to recognize and attack their tumors.

Andrei Thomas-Tikhonenko, PhD, and Stephan A. Grupp, MD, PhD, investigators from CHOP’s Center for Childhood Cancer Research (CCCR), have begun a unique collaboration that will contribute to the understanding of how immunotherapy can improve the survival of children with B cell acute lymphoblastic leukemia (B-ALL) that resists standard therapy. As the team moves aggressively into this area of research, Dr. Thomas-Tikhonenko described their investigations as “very fresh, new, and exciting.”

B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. Most children with B-ALL are highly responsive to treatment, but 15 percent will have high-risk relapsed or refractory disease that is not curable with chemotherapy.

The biological importance of CD19, a protein that is broadly expressed on the surface of B-cell tumors, has been a research focus for many years in the lab of Dr. Thomas-Tikhonenko, a cancer cell biologist. Yet he never anticipated that his work would be of assistance to a high profile project that used CD19 as a prime target for an innovative cell therapy with some remarkable success for patients with B-ALL who were out of therapeutic options.

Dr. Grupp — who is an attending physician and the CCCR’s director of Translational Research  — and his colleagues from the University of Pennsylvania, demonstrated in a groundbreaking trial that they could genetically re-engineer immune cells taken from a patient’s own blood, called T cells, and return them to the body where they multiplied rapidly to seek and destroy cancer cells that expressed CD19. These chimeric antigen receptor-armed T cells (CTL019) — formerly known as CART19 — received widespread attention last year when an article in the The New England Journal of Medicine described how one of the first pediatric patients to receive the investigational treatment achieved a complete response and remained cancer-free.

Responding to Relapse

However, another patient who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor CD19, essentially making them invisible to CTL019. Drs. Thomas-Tikhonenko and Grupp are working together to determine the mechanism of relapse after successful CART19 therapies and to investigate the potential use of the drug dasatinib to stave off such relapses.

A Quest for Cures two-year grant from the Leukemia & Lymphoma Society will support their work. What the research team learns about resistance will help to inform how chimeric antigen receptors potentially can be designed better as personalized therapies for subsets of patients.

“It was part serendipity and part rational design that basic scientists like myself and physician-scientists like Dr. Grupp are in the same institution,” Dr. Thomas-Tikhonenko said. “We talk to each other and learn from each other. That could only happen in a place like CHOP where basic research is valued.”

Together, they will conduct comprehensive profiling of the B-ALL cells that are no longer making CD19. The investigators want to know how B-cell tumors grow without CD19. Do they have alternative mechanisms of survival, rather than CD19-based? Can production of CD19 be restarted so that the cancer cell is once again visible to the immune system?

“We are going to look at the major proteins that are activated upon CTL019 treatment and interrogate their expression patterns, to see if we can get any hints as to what would make B-ALL cells uniquely susceptible to another therapy,” Dr. Thomas-Tikhonenko said. “We need more targets.”

A central hypothesis that they are testing is that the emergence of pre-existing CD19-negative B-ALL cells can be prevented by combining CTL019 and dasatinib. Dasatinib is a drug in a class of medications that is efficient at stopping activity of another cancer-related protein called Lyn that CD19 turns on. Even when CD19 is gone, Lyn appears to remain as a second in command signaling the tumor cells to multiply. So far, preliminary research in mice performed by another CHOP collaborator, David M. Barrett, MD, shows that using CTL019 and dasatinib together is beneficial in some cases.

Another important research direction is to understand the mechanism of CD19 silencing. When tumor cells are put under pressure, whether it is chemotherapy, radiation, or immunotherapy, they often rearrange their genomes and get rid of genes that are not helpful to them. One possibility is that following CTL019 therapy the CD19 gene is forever lost. But is it also possible that it is retained in CD19-negative B-ALL cells, but simply fails to become active or function properly.

“This would be good news,” Dr. Thomas-Tikhonenko explained. “If we can find some defects in how the protein is made, then potentially we can correct the problem with drugs that restore protein production — and sensitivity to CTL019.” Elena Sotillo, PhD, a CHOP scientist, is currently pursuing this part of the Quest for the Cure study.

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