Advaxis lights up the future for cervical cancer and maybe some head and neck cancers

24th February 2010 17:44

Invasive carcinoma of the cervix is the second most common cancer in women worldwide with over 450,000 new cases and 230,000 deaths annually, most of them occurring in developing countries. Persistent infection with high-oncogenic risk HPV, especially HPV16 and HPV18 are common underlying causes of malignant lesions, accounting for over 70% of Invasive carcinoma of the cervix and over 50% of high-grade precursor lesions.

According to our 2007 feature Gynecological Cancers - Niche opportunities in advanced disease the incidence of cervical cancer is set to fall with the advent of prophylactic HPV vaccines. However cervical cancer will remain a problem for many years for two reasons. Firstly, prophylactic vaccines are unlikely to offer significant benefit to those women already infected with HPV. Consequently cervical cancer will continue to be a problem in women who were sexually active prior to the introduction of the vaccine. Secondly, worldwide implementation of such vaccines remains a challenge.

Given that cervical cancer will continue to be a problem it is particularly disappointing that few advances in this area of oncology have been witnessed over recent years. The best hope for women at risk of cervical cancer is early detection. Prognosis for women with early stage disease is good with cure rates of 60%-80% and fortunately there have been advances in diagnostics. For example DailyUpdates reported news from BD Diagnostics 2008 that the FDA had approved its FocalPoint GS imaging system [press release]. In May 2009 we also reported that Israeli company Zetiq had demonstrated improvements over Pap staining. Pharmacological options remain in a state of relative inertia however.

According NCCN guidelines the first line approach to later stage disease remains radiotherapy with concurrent cisplatin-based chemotherapy. Response rates are quite low (20%-30%) and complete responses rare; overall survival with cisplatin is 6-9 months. Second line treatments are chemotherapeutic and associated with limited efficacy and significant toxicity. There is an obvious need for more targeted therapy that can offer improvements over cisplatin and possibly alternatives/adjuncts to surgery and radiotherapy.

With the exception of SRI International's cytotoxin, tirapazamine and PharmaMar's Zalypsis in (Phase 3 and 2 respectively) little development is being seen in the form of small molecules. Instead most activity is from the biologics sector. YM Bioscience is developing EGFR antibody, nimotuzumab, but by far the greatest efforts are currently being focussed on therapeutic vaccines (for background on this field see our 2007 feature, World market for cancer vaccines 2007-2012).

To our knowledge four candidates are currently in the clinic for cervical cancer or the premalignant disease, cervical intraepithelial neoplasias (CIN). Inovio is developing a DNA vaccine targeting E6 and E7 proteins of HPV16 and HPV18, VGX-3100 for the treatment of CIN. This candidate is in Phase 1 development. More advanced is Roche's RG-3484, a modified vaccinia Ankara vaccine expressing E6 and E7 along with IL-2. Phase 2 trials opened last year, again focusing on CIN. A third vaccine is being developed by ISA Pharmaceuticals. In contrast to the Inovio and Roche vaccines this candidate is being developed for both CIN (Phase 2) and cervical cancer (Phase 1).

Today's edition of DailyUpdates features a paper describing a fourth therapeutic vaccine in development for the treatment of cervical cancer, Advaxis' ADXS11-001 (formerly Lovaxin C). The technology being developed by Advaxis differs from other thereapeutic vaccines as it is the only live bacterial vaccine currently in clinical trials. It is based upon attenuated, bioengineered Listeria monocytogenes that provides very strong stimulation of innate immunity as well as both arms of the adaptive immune system, alters the tumor microenvironment to remove regulatory T cells (Tregs) and Myeloid Derived Suppressor Cells (MDSC) that are sources of immune inhibition, increases the pool of mature immune cells, facilitates migration of immune cells into tumors, and other effects.

The paper featured today describes data from a Phase 1 study in which the vaccine was administered safely to women with cervical cancer and who had failed surgical, radiation and/or chemotherapeutic intervention. Patients were inoculated twice, at day 1 and day 22; the protocol required administration of antibiotics five days post-inoculation to attenuate the live vaccine. Adverse events were generally flu-like and transient.

The women recruited to the study would normally be expected to have a median survival of only 6 months with a 1 year survival of 5%. In this study, the median survival was doubled and the 1 year survival increased 10-fold. Remarkably, Advaxis recently reported updated data showing that 2 of 13 patients were alive at 3 years.

The data reported in the present study are fascinating, especially given the advance stage of disease and the fact that responses were seen with just two inoculations. Further studies, perhaps with booster vaccinations built into the protocols are awaited with great interest. In addition the promise shown in the present study suggests that evaluation of the vaccine in earlier stage CIN may be worthwhile. LeadDiscovery understands that further trials are planned for this year - one a Phase 2 study of cervical cancer patients; another a study of CIN patients.

Finally, a paper was published by Maxwell et al last year in the journal head and neck linking HPV to a rare head and neck cancer, nasopharyngeal carcinoma. We understand that a further trial is planned evaluating ADXS11-001 in this disease. This is not only of great clinical importance, it may also be of commercial importance. Advaxis failed to gain orphan drug status from the FDA last year on a cervical cancer indication. The company may be able to refile for an orphan indication on this new indication (for further information on head and neck cancer, including pharyngeal cancers read Stakeholder Opinions: Head and Neck Cancer).

http://leaddiscovery.co.uk/editorials/4/advaxis-lights-up-the-future-for-cervical-cancer-and-maybe-some-head-and-neck-cancers

Cancer Research UK to Fund Clinical Trial of ADXS11-001 for the Treatment of Head and Neck Cancer

Advaxis, Inc., , the live, attenuated Listeria monocytogenes (Lm) immunotherapy company, is pleased to announce that Cancer Research UK (CRUK), the UK philanthropy dedicated to cancer research, has agreed to fund the cost of a clinical trial to investigate the use of ADXS11-001, Advaxis’ lead human papilloma virus (HPV)-directed vaccine candidate, for the treatment of head and neck cancer.

This sponsored-clinical trial will investigate the safety and efficacy of ADXS11-001 in head and neck cancer patients who have previously failed treatment with surgery, radiotherapy and chemotherapy – alone or in combination. Advaxis will provide the vaccines with all other associated costs to be funded by CRUK.

The study is to be conducted at Aintree Hospital at the University of Liverpool, Royal Marsden Hospital in London, and Cardiff Hospital at the University of Wales. Patient enrollment is slated for the latter part 2010. At such time, enrollment officials anticipate recruiting a maximum of forty-five (45) patients.

“Both acceptance by the scientific community and interest in collaborating on live, attenuated Listeria vaccines is accelerating,” said Advaxis Executive VP of Science & Operations John Rothman. “The high caliber of collaborating clinical researchers, such as CRUK and NCI, will result in an excellent development programs. The development of new vaccines, at the pre-clinical level, is being spurred by collaborations with such noteworthy institutions as the City of Hope, the Roswell Cancer Institute and the University of Pittsburgh.”

About Head and Neck Cancer

Oropharyngeal (upper) head and neck cancer, like cervix cancer, is believed to be caused by persistent HPV infection in people whose immune systems fail to clear the virus. According to the National Cancer Institute (NCI), head and neck cancers represent approximately 3 to 5 percent of all cancers in the United States, with these types of cancers being more common in men. Historically, head and neck cancer has been associated with people over the age of 50, and the use of alcohol and tobacco (including smokeless tobacco). Recently, however, this form of cancer is increasing dramatically in younger people with no history of tobacco use.

About Cancer Research UK

Cancer Research UK is the largest single funder of cancer research in the UK and the world’s largest charity dedicated to cancer research. It funds research on all aspects of cancer, from basic cell biology to large clinical studies of entire populations. The organization funds the work of more than 4,500 scientists, doctors and nurses across the UK and runs specialized institutes dedicated to cancer research. Cancer Research UK currently funds more than 180 clinical trials. Since the early 1980’s, Cancer Research UK has taken over 100 new drugs into clinical trials with more than 100,000 patients taking part in trials since 1995. For more information, please visit: cancerresearchuk.org

About the Clinical Sites

The Aintree University Hospitals NHS Foundation Trust was established on August 1, 2006 as a public benefit corporation authorized under the National Health Service Act 2006. It is a large, complex organization providing acute healthcare to a population of 330,000 in North Merseyside and surrounding areas. The immediate catchment covers some 33 square miles, which is largely urban with significant areas of commerce including docklands. The Aintree University Hospitals NHS Foundation Trust provides acute hospital services to the residents of South Sefton, North Liverpool and Kirkby. It is also a teaching hospital for the University of Liverpool and a tertiary centre providing specialist services to a much wider population of around 1.5 million in Merseyside, Cheshire, South Lancashire and North Wales. The population served by Aintree includes some of the most socially deprived communities in the country, with high levels of illness creating a high demand for hospital-based care. For more information, please visit: aintreehospitals.nhs.uk.

The Royal Marsden NHS Foundation Trust was the first hospital in the world dedicated to the study and treatment of cancer. It was founded as the Free Cancer Hospital in 1851 by Dr. William Marsden to classify tumors, research the causes of cancer, and to find new treatments. In 1991 the Royal Marsden became the first NHS hospital to be awarded the Queen’s Award for Technology for its work on drug development. The hospital achieved the international quality standard ISO 9001 for radiotherapy in 1996 and for chemotherapy in 2003. It was recognized as one of six (6) centers of excellence in the Government’s NHS Plan and has achieved four national Charter Marks for all its services, the most recent awarded in 2005. In April 2004, the hospital became one of the country’s first NHS Foundation Trusts. This new status has provided the financial freedom and greater flexibility to focus on allowing more patients to access the hospital's expertise. For more information, please visit: royalmarsden.nhs.uk.

Cardiff Hospital (University of Wales) is part of the Cardiff and Vale NHS Trust and provides day-to-day health services to a population of around 500,000 people living in Cardiff and the Vale of Glamorgan who need hospital treatment, mental health care, care for elderly people and children as well as a growing range of community-based services, including specialist dental services, and new therapies as alternatives to hospital admission. Patients also attend from across Wales for a range of specialist services, for which the Cardiff and Vale NHS Trust is regarded as a centre of excellence, including pediatric, renal, cardiac, neurological services and bone marrow transplantation. For more information, please visit: cardiffandvale.wales.nhs.uk.

Yvonne J. Paterson video interview from 2007

This is an older video interview ( 2007) of Dr. Yvonne Patterson in which she explains her personal experience and subsequent involvement in seeking relief for many stricken with cancer.

http://wbztv.com/video/?id=27635@wbz.dayport.com

The following is the article associated with the interview.

Doctor Works Toward A Breast Cancer Vaccine

The Vaccine May Stop Breast Cancer From Happening Again To Survivors

Jan 9, 2007

It's a constant worry for breast cancer survivors -- will the disease return?

Now, there is new research into a breast cancer vaccine and one doctor has made it her life's work.

Yvonne Paterson, a mother and medical researcher, was only 42 when she got the devastating diagnosis -- breast cancer. "I said, 'what do you mean?' I just wanted to have the comfort in my mind that it had gone and I had gotten rid of it… So I opted to have a mastectomy."

Now 20 years later, Paterson is more than a survivor, she's on the cutting edge of breast cancer research -- trying to develop a vaccine. "We've shown that we can either eliminate, eradicate all together or stop the growth of breast tumors in mice."

The vaccine would not prevent women from getting the disease. It's designed to prevent a recurrence in patients who have undergone treatments like radiation and chemotherapy.

"The idea is that it will promote survival by decreasing the risk of recurrence -- eliminating all of the residual tumor cells that conventional therapy hasn't managed to kill," said Paterson.

"Vaccines for the large part have been used to treat infectious diseases," said Dr. Eric Winer of the Dana Farber Cancer Institute.

Winer, head of Dana Farber's Breast Oncology Center, says scientists in general have been pessimistic about cancer vaccines, but now there is a renewed interest in this research.

"With some of the new technologies it's hoped that we can apply some of what's been done in the infectious disease setting to cancer," said Winer.

The next step for Dr. Paterson is human clinical trials. If successful? "This can give them peace of mind, like the peace of mind I didn't have 20 years ago," said Paterson.

The vaccine is called Lovaxin B and is currently in pre-trial testing. The company making the vaccine is seeking FDA approval for a clinical trial.

Both Dr. Paterson and Dr. Winer admit it will take years for a breast cancer vaccine to be approved for patients -- if it is approved at all.