Tumor cells are different from their normal counterparts in many ways, which would be expected to result in their immunological eradication. However, advanced tumors are highly immunosuppressive, giving the cancer the ability to avoid detection by the immune system. This combined with the importance of immune system at controlling and shaping developing tumors (“immuno-editing”) makes cancer a complex immunological disease and a challenging one to treat.  It seems logical to treat such a disease with immunotherapeutics, that is, to teach the immune system to fight tumors. Only the immune system is so smart that it can find any cancer cell wherever it is in the body. Also, the fact that advanced tumors are highly immunosuppressive demonstrates that importance of the immune system in this context.

Viruses represent a masterpiece of natural selection and evolutionary fitness, and they can be used as a bioweapon against cancer. An important part of the mechanism of action of oncolytic viruses which kill tumor cells through lysis, i.e. breaking down the cell, relates to the immunogenicity of the phenomenon. This is especially true when viruses are armed with immunostimulatory molecules such as GMCSF, as with our lead clinical agent CGTG-102 (Ad5/3-D24-GMCSF). A big plus in these types of drugs is that they are usually not associated with life-threatening side effects and are well tolerated in comparison to most chemotherapeutics, for example. But even though understanding the mechanisms underlying tumor immunity has led to development of more efficient anti-cancer immunotherapeutics, a problem is that early phase clinical trials, including vaccine trials, tend to be in  very late-stage disease. In this setting the immunosuppressive state of the tumors definitely has a negative impact on the treatment response. In addition, late stage cancer patients are often immunocompromised, and immunotherapy works best in patients with healthy immune systems. And the earlier the patient is treated, the smaller the tumor mass to be eradicated.

In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on advanced cancer. Recently, a number of clinical studies have reported clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. It is also noteworthy that the standard criteria used to define tumor response and progression may not adequately reflect patient responses to immunotherapeutic agents, since the responses can take a longer time than with traditional drugs. Also, immune response related inflammatory swelling can complicate tumor size measurements. Therefore, overall survival is expected to be a better endpoint in vaccine studies.

Rapidly accumulating clinical and immunological information enables rationale-driven vector design and improved treatment protocols. Given the recent advances and excitement in the field I expect it won’t be too long before some of the potential of oncolytic viruses as immunotherapeutics translate into clear-cut patient benefits.

Dr. Lotta Kangasniemi works as Resarch Director at Oncos Therapeutics, a biotech company developing novel cancer therapies based on its next-generation oncolytic viruses.

“It’s a call option on a late-stage, potential blockbuster drug for Amgen,” as put by Michael Yee, an RBC Capital analyst in a Bloomberg interview.

A deal with $ 425m in an upfront payment is quite rare these days, validating the blockbuster potential further. As an oncolytic virus, it also has potential across multiple tumor types beyond melanoma, as commented also by Roger Perlmutter, Amgen’s executive vice president for R&D: “The virus should be generally applicable in tumor settings.” And finally, the deal this large is a sign of the strong data being generated from the ongoing Phase III program, likely to complete in the immediate near-future.

For oncolytic virus companies this is great news. The first top industry partner has validated what the oncolytic virus companies already know: viruses as “dual mechanism cancer therapies”  - both killing cancer cells and inducing anti-tumor immune response – represent one of the most promising new strategies to treat cancer.

Figure. Mechanism for the dual-action cancer therapy. Source: BioVex

This is what I repeatedly heard from the top pharma licensing and business development executives in the BIO-Europe 2010 conference. Oncolytic viruses are becoming a highly recognized, potential new strategy to treat cancer – and there are not too many promising novel strategies – unfortunately – available at the moment.

Many of the oncolytic virus companies are on the edge of getting high quality data sets produced: BioVex from its phase III advanced melanoma trial, supposedly early next year. Jennerex and Oncolytics Biotech are working to finalize phase II trials, and Oncos Therapeutics has been running its ATAP, the Advanced Therapy Access Program, now for long enough to have overall survival data available.

Year 2011 will certainly be very interesting for the industry that will reach a significant step. The excellent safety profile of oncolytic viruses is well established. The eyes of the industry are turned to data from the first randomized trials.

In addition to maturing data, oncolytic viruses fit into the epicenter of today’s cancer research. A large part of the efficacy seems to be linked to the anti-tumor immunity that potent viruses effectively induce. Repeated dosing seems to keep even advanced tumors from growing in many patients.

I am confident that a therapeutic cancer vaccine – capable of being manufactured in large scale, personalized in situ – is surprisingly close to being a standard clinical practice. And it is an oncolytic virus.

Pekka Simula is CEO and Co-Founder of Oncos Therapeutics, a biotech company developing new cancer therapeutics based on its oncolytic virus platform. Until today, viruses have been used to treat over 200 advanced solid tumor cancer patients.

BioVex started its pivotal phase III OPTiM trial in April 2009. People close to BioVex are rumoring the trial to be ready soon and announcing very strong results still this year. If that happens, what will be the implication for melanoma patients and oncolytic virus therapies?

First, melanoma patients will benefit greatly. The current ‘gold standard’ adjuvant treatment in advanced melanoma is PROLEUKIN. If OncoVEX delivers in the phase III OPTiM trial similar results to its completed phase II, the amount of responses it generates compared to PROLEUKIN is almost double. This is good news for melanoma patients, and a real advancement achieved with a new class of agents – oncolytic viruses (Table below).

Second, it will definitely be good for oncolytic viruses. BioVex would be the first company to have a replication-competent oncolytic virus product approved in the Western World, after Oncorine being approved in China. With these results it is likely, knowing the SPA approval it got for the pivotal trial in April 2008.

While close to the market, BioVex should have eye on the competition. One promising agent is ipilimumab, an antibody that activates the body’s immune system to fight melanoma by inhibiting the CTLA-4 molecule. Its three previous phase II clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51%  for people with stage III or IV melanoma, which is almost double the average — and on par with what BioVex has delivered. Ipilimumab’s phase III continued to deliver similar results in 2010, nearly doubling the 12-month survival rates from 25% to 46%.

One thing is for sure: there are a lot of people eagerly waiting for BioVex trial results.

Timo Ahopelto is VP Strategy at Oncos Therapeutics. He invites you to post your comments and share your views, either by responding to this blog or via email directly firstname dot lastname at oncos dot com.

Building an own GMP facility is often not an option – at least for the first clinical trials – due to time, resources and expertise required for building the facility and running it. There are more than 100 CMOs who claim to have vast experience in the production of biologics. However, as many biotechs have found, the real skill and experience today is low. Some have paid a high price in teaching the selected CMO partner through the process.

So what are the real alternative strategies and how to succeed?

In Phase I trials, the number of patients is typically rather low and thus a small scale production process can be used. Sometimes even lab scale provides with a sufficient virus quantity. Geography may make a big difference: for instance in the USA full GMP may not be required in Phase I, unlike in the EU. Regardless, when full GMP is required, it means not only producing one virus batch in a controlled environment with GMP compliant raw materials, but also establishing a complex production process. For oncolytic viruses this could take 12-24 months:

• First, the basic cultivation process needs to be set up, including selection and banking of a host cell line.
• The Master Cell Bank (MCB) needs to be characterized.
• Using the MCB, the master viral seed stock (MVSS) is prepared and characterized.
• GMP production starts with an engineering batch that verifies the manufacturing and analytical methodology, and provides the detailed information that is required for the preparation of Standard Operating Procedures (SOPs) that are used in the GMP manufacturing.
• Finally the production of GMP batch(es) starts. It is only possible after the previous steps have been successfully completed.

Characterization is a major challenge. As oncolytic viruses are new from regulatory viewpoint there are no established guidelines on how purity testing should be conducted to ensure approval for a clinical study. A special challenge arises from the oncolytic viruses being replication competent: Assays used for the detection of possible adventitious agents are based on cell culture and in vivo studies in which a replication competent oncolytic virus needs to be neutralized prior to the assays.

As a  conclusion most oncolytic viruses will be GMP-manufactured by a CMO. There is one key to success: You must have a detailed understanding of everything the CMO will need to do to comply with regulations. If you have no experience, hire suitable people or use highly trusted consultants. Select the CMO carefully – and verify carefully that they really possess the skills and experience that you require. And DO NOT rely on only one opinion from one consultant as there are no well-rounded experts yet on the field. It’s not possible to outsource the key decisions: Eventually you are held responsible.

Dr. Antti Vuolanto is VP Quality and Manufacturing at Oncos Therapeutics with good experience in biologicals manufacturing. He invites you to post your comments and share experiences, either by responding to this blog or
via email directly firstname dot lastname at oncos dot com.

I believe that the Advanced Therapy Access Program (ATAP) of Oncos Therapeutics is a glimpse to the future of drug development. Many other industries have already successfully implemented adaptive approaches over the past decades. As a global first, Oncos has introduced ATAP as an adaptive approach to clinical R&D.

ATAP is intended for cancer patients who seek experimental treatments after routine therapies have failed. Therefore strict ethical principles apply. For instance, patients may only enroll in ATAP if they have a progressing disease after those routine therapies. All therapeutic and diagnostic interventions are planned with the benefit of the patient in mind. However, in a perfect marriage of patient needs and improvement of the science, all data is collected and analyzed carefully which helps improve the approach further. Patient’s informed consent and medical inclusion and exclusion criteria are most important. Under conditions carefully monitored by regulatory authorities, 200 patients representing 18 cancer types have been treated in ATAP with 9 different oncolytic adenoviruses, often in combination with drugs that enhance the oncolytic effect. Thus, the overall number of different treatment combinations is several dozen. How many clinical trials would it have taken to learn as much of safety and efficacy – on a personalized level?

The benefits of ATAP compared to a traditional clinical development are enormous. The treatment course is planned and adjusted for each patient based on individual needs and signs of efficacy, with a variety of therapeutics and combinations to choose from, for truly personalized care. The oncologists learn more with each treatment to benefit the same patient in consecutive treatments and also future patients. The scientists will gain a much better understanding of activity in humans – another huge benefit since in oncology preclinical data often fail to predict true clinical efficacy.

Cancer is an immensely complex and versatile disease group. By definition, treatment for each patient is always personalized, starting from the optimal combination of therapies: Chemo, radiotherapy, etc. However, this has not been the case in clinical trials which typically follow strict and inflexible protocols and whose results do not always reflect the practical situation. With the face of oncology turning towards increasingly complex biological agents and regimens, personalization will have to extend to the level of trials. Today, there are few examples such as ATAP, or the FDA-approved experimental I-SPY 2 trial. Over the next years we will see many more.

Hepatocellular carcinoma (HCC) is a cancer of its own kind to develop treatments for: typically being secondary to a viral hepatisis B or C infection it is endemic – and thus a big problem – in many Asian countries, Japan and South-Korea, while orphan in the US and EU. It is also very deadly: the usual outcome is poor as only 10 – 20% of hepatocellular carcinomas can be removed completely using surgery. And if the cancer cannot be completely removed, the disease is often deadly within 3 to 6 months.

The gold standard drug treatment today is Nexavar® (sorafenib) – the first HCC drug therapy approved by EMEA. Jennerex intends to start the pivotal JX-594 (an oncolytic vaccinia virus with GMCSF) phase III trial later this year for first line therapy with JX-594 followed by Nexavar®.

Comparing efficacy results generated so far – at the same time knowing that such comparisons have their obvious pitfalls – Jennerex and oncolytic viruses present a strong promise for the future patients.

In contrast, oncolytic viruses can be engineered to take advantage of specific tumor associated molecular changes. One example is Rb/p16 pathway selective oncolytic adenoviruses, which replicate preferentially in tumor cells defective in this central growth control circuit. Since Rb/p16 deficiency is one of the hallmarks of cancer, and probably a requirement for tumor formation, this pathway is abnormal in basically all tumors. However, in normal tissues with intact Rb/p16, little virus replication is seen. Similar approaches have been used to render oncolytic vaccinia viruses dependant on excess nucleotides (DNA building blocks) as found in tumors, and overactivity of the EGFR pathway, another classic tumor associated feature.

A useful feature of normal tissues is the cellular interferon response, which can protect against many types of viruses. Defective interferon signaling is another hallmark of cancer and this yields additional selectivity to many oncolytic viruses. The difference in interferon responses has even allowed use of some unmodified naturally occurring  viruses for experimental cancer treatment. Chemotherapy and radiation therapy kill tumor cells by inducing DNA damage, which is then recognized by cellular quality control circuits. Some damage may be repaired but as it accumulates the cell is eventually instructed to self-destruct (apoptosis).

However, advanced tumors are able to develop resistance to apoptosis, which restricts the efficacy of these therapeutics. And in contrast, such tumors are not resistant to oncolytic viruses. Oncolytic viruses are similar to other targeted drugs, such as small molecular inhibitors and monoclonal antibodies, in that their selectivity if dependant on tumor associated molecular features.

A major difference is that molecular inhibitors only inhibit cells, they do not kill them. Thus, while the “red light” is on, tumors are under pressure to develop resistance mechanisms, which allow them to continue growth. In contrast, oncolytic viruses only the need the “green light” from the molecular defect and then they will proceed with killing the cell without allowing it to develop resistance.

Advanced tumors are experts in self-protection. They often express high levels of special ion channels which can pump out toxic molecules such as chemotherapeutics and also small molecular inhibitors. However, this feature does not protect them from oncolytic viruses.

In summary: while advanced tumors have several means they can employ to develop resistance to conventional therapeutics, these features do not confer resistance to oncolytic viruses.

What can we learn?

First, it really was a disappointment for the industry and cancer gene therapy. TNFerade had advantages – at least in theory – over drugs like Advexin with its TNF-Alpha -mediated radio- and chemosensitizing “bystander effect”: TNFerade affects also nearby cells, not just cells directly infected by the vector. I am sure we all would have liked the product to survive Phase III.

Since the announcement, many potential reasons have been raised in public debate. Some people ask if pancreatic cancer, ‘the drug killer’ indication, was a too ambitious target? For sure TNFerade’s story is not at its end yet as it is thought to have a broader applicability.

However, there might be a more fundamental reason for failing to reduce mortality dramatically enough for consideration for approval.

TNFerade is “an adenovector, or DNA carrier, which contains the gene for tumor necrosis factor-alpha (TNFα), an immune system protein, for direct injection into tumors”. So, it is a gene transfer vector – like many others that have not made it to the market for a single reason: maybe the non replication –capable, non-infectivity enhanced gene vectors are just not effective enough, fundamentally?

The next wave of the industry is currently developing replication -capable oncolytic viruses – such as OncoVEX, JX-594, CGTG-102, REOLYSIN and Cavatak – that have high potency in replication and strong local amplification to treat cancer systemically. These results from randomized trials are yet to be published, but the promise of these next wave therapeutics is very strong.

A snapshot conversation at BIO Europe Spring 2010 with in-licensing executives from Amgen: “A year ago you would have been thrown out of the room if you had started to talk on oncolytic viruses. Today, you can stay in and everyone is highly interested.”

Some other significant news already in 2010, demonstrating the momentum:

• Jennerex plans to start the phase III liver cancer trial later part of 2010 with JX-594, following the earlier orphan drug designation in Europe for hepatocellular carcinoma in 2009.

• BioVex completed $ 70 million in funding against strong clinical results, to finalize its Phase III program and pre-marketing activities for melanoma with their oncolytic virus OncoVEX. Some industry experts expect BioVex to release very strong trial data towards the year end. The patients with advanced melanoma can enroll at the OPTiM trial site.

• Oncos Therapeutics presented at BIO Europe Spring 2010 data from the Advanced Therapy Access Program and its CGTG-102 lead candidate: 70% clinical benefit rate and 200-day survival of 77% in the program active for terminal patients since 2007 is a very strong result. The GM-CSF armed, capsid-modified adenovirus virus is expected to go into clinical trials soon.

• Today, Oncolytics Biotech announced recruitment start for their Phase II REOLYSIN trial in the US targeting non-small cell lung cancer.

And this is only the first quarter.

If I forgot something essential, please comment to the below.