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Mar 21, 2013

Cell Therapy Leads to ALL Remission

  • An experimental cell therapy that manipulates the immune system to treat the normally deadly recurrent B-cell acute lymphoblastic leukemia (ALL) showed success in Phase I of an ongoing clinical trial.

    By genetically modifying a patient’s lymphocytes to attack the tumor cells causing ALL, researchers killed those cells in all five patients studied, enabling their cancers to go into rapid and complete remission, according to the study, which was published yesterday in Science Translational Medicine.

    All five patients underwent the cell therapy following the failure of chemotherapy. Four of the five patients received an additional bone marrow transplant. Of those, three have remained in remission for between five and 24 months. A fourth died while in remission two months after the transplant from complications unrelated to the cancer therapy. The fifth, who was ineligible for the transplant because of health risks, died after relapsing.

    Yet those results offer dramatic improvement from what researchers in the study said was the usual “dismal prognosis” of patients with ALL. Nearly 6,100 people will be diagnosed with ALL this year, of which more than 1,400 are expected to die, according to figures from the National Cancer Institute.

    “This is a very exciting finding for patients with B cell ALL and a major achievement in the field of targeted immunotherapy,” Michel Sadelain, M.D., Ph.D., director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center, said in a statement. Dr. Sadelain led the study along with Renier J. Brentjens, M.D., Ph.D., a medical oncologist specializing in the treatment of acute and chronic leukemias at Memorial Sloan-Kettering and the study’s corresponding author.

    Drs. Sadelain and Brentjens are among the Memorial Sloan-Kettering researchers who have spent the past decade studying the targeted immunotherapy approach, which involves removing T cells from patients and using an engineered viral vector to introduce a new gene into the cells.

    After that gene is transferred and expressed, the T cells are infused back into patients, multiply, and cause immune responses aimed at attacking the cancer cells. The genetically engineered cells express chimeric antigen receptors (CARs), enabling them to recognize and destroy the CD19 protein present in B cell ALL tumor cells.

    The study results “demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent [allogeneic hematopoietic stem cell transplantation],” the investigators concluded.

    By serving as a bridge to a stem cell transplant, Dr. Brentjens said in the statement, the therapy could potentially help cure adult patients with B cell ALL that have relapsed and who are chemotherapy resistant.

    “Otherwise, these patients have a virtually incurable disease,” Dr. Brentjens added. “We need to examine the effectiveness of this targeted immunotherapy in additional patients before it could potentially become a standard treatment for patients with relapsed B cell ALL.”

    To that end, further clinical trials, including a Phase II study, have already been planned to test whether B cell ALL patients would benefit from receiving the targeted immunotherapy along with chemotherapy earlier in the disease stage—either as part of the initial frontline treatment, or after remission has been achieved to help prevent relapse.

    The therapy bore similiarities to one pioneered by the University of Pennsylvania’s Perelman School of Medicine, a gene therapy that uses infusions of patients’ own T cells that are genetically engineered to attack their tumors. The therapy entails reprogramming patients’ T cells using a HIV-derived lentivirus vector that encodes a CAR on the surface of the T cells that binds to CD19. The modified T cells are infused back into the patient's body, where they start expressing the CAR, focusing their killing activity on cells that express CD19 while ignoring all other cells.

    All but one of the latest study’s 25 co-authors was from Memorial Sloan-Kettering. Lindsay G. Cowell, Ph.D., is based at University of Texas Southwestern Medical Center in Dallas. 


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