Engineered T Cells Help a Child Get Rid of Leukemia


Pediatric oncologists from The Children’s Hospital of Pennsylvania (CHOP) and collaborating scientists from the University of Pennsylvania (UPenn) have used genetic engineering techniques to reprogram T lymphocytes from a young cancer patient’s blood. This reprogramming drove the T cells to attack the child’s leukemia, and, to date, has completely cured the child of leukemia.

Stephan Grupp, a pediatric oncologist from CHOP, is part of a clinical trial that tests cell therapy for adult chronic lymphocytic leukemia (CLL). CLL is the most common type of leukemia in adults and usually occurs during or after middle age and only rarely occurs in children.

As regular readers of this blog are aware, the bone marrow contains a stem cell population called hematopoietic stem cells. While this stem cell population is not a homogeneous one, these stem cells divide to renew themselves and replenish all the blood cells that we lose each day. When the hematopoietic stem cells divide, they renew themselves and give rise to either a myeloid or lymphoid progenitor cells. Myeloid progenitors differentiate into one of three types of mature blood cells: 1) red blood cells, which carry oxygen and the other substances to all tissues in the body; 2) white blood cells that fight infection and disease; 3) platelets that form blood clots to stop bleeding. Lymphoid progenitors become lymphoblast cells which then differentiate to become one of three cell types: 1) B lymphocytes, which make antibodies to fight infection; 2) T lymphocytes that help B lymphocytes to make antibodies to fight infection; 3) natural killer cells that attack cancer cells and viruses.

Hematopoietic stem cells

CHOP’s Stephen Grupp and Carl June, of the Perelman School of Medicine at the Univ. of Pennsylvania, lead this research group. Together, they have presented new data at the American Society of Hematology annual meeting in Atlanta that shows nine of 12 patients with advanced leukemias in the clinical trial, including two children, who responded to treatment with their newly engineered cells. This treatment strategy uses an engineered T lymphocyte that Grupp and June call “CTL019 cells.” By reprogramming the T cells to specifically attack this aggressive form of leukemia, some of these patients showed a complete remission of their leukemias.

Of the nine patients who responded to CTL019 treatment, one was a 7-year-old patient who suffered from acute lymphoblastic leukemia (ALL). Grupp and Penn colleagues adapted their treatment to combat ALL, which is the most common type of childhood leukemia and the most common childhood cancer. Although physicians cure roughly 85 percent of ALL cases, the remaining 15 percent of such cases stubbornly resist treatment.

Grupp’s research builds on his ongoing collaboration with scientists from UPenn. These UPenn researchers developed modified T cells as a treatment for B-cell leukemias. T cells are at the center of the immune response. T lymphocytes recognize and attack invading foreign invaders, but cancer cells slip under their surveillance net because they are so similar to normal cells. CAR T cells, which stands for “chimeric antigen receptor T cells” are engineered to specifically detect and target cancerous B cells. Since the B cells are the cancerous cells in the case of certain leukemias, such as ALL and CLL, CAR T cells can purge the body of these cancers rather effectively.

On the surface of B cells is a protein called CD19. By raising high-affinity antibodies to CD19 and then physically attaching those antibodies to T cells, UPenn researchers invented a kind of guided missile that detects and destroys B cells and B-cell leukemias.

When Grupp and his crew used CLT019 in his pediatric patients, they found that the engineered T cell was very active, but it caused an undesirable side effect called cytokine release syndrome. The child became very ill and was admitted to the intensive care unit. However, Grupp and his team counteracted these toxic side effects by using two 2 drugs that suppress the immune response and these thwarted the overactive immune response and rapidly relieved the child’s treatment-related symptoms. An added bonus was that these drugs had no effect on the engineered T cells, which still destroyed leukemia cells until the cows came home. These results were so effective, that this clinical approach is now being successfully incorporated into CTL019 treatments for adults as well.

The CHOP/UPenn team reported on early results of this clinical trial in adult chronic lymphocytic leukemia (CLL) patients in August of 2011. In their seven-year-old patient, they engineered her own T cells to attack her aggressive form of childhood leukemia. Without this treatment, she faced grim prospects once her cancer relapsed after conventional treatment. However, with this innovative CTL019 experimental therapy, the bioengineered T cells multiplied rapidly in her body and destroyed the leukemia cells. After her CTL019 treatment, the child’s doctors found that she had no evidence of cancer.

According to Grupp: “These engineered T cells have proven to be active in B cell leukemia in adults. We are excited to see that the CTL019 approach may be effective in untreatable cases of pediatric ALL as well. Our hope is that these results will lead to widely available treatments for high-risk B cell leukemia and lymphoma, and perhaps other cancers in the future.”

Susan Rheingold, one of the leaders in the Children’s Hospital program for children with relapsed leukemia added: “This type of pioneering research addresses the importance of timing when considering experimental therapies for relapsed patients. To ensure newly relapsed patients with refractory leukemia meet criteria for options like CTL019, we must begin exploring these innovative approaches earlier than ever before. Having the conversation with families earlier provides them more treatment options to offer the best possible outcome.”

In August 2012, the biotechnology company Novartis acquired exclusive rights from UPenn to CART-19, the therapy that was the subject of this clinical trial and which is now known as CTL019.