Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4

Post, Dawn E.; Sandberg, Eric M.; Kyle, Michele; Devi, Narra S.; Brat, Daniel J.; Xu, Zhiheng; Tighiouart, Mourad; Meir, Erwin G. Van

doi:10.1158/0008-5472.can-06-3244

Cited by 92 publications

(83 citation statements)

References 44 publications

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“…They are capable to destroy human tumors (1) and probably also lymph node metastases (2) in immunodeficient nude mice by intratumoral spreading of infection and tumor-wide oncolysis. Recently, attention has been paid to the role of virotherapy in promoting antitumor immune response (3)(4)(5)(6)(7)(8). Although cytotoxic T cells directed against tumor antigens have been frequently observed in animal tumor models and cancer patients, immunotherapy with tumor antigens is usually ineffective against established tumors in animal experiments or clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Antitumoral Immune Response by Recruitment and Expansion of Dendritic Cells in Tumors Infected with Telomerase-Dependent Oncolytic Viruses

et al. 2009

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Virotherapy can potentially be used to induce tumor-specific immune responses and to overcome tumor-mediated tolerance mechanisms because apoptotic tumor cells are exposed together with viral danger signals during oncolysis. However, insufficient numbers of dendritic cells (DC) present at the site of oncolysis can limit a tumor-specific immune response and the resulting therapeutic benefit. We investigated MHC class I peptide-specific immune responses against model antigens ovalbumin (OVA) and hemagglutinin (HA) in mouse tumor models that support efficient replication of the oncolytic adenovirus hTert-Ad. Virotherapy resulted in peptide-specific cytotoxic T-cell responses against intracellular tumor antigens. Triggering of DC and T-cell infiltration to the oncolytic tumors by macrophage inflammatory protein 1A (MIP-1A, CCL3) and Fms-like tyrosine kinase-3 ligand (Flt3L) enhanced both antitumoral and antiviral immune responses. Although immune-mediated clearance of the virus can restrict therapeutic efficacy of virotherapy, MIP-1A/FLT3L-augmented hTert-Ad virotherapy inhibited local tumor growth more effectively than virotherapy alone. In agreement with the hypothesis that immune-mediated mechanisms account for improved outcome in MIP-1A/FLT3L virotherapy, we observed systemic antitumoral effects by MIP-1A/FLT3L virotherapy on uninfected lung metastasis in immunocompetent mice but not in nude mice. Furthermore, MIP-1A/FLT3L virotherapy of primary tumors was strongly synergistic with tumor DC vaccination in inhibition of established lung metastasis. Combined viroimmunotherapy resulted in long-term survival of 50% of treated animals. In summary, improvement of crosspresentation of tumor antigens by triggering of DC and T-cell infiltration during virotherapy enhances antitumoral immune response that facilitates an effective viroimmunotherapy of primary tumors and established metastases.

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Section: Introductionmentioning

confidence: 99%

Antitumoral Immune Response by Recruitment and Expansion of Dendritic Cells in Tumors Infected with Telomerase-Dependent Oncolytic Viruses

et al. 2009

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“…Moreover, this approach fails to target metastatic tumors growing at distant sites (23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

et al. 2011

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New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/ B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells. Cancer Res; 71(5); 1805-15. Ó2011 AACR.

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“…Targeting of adaptive resistance mechanisms and blocking of immune suppression can be accomplished in the intermediate phase (27,29,157). Creatively engineered virotherapies can also be considered to target all GSCs, including RISC cells (169)(170)(171).…”

Section: Future Therapeutic Strategymentioning

confidence: 99%