Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists

Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation.

[1]  C. E. Engeland,et al.  Immunomodulation in Oncolytic Measles Virotherapy. , 2020, Methods in molecular biology.

[2]  Daniel J. Freeman,et al.  Optimizing oncolytic virotherapy in cancer treatment , 2019, Nature Reviews Drug Discovery.

[3]  Johannes P. W. Heidbuechel,et al.  Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo. , 2019, Journal of visualized experiments : JoVE.

[4]  D. Bartlett,et al.  Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  B. Nelson,et al.  Oncolytic viruses as engineering platforms for combination immunotherapy , 2018, Nature Reviews Cancer.

[6]  C. von Kalle,et al.  Enhanced Control of Oncolytic Measles Virus Using MicroRNA Target Sites , 2018, Molecular therapy oncolytics.

[7]  C. von Kalle,et al.  Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors , 2018, Clinical Cancer Research.

[8]  Xiaojing Xu,et al.  Newcastle disease virus co‐expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy , 2018, Cancer science.

[9]  K. Schluns,et al.  The potential and promise of IL-15 in immuno-oncogenic therapies. , 2017, Immunology letters.

[10]  Xiaojing Xu,et al.  Rescue of nonlytic Newcastle Disease Virus (NDV) expressing IL-15 for cancer immunotherapy. , 2017, Virus research.

[11]  E. Galanis,et al.  Potential and clinical translation of oncolytic measles viruses , 2017, Expert opinion on biological therapy.

[12]  C. von Kalle,et al.  Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation , 2017, Oncoimmunology.

[13]  Simon J. Dovedi,et al.  Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery , 2016, Cancer Immunology Research.

[14]  A. Fielding,et al.  Measles to the Rescue: A Review of Oncolytic Measles Virus , 2016, Viruses.

[15]  Y. Furukawa,et al.  Oncolytic Activity of a Recombinant Measles Virus, Blind to Signaling Lymphocyte Activation Molecule, Against Colorectal Cancer Cells , 2016, Scientific Reports.

[16]  L. Galluzzi,et al.  First oncolytic virus approved for melanoma immunotherapy , 2016, Oncoimmunology.

[17]  C. von Kalle,et al.  CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  G. McFadden,et al.  Myxoma Virus Expressing a Fusion Protein of Interleukin-15 (IL15) and IL15 Receptor Alpha Has Enhanced Antitumor Activity , 2014, PloS one.

[19]  L. Radvanyi,et al.  The IL-2 cytokine family in cancer immunotherapy. , 2014, Cytokine & growth factor reviews.

[20]  C. von Kalle,et al.  Granulocyte-macrophage colony-stimulating factor-armed oncolytic measles virus is an effective therapeutic cancer vaccine. , 2013, Human gene therapy.

[21]  F. Tangy,et al.  Natural Oncolytic Activity of Live-Attenuated Measles Virus against Human Lung and Colorectal Adenocarcinomas , 2013, BioMed research international.

[22]  H. Heslop,et al.  Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma , 2012, Clinical Cancer Research.

[23]  J. Ingle,et al.  Expression of immunomodulatory neutrophil-activating protein of Helicobacter pylori enhances the antitumor activity of oncolytic measles virus. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  A. Ashkar,et al.  Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity , 2011, Cancer Gene Therapy.

[25]  T. Waldmann,et al.  Interleukin-15 biology and its therapeutic implications in cancer. , 2012, Trends in pharmacological sciences.

[26]  Wenbo Xu,et al.  Genetic characterization of measles vaccine strains. , 2011, The Journal of infectious diseases.

[27]  D. Dingli,et al.  Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy , 2010, Cancer Gene Therapy.

[28]  T. Waldmann,et al.  Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer , 2009, Proceedings of the National Academy of Sciences.

[29]  M. Billeter,et al.  Reverse Genetics of Measles Virus and Resulting Multivalent Recombinant Vaccines: Applications of Recombinant Measles Viruses , 2009, Current topics in microbiology and immunology.

[30]  S. Russell,et al.  Measles virus as an oncolytic vector platform. , 2008, Current gene therapy.

[31]  T. Waldmann,et al.  Preassociation of IL-15 with IL-15Rα-IgG1-Fc Enhances Its Activity on Proliferation of NK and CD8+/CD44high T Cells and Its Antitumor Action1 , 2008, The Journal of Immunology.

[32]  L. Lefrançois,et al.  Combined IL-15/IL-15Rα Immunotherapy Maximizes IL-15 Activity In Vivo1 , 2006, The Journal of Immunology.

[33]  D. Weiner,et al.  Regression of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing plasmid followed by in vivo electroporation , 2006, Cancer Gene Therapy.

[34]  P. Staeheli,et al.  RNA Polymerase II-Controlled Expression of Antigenomic RNA Enhances the Rescue Efficacies of Two Different Members of the Mononegavirales Independently of the Site of Viral Genome Replication , 2006, Journal of Virology.

[35]  J. Sprent,et al.  Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Plet,et al.  Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. , 2006, The Journal of biological chemistry.

[37]  Leo Lefrançois,et al.  Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. , 2006, Journal of immunology.

[38]  C. James,et al.  Rescue and propagation of fully retargeted oncolytic measles viruses , 2005, Nature Biotechnology.

[39]  P. Burkett,et al.  Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis , 2004, The Journal of experimental medicine.

[40]  S. Russell,et al.  High CD46 Receptor Density Determines Preferential Killing of Tumor Cells by Oncolytic Measles Virus , 2004, Cancer Research.

[41]  D. Dingli,et al.  Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. , 2004, Blood.

[42]  Rafał Kamiński,et al.  Complete tumour regressions induced by vaccination with IL-12 gene-transduced tumour cells in combination with IL-15 in a melanoma model in mice , 2004, Cancer Immunology, Immunotherapy.

[43]  R. Cattaneo,et al.  Neutrophils contribute to the measles virus-induced antitumor effect: enhancement by granulocyte macrophage colony-stimulating factor expression. , 2003, Cancer research.

[44]  T. Waldmann,et al.  IL-15Rα Recycles and Presents IL-15 In trans to Neighboring Cells , 2002 .

[45]  D. Gerlier,et al.  Restriction of Measles Virus RNA Synthesis by a Mouse Host Cell Line: trans-Complementation by Polymerase Components or a Human Cellular Factor(s) , 2002, Journal of Virology.

[46]  T. Waldmann,et al.  IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. , 2002, Immunity.

[47]  H. Hirai,et al.  In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice , 2001, Gene Therapy.

[48]  T. Waldmann,et al.  IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Musiani,et al.  The Combined Action of IL-15 and IL-12 Gene Transfer Can Induce Tumor Cell Rejection Without T and NK Cell Involvement1 , 2000, The Journal of Immunology.

[50]  Y. Nimura,et al.  Synergistic effect of interleukin-15 and interleukin-12 on antitumor activity in a murine malignant pleurisy model , 2000, Cancer Immunology, Immunotherapy.

[51]  T. Evans,et al.  Effects of interleukin-15 on in vitro human T cell proliferation and activation. , 2000, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[52]  J. Sprent,et al.  Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. , 1998, Immunity.

[53]  R. Mulligan,et al.  Bioactive murine and human interleukin-12 fusion proteins which retain antitumor activity in vivo , 1997, Nature Biotechnology.

[54]  M. Billeter,et al.  Rescue of measles viruses from cloned DNA. , 1995, The EMBO journal.

[55]  M. Caligiuri,et al.  Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor , 1994, The Journal of experimental medicine.

[56]  L. Roux,et al.  The rule of six, a basic feature for efficient replication of Sendai virus defective interfering RNA , 1993, Journal of virology.

[57]  P. Hand,et al.  Transduction and expression of the human carcinoembryonic antigen gene in a murine colon carcinoma cell line. , 1991, Cancer research.

[58]  M. Billeter,et al.  Altered ratios of measles virus transcripts in diseased human brains. , 1987, Virology.

[59]  W. Seaman,et al.  Depletion of natural killer cells in mice by monoclonal antibody to NK-1.1. Reduction in host defense against malignancy without loss of cellular or humoral immunity. , 1987, Journal of immunology.