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Hope For Children with Acute Lymphoblastic Leukemia

By: Ada Seldin, Staff Editor

Emily Whitehead, a 7-year-old girl who fought off relapsing acute lymphoblastic leukemia (ALL), has captured the hearts and prayers of the masses. Her story is an inspiration to those battling any disease with a poor prognosis and particularly holds promise for the 15% of children with ALL resistant to intensive chemotherapy. Emily was one of two children who enrolled in an experimental T cell therapy involving CTL019, a chimeric antigen receptor with specificity for CD19 on B cells. Within a month of therapy, she demonstrated an astounding recovery and has been in remission since.1

In acute lymphoblastic leukemia, immature lymphocytes in the bone marrow, known as lymphoblasts, remain in their immature state. T cells normally recognize these mutated cells and kill them before they are able to multiple exponentially, but in the case of this disease, the abnormal cells remain undetected. The disease progresses quickly as the cancerous blast cells spread to the blood, liver, spleen, and lymph nodes.2 The premise of the experimental treatment was to reengineer the patient’s T cells to express anti-CD19 receptors that would target and destroy the invading B cells. This procedure had already been successfully carried out in three adult patients with chronic lymphoblastic leukemia, but the effects on children with ALL were still uncertain.3

Emily had been diagnosed with acute lymphoblastic leukemia two years prior to initiating the experimental therapy. Prior to her participation in the study, her disease had relapsed, and several rounds of high-dose chemotherapy were performed with little avail.1 For the study, a sample of Emily’s and the other patient’s T cells were extracted and engineered to express the chimeric antigen receptor using lentiviral-vector technology. The cells were subsequently infused into the patients’ blood stream over a period of three days.3

One month after the CTL09 infusion, both patients experienced morphologic remission which is defined by less than 0.01% of residual disease. As hoped, the chimeric T cells multiplied in the blood and bone marrow to levels more than 1000 times that of the original levels introduced into the body. Much to the researchers’ surprise, the CTL019 colony also spread to the cerebral spinal fluid, a phenomenon that had not been observed  in previous studies with adults. Furthermore, researchers had not predicted CTL019 migration into the CSF because neither child had detectable central nervous system leukemia. Such findings identify chimeric antigen receptor-modified T cells as a means of preventing lymphomas from spreading to the CNS and as potential treatment modalities against primary CNS cancers.3

Emily’s recovery was nothing short of a miracle. The other child’s cancer, however, proved to be more resilient. The cancerous blast cells reappeared in the circulatory system two months after CTL019 infusion. They had muted to no longer express CD19, thereby evading the T cells that depend on this antigen for recognition. According to evidence uncovered by IGH sequencing, the CD19- clone was present in the peripheral blood and bone marrow as early as day 23. The probability of this event occurring in future patients can be reduced by the addition of chimeric T cells with different antigen receptors, such as CD22. In addition, because this event has not yet occurred in adults with CLL, researchers have reason to believe that it is specific to a certain subset of acute leukemias.3

Although CTL09 therapy clearly demonstrates anti-leukemic effects, it is not devoid of safety issues. Both children experienced acute toxicity secondary to the cytokine-release syndrome, including high fevers. Emily was transferred to the pediatric intensive care unit on day 5 as her condition necessitated ventilation and blood-pressure support. The new population of T cells had released a surge of cytokines, which in turn, caused systemic inflammation. Glucocorticoids were not successful, but the anticytokine monoclonal antibodies etanercept and tocilizumab brought Emily back to normal within hours. Both patients also displayed laboratory evidence of the macrophage activation syndrome, namely elevated levels of ferritin, aminotransferase, triglycerides, and serum D-dimer.3

     The use of T-cells to treat leukemia is still under investigation and much remains to be learned. As such, it is not employed first-line in children newly diagnosed with acute lymphoblastic leukemia, because many of them will benefit from standard chemotherapy. It is, however, a viable option for patients with relapsing disease. In the last decade, scientists have turned to immunotherapy,  which involves manipulating the host’s immune cells to eradicate cancerous cells.  An unprecedented advantage of CTL09 is that the reengineered T cells are able to thrive in the body, reaching adequate numbers to induce remission of disease.4 With further data and improvements, T cell therapy may just prove to be the perfect cure.

 

SOURCES:

  1. Emily Whitehead’s Story: T cell therapy to treat acute lymphoblastic leukemia. The Children’s Hospital of Philadelphia Website. http://www.chop.edu/service/oncology/patient-stories-cancer/leukemia-story-emily.html Accessed August 16, 2013.
  2. What is acute lymphoblastic leukemia. American Cancer Society Website. http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-what-is-all Accessed August 16, 2013.
  3. Stephan A. Grupp, M.D., Ph.D., Michael Kalos, Ph.D., David Barrett, M.D., Ph.D., et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. The New England Journal of Medicine. 2013; 368(16): 1509-1518.
  4. First Pediatric Patients Treated in T cell therapy Clinical Trial. The Children’s Hospital of Philadelphia Website. http://www.chop.edu/service/oncology/pediatric-cancer-research/t-cell-therapy.html Accessed August 16, 2013.
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