The In Vivo Therapeutic Efficacy of the Oncolytic Adenovirus Delta24-RGD Is Mediated by Tumor-Specific Immunity

The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.

[1]  K. Partanen,et al.  Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  K. Partanen,et al.  Antiviral and Antitumor T-cell Immunity in Patients Treated with GM-CSF–Coding Oncolytic Adenovirus , 2013, Clinical Cancer Research.

[3]  M. Willingham,et al.  Variation in susceptibility of human malignant melanomas to oncolytic vesicular stomatitis virus. , 2013, Surgery.

[4]  J. Sarkaria,et al.  Oncolytic measles virus strains have significant antitumor activity against glioma stem cells , 2012, Gene Therapy.

[5]  M. Caligiuri,et al.  NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors , 2012, Nature Medicine.

[6]  S. Sengupta,et al.  Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy , 2012, Clinical & developmental immunology.

[7]  I. McNeish,et al.  Failure of translation of human adenovirus mRNA in murine cancer cells can be partially overcome by L4-100K expression in vitro and in vivo. , 2012, Molecular Therapy.

[8]  J. Larkin,et al.  Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies , 2012, Clinical Cancer Research.

[9]  L. Hwang,et al.  Oncolytic Sindbis virus targets tumors defective in the interferon response and induces significant bystander antitumor immunity in vivo. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  S. Sengupta,et al.  Mechanisms of immune evasion by gliomas. , 2012, Advances in experimental medicine and biology.

[11]  E John Wherry,et al.  T cell exhaustion , 2011 .

[12]  R. Weissleder,et al.  Distinguishing Inflammation from Tumor and Peritumoral Edema by Myeloperoxidase Magnetic Resonance Imaging , 2011, Clinical Cancer Research.

[13]  M. Raffeld,et al.  Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  P. Marcato,et al.  Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity , 2010, Molecular Cancer Therapeutics.

[15]  Raymond D. Harris,et al.  A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases , 2010, Clinical Cancer Research.

[16]  J. Verweij,et al.  Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells , 2010, Cancer Immunology, Immunotherapy.

[17]  M. Opp,et al.  Lipopolysaccharide-induced increases in cytokines in discrete mouse brain regions are detectable using Luminex xMAP® technology , 2008, Journal of Neuroscience Methods.

[18]  J. Sagartz,et al.  Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  N. Parameswaran,et al.  Adenovirus Vector-Induced Innate Inflammatory Mediators, MAPK Signaling, As Well As Adaptive Immune Responses Are Dependent upon Both TLR2 and TLR9 In Vivo1 , 2008, The Journal of Immunology.

[20]  F. Lang,et al.  Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[21]  J. Fallon,et al.  Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  W. Vandertop,et al.  Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma , 2007, Clinical Cancer Research.

[23]  W. Yung,et al.  Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. , 2007, Cancer research.

[24]  W. Vandertop,et al.  AdΔ24 and the p53‐expressing variant AdΔ24‐p53 achieve potent anti‐tumor activity in glioma when combined with radiotherapy , 2007 .

[25]  M. Magnusson,et al.  An oncolytic adenovirus redirected with a tumor-specific T-cell receptor. , 2007, Cancer research.

[26]  H. Colman,et al.  Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. , 2007, Journal of the National Cancer Institute.

[27]  L. Boon,et al.  CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo , 2007, International journal of cancer.

[28]  R. Vile,et al.  Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. , 2007, Cancer research.

[29]  W. Vandertop,et al.  AdDelta24 and the p53-expressing variant AdDelta24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy. , 2007, The journal of gene medicine.

[30]  Ralph Weissleder,et al.  Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  A. Kiang,et al.  Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[32]  M. Caligiuri,et al.  Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[33]  H. Hamada,et al.  Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy , 2006, Cancer science.

[34]  J. Gomori,et al.  Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  J. Cidlowski,et al.  Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. , 2005, The New England journal of medicine.

[36]  D. Sze,et al.  Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin , 2005, Cancer Gene Therapy.

[37]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[38]  J. Sloan,et al.  Phase I–II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas , 2005, Gene Therapy.

[39]  D. Muruve,et al.  The innate immune response to adenovirus vectors. , 2004, Human gene therapy.

[40]  J. Olson,et al.  A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  D. Pardoll,et al.  Dexamethasone Mediated Inhibition of Local IL-2 Immunotherapy is Dose Dependent in Experimental Brain Tumors , 2004, Journal of Neuro-Oncology.

[42]  D. Curiel,et al.  Evaluation of a selectively oncolytic adenovirus for local and systemic treatment of cervical cancer , 2004, International journal of cancer.

[43]  R. Alemany,et al.  Conditionally Replicative Adenovirus with Tropism Expanded towards Integrins Inhibits Osteosarcoma Tumor Growth in Vitro and in Vivo , 2004, Clinical Cancer Research.

[44]  Jaap Goudsmit,et al.  Quantifying Adenovirus-Neutralizing Antibodies by Luciferase Transgene Detection: Addressing Preexisting Immunity to Vaccine and Gene Therapy Vectors , 2003, Journal of Clinical Microbiology.

[45]  A. Pathak,et al.  Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps. , 2003, Neuro-oncology.

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

[47]  G. Fuller,et al.  Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. , 2003, Journal of the National Cancer Institute.

[48]  W. Vandertop,et al.  Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy. , 2002, Cancer research.

[49]  D. Nettelbeck,et al.  Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. , 2002, Cancer research.

[50]  R. Alemany,et al.  A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[51]  Becky,et al.  Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study. , 2000, Journal of neurosurgery.

[52]  R. Martuza,et al.  Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial , 2000, Gene Therapy.

[53]  P. Lowenstein,et al.  Interleukin-1 Mediates a Rapid Inflammatory Response After Injection of Adenoviral Vectors into the Brain , 1999, The Journal of Neuroscience.

[54]  A. Houweling,et al.  Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. , 1996, Human gene therapy.

[55]  S. Sierakowski,et al.  Mechanism of action of glucocorticosteroids. Inhibition of T cell proliferation and interleukin 2 production by hydrocortisone is reversed by leukotriene B4. , 1986, The Journal of clinical investigation.