Leukemia Cell-Rhabdovirus Vaccine: Personalized Immunotherapy for Acute Lymphoblastic Leukemia
| Autor: | Theresa Falls, Kelley Parato, David P. Conrad, Fabrice Le Boeuf, Jean-Simon Diallo, Chantal G Lemay, Harold L. Atkins, John C. Bell, Jovian Tsang, Meaghan Maclean |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Cell Survival viruses medicine.medical_treatment Mice Nude Cancer Vaccines Immunotherapy Adoptive Virus Mice Immune system Cell Line Tumor Chlorocebus aethiops Splenocyte Animals Humans Medicine Precision Medicine Vero Cells Bone Marrow Transplantation business.industry Cancer Immunotherapy Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Adoptive Transfer Mice Inbred C57BL Leukemia Oncology Mice Inbred DBA Apoptosis Immunology Rhabdoviridae business Neoplasm Transplantation Ex vivo |
| Zdroj: | Clinical Cancer Research. 19:3832-3843 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-12-3199 |
| Popis: | Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia. Clin Cancer Res; 19(14); 3832–43. ©2013 AACR. |
| Databáze: | OpenAIRE |
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