Cuban cancer immunotherapy

12 Mar 2010
Cuban cancer immunotherapy

If there is one aspect of the policy of Castro’s Cuba that has attracted almost universal worldwide approval, it is its free, publicly funded health system. And, as all universally collected outcome statistics show, this is a very successful one. The life expectancy of a Cuban national at birth, for example, is now higher than that of a citizen of any other country in the Americas except Canada. Cuba’s infant mortality is among the lowest in the world, and its universal vaccination programme has been rated as exemplary. Cancer treatment, including radiotherapy and chemotherapy, is more widely available than in other countries with comparable GDP, and cancer survival statistics are generally good. Unsurprisingly, however, in a country that is perhaps indelibly linked to tobacco, smoking rates and, consequently, prevalence rates for smoking-related cancers, are still high.

Cuba’s healthcare achievements are even more impressive when they are put alongside the embargo that has prevented any trade and almost any contact between the US and Cuba since 1962. Relations between the two countries, already very bad, deteriorated further during the Bush years, and a change in atmosphere after Obama's election, although welcomed, has not yet resulted in significant policy changes.

It is less well known that Cuba has a significant base in bioscience research and a well-regarded biotechnology industry that has seen some commercial success. And some of its most conspicuous successes are in the cancer field: more specifically, in immunology and cancer immunotherapy.

Cuba’s investment in both basic and applied immunology research derives from its understanding of the importance of the link between immunology and public health and long-standing and successful public vaccination programme. Most of Cuba’s life-sciences research is based in Havana. Initially, much was devoted to vaccine development for infectious diseases. However, the prestigious Centre for Molecular Immunology (CIM) which opened in 1994, has always focused on immune therapies for cancer, one of the diseases that its director, Agustín Lage Dávila, terms “chronic diseases of adulthood”. The most advanced compound in CIM’s extensive anti-cancer product pipeline is nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR). This product has marketing approval in some 23 countries, mainly developing ones, and in advanced clinical trials in others including the US, Japan and many European countries. Other products in clinical development include CimaVax, a vaccine against lung cancer, and a vaccine that targets a specific ganglioside that is expressed in humans only on cancer cells.

EGFR, or HER1, is a membrane-bound tyrosine kinase that is over-expressed on the surface of many types of cancer cells. Both “small molecule” inhibitors of EGFR’s enzyme activity and monoclonal antibodies that target it have been successfully developed as anti-cancer drugs in recent years; a closely related protein, HER2, is the target of Herceptin™. Researchers at CIM were probably among the first in the world to research anti-EGFR antibodies, but US and European companies, with their vastly superior resources, were able to move faster into the development phase. CIM’s antibody, nimotuzumab, is now in direct competition with products such as Erbitux™ (cetuximab). Originally developed by researchers in Israel and marketed worldwide through Bristol-Myers Squibb and Merck KGaA, this drug has now attained the elusive “blockbuster” status as its yearly sales stand at over $1.5 billion. In contrast to Erbitux, a chimeric antibody with principally mouse characteristics, nimotuzumab is a humanized monoclonal antibody with a preponderance of human-like epitopes grafted onto a murine antibody structure. It is available to patients in Cuba and other developing countries including Brazil, Argentina, Mexico, India and China for the treatment of paediatric and adult glioma, head and neck cancer and some other solid tumours.

Development of nimotuzumab in the main Western markets has for over ten years been the responsibility of the Canadian company YM BioSciences, a public company listed on the NYSE Amex. However, progress was severely constricted by the earlier difficulty in raising capital because of the embargo, and a general lack of awareness of Cuban medical biotechnology. Lage told the Lancet Oncology in 2006 that the US FDA and OFAC, the agency that administers the embargo, had to be so closely involved in YM BioSciences’ programme for its compassionate use, off-license, in paediatric glioma that “the whole bureaucratic and time-consuming procedure had to be repeated for each patient”. YM has, in turn, licensed nimotuzumab to other companies for trials in Europe and the Far East. Currently, the website lists sixteen trials of the drug, including four in Phase III, covering Europe, the US and Canada, and several Far Eastern countries. Some trials in China are sponsored by Peking University. “Following Phase III trials in paediatric and adult glioma, our partner, Oncoscience AG intends to submit nimotuzumab to the EMEA for approval”, says David Kennard, European director of YM Biosciences.

So far, trials results indicate that nimotuzumab’s anti-cancer efficacy is similar to that of the currently marketed anti-EGFR antibodies in worldwide clinical use. These blockbuster drugs typically add a few months to the lifespan of advanced cancer patients. The Cuban drug does, however, have a particular advantage: fewer and less severe side effects. Anti-EGFR inhibitors commonly cause side effects including pruritis, severe diarrhaea, hypomagnesemia requiring hospitalization for magnesium replenishment, Grade 4 radiation dermatitis and a severe, body-covering rash which, interestingly, is correlated with response: the more severe the rash, the more likely a positive response. Reports of such severe side effects are extremely rare with nimotuzumab. This is due to it having a more appropriate affinity for the receptor than its competitors, as Kennard explains. “Cetuximab, for example, is a very high-affinity antibody, and it will bind to EGFR wherever it is expressed in the body including normal skin and intestine. In contrast, nimotuzumab is a lower-affinity antibody that, like Herceptin, binds to the receptor only where it is significantly over-expressed. As this over-expression is generally restricted to tumour cells, nimotuzumab’s activity is concentrated at the tumour site, and the drug has fewer side effects.”

In contrast with antibodies, which directly interact with molecules expressed on cancer cells, therapeutic cancer vaccines act by stimulating the patient’s immune system to target such molecules and destroy the cells. CIM has a number of cancer vaccines in development, and one, CimaVax, in clinical use. This vaccine targets EGFR’s ligand, epidermal growth factor (EGF). It was approved for use in non-small cell lung cancer (NSCLC) in Cuba in June 2008, which made it the first cancer vaccine to be approved for this indication anywhere in the world. It has been in clinical trials in other markets, including Canada, the UK and Malaysia, and is most likely to be licensed next in Peru. A recent randomised Phase II clinical trial in NSCLC patients with stage IIIB/IV disease who had already completed first line chemotherapy showed a statistically significant survival benefit in patients under the age of sixty. Licensing in any major market is at best two to three years away, but patients from outside Cuba can already receive the vaccine if they travel there or to any one of the other 22 countries where the drug is approved.. Such health tourism is a growing industry and a valuable source of foreign exchange for Cuba.

Receptors such as EGFR and their signalling are targets for immunotherapy because they are over-expressed by many types of tumour cell. However, side effects of both types of treatment can arise when the antibodies also interact with the same receptors on normal cells. The most ideal targets for antibodies and cancer vaccines are molecules that are expressed only on tumour cells. Another cancer vaccine in development at CIM targets one of these key molecules: a ganglioside known as NeuGcGM3.

The name ganglioside is given to specific glycosphingolipids (glycolipids containing the amino alcohol, sphingosine) found on cell surfaces. Different organisms, and different cell types, express a different pattern of gangliosides. What makes NeuGcGM3 important is that a gene for its synthesis has been lost in the human lineage alone: it is found on the cells of all mammals but humans. Crucially, however, it can often be found in human cancer cells, so a cancer vaccine targeted to NeuGcGM3 could be expected to show exquisite specificity. CIM’s vaccine, developed by combining the ganglioside itself with the outer membrane complex of the bacterium Neisseria meningitides to form proteoliposomes, is showing promise in early clinical trials in Cuba. One such Phase I trial in advanced breast cancer has showed the vaccine to be well tolerated and to elicit a reproducible immune response.

In all drug and vaccine development it is self-evidently essential to test candidate molecules in an animal model – often a mouse – that mimics the human condition as nearly as possible. Wild type mice, however, are an imperfect model for testing the NeuGcGM3 vaccine as they, like all other mammals, synthesise this ganglioside in normal cells. A much better model would be a NeuGcGM3 knockout mouse. Ajit Varki’s group at the University of California San Diego developed such a mouse and published the study in 2007. Varki would be very happy to collaborate with the Havana group, but the embargo prevents export of his mice to Cuba. Scientists at the Systems Biology Laboratory UK (SBL), a non-profit clinical research company based in Oxfordshire, UK, have now duplicated Varki’s mice. “Our mouse model is not novel, so we can’t publish it until it has generated new clinical results”, explains Janet Fernihough, Medical Projects Manager at SBL. “We wanted to repeat the work in order to make the mice available in Havana where they are needed.”

Although US exports of agricultural products from the US to Cuba have been approved by the US since 2000 and a considerable proportion of Cuban food requirements are supplied directly by the US, non-agricultural trade, direct investment or imports from Cuba remain prohibited. There has certainly been a change in atmosphere, if not yet in policy, since Obama replaced Bush and Fidel Castro yielded power to his brother Raúl. Many on both sides are beginning to hope for a thaw in relations: “There is a lot of hope for change in Cuba”, says Fernihough. As early as February 2009, a report from a group of US senators visited Cuba on a fact-finding mission and published a report, “Changing Cuba Policy – In the National Interest” that recommended that the US government should “begin treating Cuba as it does other nations with whom it has fundamental disagreements, but where engagement advances broader interests”. One of its most specific recommendations was “to permit pharmaceutical imports from Cuba’s rapidly developing biotech industry”. It is clear that any such engagement and particularly a wider exposure to innovative Cuban research would be of great benefit to oncologists in both countries and the patients they serve.