Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF

Abstract

Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

“…4,45 In this study, we report the construction of a novel Ad3 virus that expresses human CD40L. Serotype 3 was selected over the more common serotype 5 because human data from ATAP ( Fig 1A) and based on a previous publication indicating that the Ad3 capsid allows effective intravenous delivery.…”

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…The treatment viruses Ad5/3-D24 and Ad5/3-D24-hGMCSF have been described (10,14). Briefly, the virus consists of a human adenovirus serotype 5 (Ad5) nucleic acid backbone, a 5/3 chimeric fiber knob, and a 24-bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1.…”

“…Adenovirusbased oncolytic viruses have been shown to trigger potent innate and adaptive antiviral and antitumor immune responses (9), while still maintaining good safety profile in patients (10). Adenovirus infection of tumors results in chemokine secretion, release of tumor-associated antigens (TAA) from infected dying tumor cells, and activation of APCs, which recognize the multiple pathogen-associated molecular patterns (PAMP) of the virus (9).…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…ONYX-015, H101 (Oncorine) and other first-generation oncolytic crHAdVs have gone through several phase I/II trials without relevant signs of high grade toxicity but also without significant therapeutic effects, resulting in discontinuation of further trails. 48 More recent clinical trials employing new generations of crHAdVs like RGD retargeted oncolytic crHAdVs, 20,49,50 crHAdV-5/3 chimeric vectors, 32,[51][52][53][54] ColoAd1, 55 hTERT-promoter driven crHAdV-5 vector Telomelysin, 56 E2F-1-promoter driven CG0070 33 , Rbtargeted crHAdV expressing hyaluronidase (VCN-01) 57 and crHAdV vectors expressing immunomodulating genes have shown safety (low toxicity) with some promising preliminary results.…”

“…immunomodulatory, pro-apoptotic or prodrug converting enzyme genes. [30][31][32][33] Despite their capacity to achieve tumor infection in animal models and in clinical trials, the therapeutic efficacy of rdHAdVs in clinical trials has been disappointing; Advexin and Cerepro have not been approved by the FDA and EMA, although a similar agent called Gendicine has been approved for cancer therapy in China. 34,35 The discrepancy between preclinical and clinical studies using HAdV-5 could be explained by the differences in expression of CAR in primary tumors compared to established laboratory cell lines.…”