PracticeUpdate: Conference Series - EHA 2018

CLL1-CD33 cCAR T-cell Therapy Promising for AML CLL1 and CD33may eliminate both AML bulky disease and leukemia stemcells CLL1-CD33 cCAR T is a promising immunotherapy for acute myeloid leukemia (AML), according to new research findings presented at EHA 2018. “We demonstrated the feasibility and safety of targeting both CLL1 and CD33 to achieve complete response (CR). Our findings suggest further exploration of CLL1-CD33 cCAR T therapy as a stand-alone therapy or ‘bridge to transplant’ for patients with aggressive, relapsing/refractory AML leukemia,” the researchers stated in their abstract. This was the first in-human clinical trial for the therapy. CAR T-cell therapy relies on the use of a patient’s own immune system cells to fight the cancer in their body. The process typically involves modifying a specific set of cells from the patient’s blood to strengthen the immune system’s natural response to the disease. Anti-CD19 CAR T-cells have already shown impressive efficacy in acute lymphoblastic leukemia (B-ALL) and lymphoma, and approval from the Food and Drug Administration (FDA) in the United States has now been obtained. However, treatment of relapsed/refractory AML remains a substantial clinical challenge, noted the study team, led by Dr. Fang Liu, with the Department of Hematology at the Chengdu Military Hospital in China. AML bears heterogeneous cells that can offset killing by single CAR- based therapies, resulting in a relapse. Leukemic stem cells associated with CLL1 expression comprise a rare population that also play an impor- tant role in both disease progression and relapse. CD33 is a myeloid marker found on bulk AML disease cells in the majority of these patients. The present study is the first to treat refractory AML in patients using compound CAR T-cells with discrete scFv domains that target two AML antigens at the same time. The goal was threefold: to provide antigen escape, to ensure the process was safe, and to ensure the treatment was well tolerated. “Our findings indicate that targeting both CLL1 and CD33 on AML cells may be an effective strategy for eliminating both AML bulky disease and leukemia stem cells that may potentially prevent relapse due to antigen escape or the persistence of leukemia stem cells,” Liu said during his presentation. A cCAR bearing two complete CAR constructs connected by a self- cleavable peptide linker, P2A, was generated. Then the anti-leukemic activities of CLL1-CD33 cCAR T cells were evaluated in vitro with killing assays using multiple AML cell lines, primary human AML samples and REH cells expressing either CLL1 or CD33. The research team tested cCAR in multiple animal models that involved injecting mice with REH expressing CLL1 or CD33 or U937 cell line. They also tested an alemtuzumab safety switch that allows for rapid cCAR therapy termination in vivo. “Mice treated with CLL1-CD33 cCAR showed significantly improved survival as compared to control-treated mice,” the researchers stated. “We also showed that CLL1-CD33 cCAR promoted sustained in vivo anti-leukemic activity against the AML U937 cell line, as well as supe- rior murine survival in both models.” Next the researchers conducted a single-patient phase I clinical trial. Additional patients are being enrolled in the study. It is anticipated that 20 patients with relapsed/refractory AML will receive the treatment.

of tobacco abuse, incisions on lower extremities that inherently impair post-operative ambulation, high rates of wound complications and soft tissue infections, and concomitant amputations at times of digits that further impair early ambulation. Additionally, he told Elsevier’s PracticeUpdate , cer- tain vascular patients, especially those with metabolic syndrome and uncontrolled diabetes with or without smoking, may harbor an underlying hypercoaguable disorder that has yet to be diagnosed. “All of these risk factors and unique characteristics of vascular bypass patients make them inherently higher risk for thrombo- embolic disease.” “I would like to see more stratification of risk factors and comorbid conditions that exist in these patients,” said Dr. Vasquez. “Ultimately a reliable scoring system could be developed that would deem a patient at a certain risk category for a post-operative DVT/PE event. This may allow the treatment team to be more liberal with adequate perioperative prophylaxis.” " Ultimately a reliable scoring system could be developed that would deem a patient at a certain risk category for a post-operative DVT/ PE event. This may allow the treatment team to be more liberal with adequate perioperative prophylaxis. "

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EHA 2018 • PRACTICEUPDATE CONFERENCE SERIES