Neural Stem Cell Based Virotherapy of Newly Diagnosed Malignant Glioma

Malignant gliomas have a very poor prognosis with median survival measured in months rather than years. It is a disease in great need of novel therapeutic approaches. Based on the encouraging results of our preclinical studies which demonstrate improved efficacy without added toxicity, the paradigm of delivering a novel oncolytic adenovirus via a neural stem cell line in combination with radiation and chemotherapy is well-suited for evaluation in newly diagnosed malignant gliomas. The standard-of-care allows application of virotherapy as neoadjuvant therapy and assessment of the cooperative effects with radiation/chemotherapy without altering the standard treatment.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Patients must have presumed malignant glioma based on clinical and radiologic evaluation (pathologic confirmation of malignant glioma must be made at the time of stereotactic biopsy or resection prior to NSC-CRAd-S-pk7 injection; if this is not possible, the injection will not be performed and the subject will no longer be eligible for the study).
* Tumor must be accessible for injection and must not be located in the brainstem, or contained within the ventricular system.
* Planning to undergo standard radiation/chemotherapy
* 18 years of age or older.
* Performance status must be KPS ≥ 70
* SGOT (AST) \< 3x upper limit of normal
* Serum creatinine \< 2mg/dl
* Platelets \> 100,000/mm3 and WBC \> 3000/mm3

Exclusion Criteria:

* Prior or ongoing liver disease including known cirrhosis, hepatitis B or C infection but not to exclude patients with a distant history of resolved hepatitis A infection.
* Immunosuppressive drugs (with exception of corticosteroid).
* Known HIV+ patients.
* Acute infections (viral, bacterial or fungal infections requiring therapy).
* Pregnant or breast-feeding patients.
* Evidence of metastatic disease or other malignancy (except squamous or basal cell skin cancers).
* Prior radiation therapy to the brain or prior treatment for brain tumor Other serious co-morbid illness or compromised organ function.

• BACKGROUNDTobias AL, Thaci B, Auffinger B, Rincon E, Balyasnikova IV, Kim CK, Han Y, Zhang L, Aboody KS, Ahmed AU, Lesniak MS. The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma. Stem Cells Transl Med. 2013 Sep;2(9):655-66. doi: 10.5966/sctm.2013-0039. Epub 2013 Aug 7. PMID 23926209
• BACKGROUNDAhmed AU, Thaci B, Tobias AL, Auffinger B, Zhang L, Cheng Y, Kim CK, Yunis C, Han Y, Alexiades NG, Fan X, Aboody KS, Lesniak MS. A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy. J Natl Cancer Inst. 2013 Jul 3;105(13):968-77. doi: 10.1093/jnci/djt141. PMID 23821758
• BACKGROUNDAhmed AU, Tyler MA, Thaci B, Alexiades NG, Han Y, Ulasov IV, Lesniak MS. A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma. Mol Pharm. 2011 Oct 3;8(5):1559-72. doi: 10.1021/mp200161f. Epub 2011 Jun 30. PMID 21718006
• BACKGROUNDAhmed AU, Thaci B, Alexiades NG, Han Y, Qian S, Liu F, Balyasnikova IV, Ulasov IY, Aboody KS, Lesniak MS. Neural stem cell-based cell carriers enhance therapeutic efficacy of an oncolytic adenovirus in an orthotopic mouse model of human glioblastoma. Mol Ther. 2011 Sep;19(9):1714-26. doi: 10.1038/mt.2011.100. Epub 2011 May 31. PMID 21629227
• BACKGROUNDUlasov IV, Sonabend AM, Nandi S, Khramtsov A, Han Y, Lesniak MS. Combination of adenoviral virotherapy and temozolomide chemotherapy eradicates malignant glioma through autophagic and apoptotic cell death in vivo. Br J Cancer. 2009 Apr 7;100(7):1154-64. doi: 10.1038/sj.bjc.6604969. Epub 2009 Mar 10. PMID 19277041
• BACKGROUNDNandi S, Ulasov IV, Tyler MA, Sugihara AQ, Molinero L, Han Y, Zhu ZB, Lesniak MS. Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells. Cancer Res. 2008 Jul 15;68(14):5778-84. doi: 10.1158/0008-5472.CAN-07-6441.