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The development of oncolytic viruses is entering an exciting phase. This field which includes non-replicating viruses that are employed to transfect cancer cells with therapeutic genes and replicating viruses that kill cells directly is evaluated in detail in our report "Developments in oncolytic viruses - An emerging approach to cancer therapeutics". One of the most advanced oncolytics is Introgen's INGN 241, a non-replicating virus that transfects cancer cells with mda-7, the gene that encodes IL-24. Three key studies of this candidate have been reported in the past two months. Two report phase I data demonstrating the safety of INGN 241 and providing evidence that its injections results in successful infection, tumor apoptosis and systemic immunogenesis. A third report demonstrates that the apoptotic effects of INGN 241 are not restricted to cells infected with the virus but that these cells secrete MDA-7 to induce apoptosis in other cancer cells.

Nearly nine million people suffer from cancer in the US alone, and more than one million new cases are expected every year. The global cancer market is forecast to grow from $38.5bn in 2003 to $53.1bn in 2009, representing an average annual growth rate of 5.49%. The market is characterized by a mix of established gold standard therapies and new innovative products rapidly capturing market share. While a number of blockbuster therapies lose patent protection, heavy R&D investment has resulted in 400 potential new drugs currently progressing through clinical trials. Significant unmet needs and high incidence of disease continue to drive market growth, leaving a number of companies competing to improve treatment efficacy and drive market share. The innovative cancer therapy class is an area that will expand dramatically over coming years and indeed revenue is expected to double from $6.4bn in 2003 to $12.5bn in 2009, by which time it will overtake the cytotoxic drug classes in value terms.

A detailed overview of cancer therapeutics is given in our feature "The Cancer Market Outlook to 2009" (click here for this report), however three particularly exciting novel approaches to the treatment of cancer have recently been highlighted by LeadDiscovery: the most established field of novel anticancer therapeutics includes monoclonal antibodies (click here for an overview) which are driving the next wave of more specific and more effective treatments of cancer; cancer vaccines are also generating significant interest with over twenty phase III cancer vaccine trials in progress (for a full evaluation of cancer vaccines see our feature report "Cancer Vaccines"). A third area on innovation in the field of cancer therapeutics focuses on oncolytic viruses.

The field of oncolytic viruses is evaluated in detail in our report "Developments in oncolytic viruses - An emerging approach to cancer therapeutics". In brief, oncolytic viruses have been engineered to selectively kill cancer cells. Cell death can be effected through the use of non-replicating viruses as vectors which transfect cancer cells with therapeutic genes; alternatively, replicating viruses are being developed that selectively replicate in and then kill cancer cells.

One of the leaders in the field of oncolytic viruses is Introgen. Their portfolio, which is evaluated in our report, is lead by ADVEXIN a non-replicating adenovirus that delivers the p53 gene into cancer cells. Less advanced is INGN 241 an adenovirus that delivers the mda-7 gene and is in phase I-II development for the treatment of various solid tumors. Most information is available with respect to melanoma, not surprising considering that the gene product, MDA-7 (also known as interleukin-24) was first identified in melanoma cells. Increased expression of the mda-7 gene was associated with growth arrest and terminal differentiation of human melanoma cells and colony formation was decreased when mda-7 was transfected into human tumor cells of diverse origin and with multiple genetic defects. Early study suggested that INGN 241 causes cancer cell death through the stimulation of apoptosis and that this effect is selective for melanoma cells compared to non-cancerous melanocytes. The efficacy of INGN 241 has been extended from melanoma cells to encompass a variety of other cancers including non-small cell lung cancer and breast cancer. In these cancers the effects of INGN 241 synergize with radio- and chemo-therapy, a phenomenon shared by other oncolytic viruses. In the case of INGN 241 the synergy occurs in part due to an inhibition of angiogenesis by sensitizing endothelial cells to ionizing radiation and also by suppressing the repair of radiation-induced DNA damage.

A key challenge in treating cancer is the spread of disease from the primary tumor to disparate sites within the body. Studies have shown that the efficacy of INGN 241 is maintained in metastatic cells, and in the case of lung cancer cells it inhibits cell migration and invasion.

Three important studies of INGN 241 have been published in the past two months in the journal Molecular Therapy. In the January edition Cunningham et al report the results of a phase I trial designed to characterize the safety and biologic activity of intratumoral injections of INGN 241 in 28 patients with resectable solid tumors. MDA-7 protein was elevated in all tumors and induced apoptosis even in heavily pretreated patients. Toxicity attributable to the injections was self-limiting and generally mild and clinical activity was found in 44% of lesions subjected to repeated injections. Tong et al also report clinical data. This group's study further investigated the bioactivity of INGN 241 and reported transient increases of serum IL-6, IL-10, and TNF-alpha, as well as marked increases of CD3(+)CD8(+) T cells posttreatment, offering evidence that in addition to direct tumor death, INGN 241 has indirect effects resulting from its immunogenic activity. Finally in December Chada et al report that INGN 241 induces a 'bystander effect' which may serve as an amplification system to kill more cancer cells. Transduction of cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. This may be responsible for the immunogenic activity of INGN 241 reported by Tong et al, however in addition, and for the first time Chada et al report that MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R) and that this induces melanoma apoptosis. This study makes an important advance demonstrating that secreted MDA-7 protein can kill neighboring cancer cells and that the secretion of MDA-7 is important not only for its immunogenic consequences but also because it can extend the apoptotic events produced by INGN 241 beyond the cells that the virus infects.

The past three months has therefore seen great strides forward in the development of oncolytic therapy in general and in particular for INGN 241. This virus has now entered phase II development and results are awaited eagerly.

Entry date Sunday, January 23, 2005

Adapted from Cunningham et al, Mol Ther. 2005 Jan;11(1):149-59; Tong et al, Mol Ther. 2005 Jan;11(1):160-72; Chada et al, Mol Ther. 2004 Dec;10(6):1085-1095