Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML)

Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML)

  • Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.

    Article 
    PubMed 

    Google Scholar
     

  • Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008;19:379–90.

    PubMed 

    Google Scholar
     

  • Loomis D, Guha N, Hall AL, Straif K. Identifying occupational carcinogens: an update from the IARC Monographs. Occup Environ Med. 2018;75:593–603.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yanada M, Naoe T. Acute myeloid leukemia in older adults. Int J Hematol. 2012;96:186–93.

    Article 
    PubMed 

    Google Scholar
     

  • Othman J, Lam HPJ, Leong S, Basheer F, Abdallah I, Fleming K, et al. Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS. Blood Neoplasia. 2024;1:100017.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schlenk RF, Müller-Tidow C, Benner A, Kieser M. Relapsed/refractory acute myeloid leukemia: Any progress? Curr Opin Oncol. 2017;29:467–73.

    Article 
    PubMed 

    Google Scholar
     

  • Schlenk RF, Jaramillo S, Müller-Tidow C. Improving consolidation therapy in acute myeloid leukemia—a tough nut to crack. Haematologica. 2018;103:1579–81.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid Leukemia. N Engl J Med. 2015;373:1136–52.

    Article 
    PubMed 

    Google Scholar
     

  • Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moarii M, Papaemmanuil E. Classification and risk assessment in AML: integrating cytogenetics and molecular profiling. Hematol Am Soc Hematol Educ Program. 2017;2017:37–44.

    Article 

    Google Scholar
     

  • Daver N, Wei AH, Pollyea DA, Fathi AT, Vyas P, DiNardo CD. New directions for emerging therapies in acute myeloid leukemia: the next chapter. Blood Cancer J. 2020;10:107.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33:299–312.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu X, Gong Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res. 2019;7:22.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617–29.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, et al. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000;6:1796–803.

    CAS 
    PubMed 

    Google Scholar
     

  • Fakler M, Loeder S, Vogler M, Schneider K, Jeremias I, Debatin KM, et al. Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood. 2009;113:1710–22.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Löder S, Fakler M, Schoeneberger H, Cristofanon S, Leibacher J, Vanlangenakker N, et al. RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. Leukemia. 2012;26:1020–9.

    Article 
    PubMed 

    Google Scholar
     

  • Chromik J, Safferthal C, Serve H, Fulda S. Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis. Cancer Lett. 2014;344:101–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Carter BZ, Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM, et al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst. 2014;106:djt440.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Amaravadi RK, Schilder RJ, Martin LP, Levin M, Graham MA, Weng DE, et al. A Phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol Cancer Ther. 2015;14:2569–75.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pemmaraju N, Carter BZ, Bose P, Jain N, Kadia TM, Garcia-Manero G, et al. Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis. Blood Adv. 2021;5:3163–73.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kadia TM, Cortes JE, Ghorab A, Ravandi F, Jabbour E, Daver NG, et al. Nivolumab (Nivo) maintenance (maint) in high-risk (HR) acute myeloid leukemia (AML) patients. J Clin Oncol. 2018;36:7014.

  • Smits EL, Anguille S, Berneman ZN. Interferon α may be back on track to treat acute myeloid leukemia. Oncoimmunology. 2013;2:e23619.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Müller L, Berkeley R, Barr T, Ilett E, Errington-Mais F. Past, present and future of oncolytic reovirus. Cancers. 2020;12:3219.

  • Achard C, Surendran A, Wedge ME, Ungerechts G, Bell J, Ilkow CS. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine. 2018;31:17–24.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–62.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Müller LME, Holmes M, Michael JL, Scott GB, West EJ, Scott KJ, et al. Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21. J Immunother Cancer. 2019;7:164.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Müller LME, Migneco G, Scott GB, Down J, King S, Askar B, et al. Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche. J Immunother Cancer. 2021;9:e001803.

  • Sheikh M, Saiyyad A, Aliunui A, Jirvankar PS. The evolving landscape of oncolytic virus immunotherapy: combinatorial strategies and novel engineering approaches. Med Oncol. 2025;42:190.

    Article 
    PubMed 

    Google Scholar
     

  • Madlambayan GJ, Bartee E, Kim M, Rahman MM, Meacham A, Scott EW, et al. Acute myeloid leukemia targeting by myxoma virus in vivo depends on cell binding but not permissiveness to infection in vitro. Leuk Res. 2012;36:619–24.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim M, Madlambayan GJ, Rahman MM, Smallwood SE, Meacham AM, Hosaka K, et al. Myxoma virus targets primary human leukemic stem and progenitor cells while sparing normal hematopoietic stem and progenitor cells. Leukemia. 2009;23:2313–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hall K, Scott KJ, Rose A, Desborough M, Harrington K, Pandha H, et al. Reovirus-mediated cytotoxicity and enhancement of innate immune responses against acute myeloid leukemia. Biores Open Access. 2012;1:3–15.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Samudio I, Rezvani K, Shaim H, Hofs E, Ngom M, Bu L, et al. UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells. Blood. 2016;127:2575–86.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shen W, Patnaik MM, Ruiz A, Russell SJ, Peng KW. Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia. Blood. 2016;127:1449–58.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dobson CC, Naing T, Beug ST, Faye MD, Chabot J, St-Jean M, et al. Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model. Oncotarget. 2017;8:3495–508.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beug ST, Tang VA, LaCasse EC, Cheung HH, Beauregard CE, Brun J, et al. Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat Biotechnol. 2014;32:182–90.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cai J, Lin Y, Zhang H, Liang J, Tan Y, Cavenee WK, et al. Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics. Proc Natl Acad Sci USA. 2017;114:6812–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tumilasci VF, Olière S, Nguyên TL, Shamy A, Bell J, Hiscott J. Targeting the apoptotic pathway with BCL-2 inhibitors sensitizes primary chronic lymphocytic leukemia cells to vesicular stomatitis virus-induced oncolysis. J Virol. 2008;82:8487–99.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Samuel S, Tumilasci VF, Oliere S, Nguyên TL, Shamy A, Bell J, et al. VSV oncolysis in combination with the BCL-2 inhibitor obatoclax overcomes apoptosis resistance in chronic lymphocytic leukemia. Mol Ther. 2010;18:2094–103.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sarkar S, Quinn BA, Shen XN, Dash R, Das SK, Emdad L, et al. Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic. Oncotarget. 2015;6:10712–27.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Prestwich RJ, Ilett EJ, Errington F, Diaz RM, Steele LP, Kottke T, et al. Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. Clin Cancer Res. 2009;15:4374–81.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L, et al. Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Ther. 2008;15:1257–70.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sborov DW, Nuovo GJ, Stiff A, Mace T, Lesinski GB, Benson DM Jr., et al. A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma. Clin Cancer Res. 2014;20:5946–55.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Parrish C, Scott GB, Migneco G, Scott KJ, Steele LP, Ilett E, et al. Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia. Leukemia. 2015;29:1799–810.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rushworth SA, MacEwan DJ. HO-1 underlies resistance of AML cells to TNF-induced apoptosis. Blood. 2008;111:3793–801.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med. 2018;10:eaam7577.

  • Rohner L, Reinhart R, Iype J, Bachmann S, Kaufmann T, Fux M. Impact of BH3-mimetics on human and mouse blood leukocytes: a comparative study. Sci Rep. 2020;10:222.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bourhis J, Licitra LF, Burtness B, Psyrri A, Haddad R, Harrington K, et al. Xevinapant or placebo plus platinum-based chemoradiotherapy in unresected locally advanced squamous cell carcinoma of the head and neck (TrilynX): a randomized, Phase III study. J Clin Oncol. 2025;43:3209–20.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heinzerling L, Künzi V, Oberholzer PA, Kündig T, Naim H, Dummer R. Oncolytic measles virus in cutaneous T-cell lymphomas mounts antitumor immune responses in vivo and targets interferon-resistant tumor cells. Blood. 2005;106:2287–94.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Packiriswamy N, Upreti D, Zhou Y, Khan R, Miller A, Diaz RM, et al. Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma. Leukemia. 2020;34:3310–22.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cook J, Peng KW, Witzig TE, Broski SM, Villasboas JC, Paludo J, et al. Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma. Blood Adv. 2022;6:3268–79.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Errington F, Steele L, Prestwich R, Harrington KJ, Pandha HS, Vidal L, et al. Reovirus activates human dendritic cells to promote innate antitumor immunity. J Immunol. 2008;180:6018–26.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fischer K, Tognarelli S, Roesler S, Boedicker C, Schubert R, Steinle A, et al. The Smac mimetic BV6 improves NK cell-mediated killing of rhabdomyosarcoma cells by simultaneously targeting tumor and effector cells. Front Immunol. 2017;8:202.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sauer M, Reiners KS, Hansen HP, Engert A, Gasser S, von Strandmann EP. Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro. Biol Chem. 2013;394:1325–31.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lecis D, De Cesare M, Perego P, Conti A, Corna E, Drago C, et al. Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity. Cell Death Dis. 2013;4:e920.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim DS, Dastidar H, Zhang C, Zemp FJ, Lau K, Ernst M, et al. Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms. Nat Commun. 2017;8:344.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beug ST, Beauregard CE, Healy C, Sanda T, St-Jean M, Chabot J, et al. Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma. Nat Commun. 2017;8:14278.

  • Hillert LK, Bettermann-Bethge K, Nimmagadda SC, Fischer T, Naumann M, Lavrik IN. Targeting RIPK1 in AML cells carrying FLT3-ITD. Int J Cancer. 2019;145:1558–69.

  • Bisaillon R, Moison C, Thiollier C, Krosl J, Bordeleau ME, Lehnertz B, et al. Genetic characterization of ABT-199 sensitivity in human AML. Leukemia. 2020;34:63–74.

    Article 
    PubMed 

    Google Scholar
     

  • Shukla DK, Katewa S, Porwal R, Dara R, Sharma L, Sharma R, et al. MRD negative CR after azacitidine and venetoclax in a young patient with AML, unfit for intensive induction followed by ASCT. Leuk Res Rep. 2021;16:100267.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar