Research on the potential of oncolytic viruses to treat various cancer types has waxed and waned over the past decade as promising early results failed to translate into clinical successes. However, these cancer destroying missiles are now firmly back on the industry's radar screen following the late 2015 FDA approval of the first oncolytic virus agent, Amgen Inc.'s Imlygic (talimogene laherparepvec) for nonresectable metastatic melanoma. The therapeutic is derived from a herpes simplex virus that has been genetically engineered to infect cancer cells and to generate granulocyte macrophage colony-stimulating factor (GM-CSF). (See BioWorld Today, Oct. 29, 2015.)

This mode of action has a one-two punch where the replicating virus first depletes cellular energy stores, causing cell lysis, which then prompts release of tumor antigens that, in concert with the virally generated GM-CSF, promotes a systemic antitumor immune response.

RENEWED ENTHUSIASM

Following Imlygic's approval in the U.S. and Europe, investments in the space have increased along with business development as companies look to gain a foothold in the advancing technology through strategic partnerships and M&A's.

The fact that oncolytic virus immunotherapy research and development is experiencing a resurgence in interest is certainly welcome news for Oncolytics Biotech Inc. It has been a long road for the Calgary, Alberta-based company, which transitioned into a public company in 1999 raising capital to begin development of its lead product Reolysin (pelareorep), a naturally occurring reovirus that is able to replicate specifically in tumor cells bearing an activated Ras pathway, which, when mutated, may account for about 30 percent of all human tumors. Along the way, the company has conducted a significant number of trials targeting a wide range of cancer types. Like the overall field itself, the company has encountered study setbacks but has gained valuable insight into the product's mode of action.

Currently, the company's clinical program comprises various phase I and phase II trials using Reolysin both alone and in combination with chemotherapy, radiotherapy and/or a checkpoint inhibitor. For example, REO 024 is an open-label phase Ib trial designed to determine the safety and dose-limiting toxicity of Reolysin in combination with Keytruda (pembrolizumab. Merck & Co. Inc.) and chemotherapy in patients with histologically confirmed, advanced or metastatic pancreatic adenocarcinoma who have failed, or did not tolerate, first-line treatment. This study, the company said, is their first to examine the effects of Reolysin in combination with a checkpoint inhibitor.

In fact, Reolysin's potential in immuno-therapy combinations could open up a number of new combo trials for them.

Last week, the company reported that cancer charity Myeloma UK launched MUK 11, a first-of-its-kind immunotherapy trial that aims to modulate the immune system to target myeloma. A phase Ib trial will study immuno-viral therapy, Reolysin, in combination with Celgene Corp.'s immunomodulatory drugs (IMiDs), Imnovid (pomalidomide) or Revlimid (lenalidomide), as a rescue treatment in relapsing myeloma patients. The safety and tolerability of these combinations will be studied as well as investigate whether the addition of Reolysin extends disease control in this patient group.

The trial plans to recruit 44 patients across up to six Myeloma U.K. Clinical Trial Network centers. The company said that the research leverages preclinical findings showing dual modes of action – cytotoxicity and immune effector cell activation – that can be enhanced by immunomodulatory agents.

In a research note RBC Capital Markets analyst Douglas Miehm said that, "We believe this collaboration could be the first of several for Oncolytics as the new management team works to achieve a commercial endpoint for Reolysin."

After 18 years the company parted ways with its long time CEO, Brad Thompson, when he stepped down in November. The company's new president and CEO Matt Coffey noted the collaboration is important since testing IMiD combinations with Reolysin represents one of the components of their clinical development plan."

In commenting on their 2016 year-end financial results Coffey acknowledged it had been a period of change for the company "highlighted by additional clinical data that saw our understanding of Reolysin's mechanism of action evolve and grow."

Going forward the company expects data readouts from about five phase II studies.

Another Canadian company, Ottawa-based Turnstone Biologics Inc. has just begun its journey in the development of oncolytic viral immunotherapies. Fueling that research was a November 2016 a series B round raise of $41.1 million. The financing followed a successful $11.3 million series A round in 2015. (See BioWorld Today, Nov. 2, 2016.)

Their approach is to use a double-mutant Maraba virus strain, MG1, which is attenuated in healthy human cells but highly virulent in cancerous cells. The technology was developed by the company's scientific founders: John Bell, of the Ottawa Hospital Cancer Center, David Stojdl, of the University of Ottawa, and Brian Lichty, of McMaster University, in Hamilton, Ontario. (See BioWorld Today, Oct. 29, 2015.)

The series A funding allowed the company to further develop its lead asset through the initial phase I/II trial to establish safety, maximum tolerated dose and evidence of immunological activity in patients with advanced solid and metastatic tumors. The new funding B supports completion of the ongoing monotherapy trial, and help fund three additional clinical programs.

Their oncolytic Maraba virus is engineered to express melanoma-associated antigen A3 (MAGEA3). Like many companies in this growing field, Turnstone plans to see how the product performs in combination with an approved checkpoint inhibitor; with a phase I/II trial planned in patients with non-small cell lung cancer (NSCLC).

NO SHORTAGE OF VENTURE INVESTMENTS

Venture capital certainly continues to flow to support companies working on oncolytic virus strategies to defeat various cancers. At the end of last year Cambridge, Mass.-based Oncorus Inc., received series A funding support from Astellas Venture Management LLC (AVM), the corporate venture arm of Astellas Pharma Inc. This new infusion of capital increased their series A proceeds to $61 million.

The company's immunotherapy platform is based on herpes simplex virus (HSV). ONCR-001, their lead candidate, is in preclinical development for glioblastoma multiforme (GBM).

Cold Genesys Inc., Santa Ana, Calif., raised $10 million in a series B financing round to advance its investigational oncolytic immunotherapy CG0070 in a pivotal study (BOND II) that is currently enrolling 122 patients with high-risk non-muscle invasive bladder cancer (NMIBC) who have failed first-line BCG therapy. In addition, proceeds from this financing will be used to develop the combination of CG0070 with immune checkpoint modulators.

CG0070 is based on a modified common cold virus backbone that contains a cancer-specific promoter and a GM-CSF transgene.

Nouscom GmbH, of Basel, Switzerland, generated €12 million (US$13.4 million) from series A financing co-led by LSP and Versant Ventures for personalized cancer vaccines and oncolytic viruses. The firm has two product candidates, the Endovax and Exovax programs. Endovax, an antigenless vaccine, is based on oncolytic viruses capable of infecting and replicating only in cancer cells and causing immunogenic cell death, thereby recruiting T cells at the tumor site and reactivating T cells exhausted in the tumor microenvironment. Exovax is a personalized patient-specific vaccine, based on viral vectors coding for strings of cancer neoantigens to induce and expand cancer and patient-specific T cells.

Helsinki-based Tilt Biotherapeutics Ltd., closed a financing round of €4 million (US$4.3 million) to help move its lead candidate, TILT-123, into phase I trials by 2018. The therapeutic, is a preclinical stage TNFα/IL2 armed oncolytic adenovirus. The company says that TILT-123 will be used to enhance tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR-T), and checkpoint inhibiting antibody therapy.

CLINICAL PIPELINE

While the original strategy of using oncolytic viruses was to take advantage of their tumor-lysing capabilities, research is now leading to their coupling with tumor antigen vaccination and immune checkpoint inhibitors. The new thinking is that initial tumor destruction with an oncolytic virus can potentially lead to an immune response directed against most if not all of the tumor antigens present within the particular tumor being targeted. This approach is gathering momentum and promising results are being reported from early stage trials.

As a result, the clinical pipeline is expanding and, according to Cortellis Clinical Trials Intelligence, there are about 20 ongoing trials and over 50 companies who are actively working in this area. (See Oncolytic viruses trials, below.)

Tocagen Inc., of San Diego, for example, reported updated data for Toca 511 (vocimagene amiretrorepvec) in combination with Toca FC (extended-release 5-flurocytosine) for the treatment of recurrent high-grade glioma at the International Oncolytic Virus Meeting in Vancouver, British Columbia. The updated response and survival data came from a phase I, ascending-dose study of Toca 511 administered at the time of tumor removal followed by cycles of orally administered Toca FC. Of the 24 evaluable patients with recurrent glioblastoma or anaplastic astrocytoma, a median overall survival of 14.3 months was shown. The overall response rate was 20.8 percent, with three complete responses and two partial responses. Median duration of response was 20.7 months. An overall clinical benefit rate, including complete and partial responses and stable disease, at eight weeks was 41.7 percent.

Viralytics Ltd., of Sydney, Australia, reported at the Society for the Immunotherapy of Cancer meeting in November updated positive clinical results from their ongoing phase Ib CAPRA (Cavatak and Pembrolizumab in Advanced Melanoma) trial of lead drug candidate, Cavatak, based on a proprietary cold virus, in combination with Keytruda.

According to the preliminary data from the first 10 patients evaluable for best overall tumor response assessment, a disease control rate (DCR) of 100 percent (10/10 patients) was demonstrated, including seven patients (70 percent) with an objective tumor response and three patients (30 percent) with stable disease.

Editor's note: In part II of this feature we will examine the deals landscape for oncolytic viruses, which in recent months has generated several major deals involving big pharma companies. We will also examine what the future holds for development of these new cancer therapies.