Abstract
Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL. Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow-transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors. Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P < 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective. Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia.
Highlights
Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy characterized by rapid accumulation of lymphoblasts in the marrow with suppression of hematopoiesis [1]
Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of immunotherapy by leukemia-oncotropic virus (iLOV)
Measures that reduce the intensity or duration of chemotherapy without compromising disease control would improve the quality of life for survivors of childhood ALL, whereas more potent therapies are required for curing adult ALL
Summary
Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy characterized by rapid accumulation of lymphoblasts in the marrow with suppression of hematopoiesis [1]. Children are treated with prolonged multiagent radio-chemotherapy, achieving at least 80% long-term survival [2], but this is associated with frequent. Authors' Affiliations: 1Ottawa Hospital Research Institute, Center for Cancer Therapeutics; Departments of 2Medicine, 3Cellular and Molecular Medicine, and 4Biochemistry, Immunology and Microbiology, University of Ottawa; and 5Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Ontario, Canada. Mediated graft versus leukemia (GvL) effects are responsible, in part, for improved outcomes in the minority of patients eligible for allogeneic hematopoietic stem cell transplantation ALL is amenable to immunotherapy as shown by the effectiveness of GvL, administering vaccines targeting residual leukemic cells remaining after induction chemotherapy may help achieve these goals
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