Development of an anti-hCGß cancer vaccine for the treatment of bladder cancer and other hCG/hCGß secreting tumours.
Submitting InstitutionMiddlesex University
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Immunology, Oncology and Carcinogenesis
Summary of the impact
Our research has underpinned the work of Celldex Therapeutics and other
US based companies, in developing a vaccine directed against hCGβ for the
adjuvant treatment of epithelial cancer. A number of Phase I trials
indicated an improvement in survival of vaccinated patients and Phase II
trials began for bladder cancer where early data showed promise by
improving the survival time. This has had a significant impact on these
patients, and has the potential to extend the life of many millions of
cancer sufferers (around 32% frequency of hCGβ secretion by carcinomas).
Our research input has helped prove the technology and further trials are
The research carried out by Dr Butler (Reader) and team of collaborators
(including Profs Roitt & Iles and Drs Ghali (Principal Lecturer) and
Naase (Senior Lecturer), Wen and Burczynska (Lecturers) at Middlesex
University has, over fifteen years, been responsible for establishing that
hCGβ was expressed by a malignant subset of bladder (and other) cancers.
The team have proven the prognostic significance of detecting hCGβ in
patient serum/urine/tissue by protein and gene expression studies, and
have determined that hCGβ promotes malignancy by inhibiting apoptosis.
Most significantly, they have shown how an anti hCGβ immunotherapy applied
to humans can neutralise the anti-apoptotic effects of hCGβ and reduce
cell survival in vitro and therefore propose to suppress tumour growth in
Prof. Roitt chaired the original WHO committee for the development of hCG
vaccines for fertility and brought his expertise to Middlesex University
to collaborate with Dr Butler and Prof. Iles. Dr Butler reviewed hCG
vaccines in a chapter of his book on hCG in 2010 where more recently
research had turned to modulating cancer metastases with hCG vaccines
rather than fertility management. The original research carried out by Dr
Butler demonstrated a specific role for hCGβ and paved the way for future
studies on the effect of immunodepletion of hCGβ as an adjuvant treatment
for advanced bladder and other epithelial cancers. Dr Butler's research
continued to explore the structure function relationship of hCG variants
in multiple cancer subtypes and demonstrated that by incubating cancer
cells with antiserum, generated by hCGβ immunogen or vaccine, cells
resumed their prospective apoptotic demise; hCGβ was protecting the cells
which secreted it in an autocrine fashion.
Dr Butler and Iles' group investigated antiserum generated from various
vaccinated sources and following Phase I studies by Celldex Therapeutics,
tested the first human antiserum in 2010. It was demonstrated that the
antiserum could effectively reduce hCGβ secreting cancer cell populations
in vitro and that the vaccine generated a titre which was both elevated
enough and specific enough to modulate tumour growth and metastasis in
vivo. This specificity and efficacy data significantly lead to the
publication of the Phase I data by Celldex Therapeutics and collaborators.
References to the research
Outputs listed have been published in leading journals in the field with
rigorous peer review systems. They are of at least internationally
1. SA Butler, MS Ikram, S Mathieu, RK Iles (2000) The increase in
bladder carcinoma cell population induced by the free beta subunit of
human chorionic gonadotrophin is a result of an anti-apoptosis effect and
not cell proliferation. British journal of cancer, 82 (9), 1553.
2. SA Butler, EM Staite EM, RK Iles. (2003) Reduction of Bladder
cancer cell growth in response to hCGβ vaccinated mouse serum. Oncology
Research and Anti-Cancer Drug Design. 14, 93-100.
3. LA Cole, SA Butler, SA Khanlian, A Giddings, CY Muller, MJ
Seckl, EI Kohorn (2006) Gestational trophoblastic diseases: 2.
Hyperglycosylated hCG as a reliable marker of activeneoplasia. Gynecologic
oncology 102 (2), 151-159
4. Delves PJ, Iles RK, Roitt IM, Lund T. (2007) Designing a new
generation of anti-hCG vaccines for cancer therapy. Mol Cell
Endocrinol. Jan 2; 260-262:276-81. Epub 2006 Oct 17. PubMed PMID:
5. LA Cole, SA Butler (2012). Hyperglycosylated hCG, hCGβ and
Hyperglycosylated hCGβ: Interchangeable cancer promoters. Molecular
and cellular endocrinology 349 (2), 232-238.
6. Morse MA, Chapman R, Powderly J, Blackwell K, Keler, T, Green J, Riggs
R, He LZ, Ramakrishna V, Vitale L, Zhao B, Butler SA, Hobeika A,
Osada T, Davis T, Clay T, Lyerly HK. (2011) Phase I study utilizing a
novel antigen-presenting cell-targeted vaccine with Toll-like receptor
stimulation to induce immunity to self-antigens in cancer patients. Clin
Cancer Res., 17(14), 4844-4853.
Details of the impact
The work of this team has established through a number of peer reviewed
publications that hCGβ is expressed by many aggressive human tumours and
that it is required for rapid cell growth. They extended this in further
publications to show that hCGβ expression could be used as a diagnostic
tool to establish tumour type and indicate potentially useful therapies,
and to show that antibodies could be used to block the action of hCGβ in
vitro, which decreased tumour cell growth by preventing the hCGβ
mediated inhibition of apoptosis. The group continued this work to develop
modified forms of hCGβ that could be used for immunotherapy or vaccine
Building on this work, and that of others, Celldex Therapeutics (Needham,
MA, USA) have developed an anti-hCGβ cancer vaccine based on their
patented technology for targeting antigen presenting cells (APC) - (Keler
et al., 2007). Termed CDX-1307, this vaccine has completed Phase 1
development and is planned to be marketed as a treatment for colorectal,
pancreatic, bladder, ovarian and breast cancers, with the potential for
others. CDX-1307 couples the entire beta chain of hCG to an APC specific
adjuvant antibody and induces both humoral and cell mediated response to
the complete molecule and not just the CTP. These Phase I trials showed a
halting of tumour progression for many patients, and their serum was
demonstrated by Dr Butler to significantly reduce cell number in vitro
(Morse et al., 2011). A Phase II study in patients with invasive bladder
cancer began in May 2010. The N-ABLE Trial (Neoadjuvant and Adjuvant
Bladder Cancer Trial), was proposed to evaluate CDX-1307 in both
neoadjuvant and adjuvant settings in patients with newly diagnosed
muscle-invasive bladder cancers with inclusion dependent on demonstrating
hCGβ expression by the tumour. Preliminary data was expected by the end of
2011. However, while initial data was very encouraging and positive data
was presented from three product candidates in four presentations at the
American Society of Clinical Oncology annual meeting, recruitment of
suitable patients was slow. Coupled with the financial crisis slowing
progress even further the trial was halted in 2011.
However, Celldex and other companies are well positioned to continue this
work when circumstances are right. Therefore, current benefits include
possible increased survival time for patients within the trial, and a
significant financial impact on whichever company runs the trial. As an
indication of the impact this may make, other US based companies have
received significant government funding to extend this work using other
immunotherapy approaches although no data have been presented as yet. The
results reported in this trial show the vaccine approach has the potential
to make significant advances in the treatment of this invasive cancer.
From our data we know that antisera appears to block anti-apoptotic
activity of hCGβ, which in turn reduces the growth and spread of tumours
to distant organs. This has a profound effect on survival and the vaccine
may target these metastatic cells directly.
Current plans are that the vaccine will be trialled over a five-year
period, amongst a group of 60 newly-diagnosed patients with the cancer.
The same molecule occurs in many epithelial cancers (32% by meta analysis)
(Butler & Iles, 2010). In time, therefore, this type of vaccine could
also offer treatment benefits across a range of other highly invasive
cancers. Bladder cancer affects four times as many men as women with
10,000 new cases a year in the UK. It is the fourth most common cancer and
the sixth most common cause of cancer death in UK men. At present, 75% of
cases are lethal. The potential beneficiaries therefore number in the
millions worldwide, with the nature of the impact being increased survival
times, and possibly long term cures of cancers.
Sources to corroborate the impact
i) Dr Michael Morse at Duke University in North Carolina,
As the first and corresponding author for Morse et al., Phase I Study,
Clinical Cancer Research.17(14):4844-53, 2011, Dr Morse is prepared to
corroborate the involvement of Dr Butler of Middlesex University in
conjunction with Celldex Therapeutics and the CDX1307 trials in
demonstrating the specificity of the vaccine for hCGbeta.
ii) The Celldex Therapeutics Cancer vaccine Web page is:
and this contains press releases and publications on the vaccine trials.
These include the following press releases:
Other Press releases and articles:
Examples of other on-line sources specifically referring to the vaccine
development and Middlesex University: