Cuba’s public health outcomes are rooted in political and social phenomena that have favored achievement of health indicators well above expectations for an economy of its size. A less studied causal component of Cuba’s development in health is the creation, from early in the 1960s, of scientific research capacity throughout the health system, including use of science to launch a domestic industry for manufacturing high-tech products. This component should play an even greater role in meeting Cuba’s 21st century health challenges, especially the demographic and epidemiological transitions, increasing prevalence of chronic diseases, rapid emergence of a complex-product biotechnology pharmacopoeia, greater molecular stratification of diseases, rising health costs, and the need to maintain communicable diseases under control in a global context of climate change and more population mobility.
Tackling these challenges will demand greater scientific influence in the health system, application of a scientific approach in all activities and at all levels, and integration with scientific endeavors of other sectors such as agriculture, industry and education.
KEYWORDS Public health, science, health care costs, health workforce, chronic disease, biotechnology, immunology, aging, Cuba
Public health systems face the contradiction of skyrocketing cancer incidence and cancer drug prices, thus limiting patient access to more effective treatments. The situation is particularly dire in low- and middle-income countries. We urgently need consensus on the main determinants of this problem, as well as specific, effective and feasible solutions.
Analysis of available data reveals that the problem has reached its current magnitude only recently and is not related to the growing complexity of drug production technology, but rather to corporate profits and the failure of market mechanisms to allocate resources based on health needs.
Despite the obstacles, there is ample room for effective intervention: joint price negotiations, cost transparency, greater support for creation of manufacturing capacity, and regulatory measures that facilitate introduction of generic and biosimilar drugs and reduce intellectual property barriers to better use of flexibilities in the Agreement on Trade-Related Aspects of Intellectual Property Rights.
Such actions will not be effective if there is no consensus around them, or if low- and middle-income countries act in isolation. This is precisely where international organizations must intervene.
KEYWORDS Public health, price, cancer drugs, inequality, less-developed countries, developing countries, Cuba
Biotechnology has changed the pharmacopeia. It is expected that in the next five years, 50% of biological products will originate from biotechnology. Yet, treatments based on effective, costly biopharmaceuticals for prolonged use hamper the goals of ensuring universal therapeutic coverage and access to the best treatments. This conflict surfaced 30 years ago with synthetic drugs, and the solution was to create generics once the developers’ patents expired. Biosimilars are not generics, strictly speaking, as it is impossible to guarantee that they are molecularly identical to the original product; nor are they completely new products, as they rely on a great deal of prior work done by other scientists. National strategies are needed to ensure the broadest possible coverage in the best interests of the population. The key to a strategy to ensure access to the best treatment available lies in the concept of “totality of evidence,” which includes all information about a given molecular structure and its mechanism of action; safety and efficacy information from the first clinical trials; and monitoring data from products’ use in medical practice. A strategy of broad biological and molecular categorization plus intense pharmacovigilance would reduce development costs, the main barrier to widespread access.
KEYWORDS Biosimilar pharmaceuticals, biosimilars, biologics, legislation, social control, health services accessibility, health services needs and demand, Cuba
Los recientes avances en la inmunología básica han producido cambios en los paradigmas del manejo del cáncer avanzado, que actualmente se reconoce como una enfermedad crónica con una prevalencia en aumento, y cuya complejidad lo hace difícil de controlar. Como una alternativa, surge la inmunoterapia con nuevos anticuerpos monoclonales, vacunas terapéuticas y una comprensión más profunda de los fenómenos fundamentales involucrados en la interacción entre el tumor y el sistema inmune. Las ideas más novedosas conciernen a los mecanismos de contracción programada de la respuesta inmune, la caracterización de los marcadores moleculares y celulares de inmunosenescencia, el papel dual de la inflamación, la caracterización de células supresoras de estirpe mieloide y las células madre cancerosas, así como los fenómenos de la apoptosis inmunogénica y la adicción oncogénica.
Además, los nuevos datos conducen a una comprensión más profunda de las cuatro barreras que habrá que vencer para el control del cáncer avanzado: la complejidad de los sistemas biológicos, la heterogeneidad de los tumores, las tasas de mutación de los tumores y la falta de correspondencia entre el genoma y el ambiente. En este nuevo paisaje destacan seis estrategias principales: manejar el cáncer avanzado como una enfermedad crónica, identificar los marcadores moleculares más importantes para la estratificación de los pacientes, desarrollar una base lógica para las combinaciones terapéuticas, dirigir las acciones hacia los lazos de control regulatorio en el sistema inmune, aumentar la capacidad de la modelación matemática y evaluar los paquetes complejos de intervención sanitaria en las condiciones del mundo real.
En este trabajo se ilustran estas transiciones en la investigación de la inmunoterapia del cáncer mediante la descripción de proyectos en ejecución en el Centro de Inmunología Molecular de Cuba.
PALABRAS CLAVE: Inmunoterapia, control del cáncer, inmunología molecular, anticuerpos monoclonales, Cuba
Recent advances in fundamental immunology are changing paradigms for management of advanced cancer, now acknowledged as a chronic disease whose prevalence will increase, and one whose complexity makes it difficult to control. Immunotherapy is emerging as an alternative, with new monoclonal antibodies, therapeutic vaccines and deeper understanding of fundamental phenomena in the interaction between tumor and immune system. These novel insights concern mechanisms of programmed contraction of the immune response, characterization of molecular and cellular markers of immunosenescence, the dual role of inflammation, characterization of myeloid-derived suppressor cells and cancer stem cells, and the phenomena of immunogenic apoptosis and oncogene addiction.
Additionally, new data drive a deeper understanding of four barriers to overcome in control of advanced cancer: the complexity of biological systems, tumor heterogeneity, tumor mutation rates, and human genome–environment mismatch. The new landscape points to six main strategies: manage advanced cancer as a chronic disease, find relevant molecular markers for patient stratification, develop a rationale for therapeutic combinations, target regulatory control loops in the immune system, expand mathematical modeling capacity, and evaluate complex health intervention packages in real-world conditions.
These transitions in cancer immunotherapy research are illustrated in this paper through description of ongoing projects at Cuba’s Molecular Immunology Center.
KEYWORDS: Immunotherapy, cancer control, molecular immunology, monoclonal antibodies, Cuba
The article presents global data on access to pharmaceuticals and discusses underlying barriers. Two are highly visible: pricing policies and intellectual property rights; two are less recognized: the regulatory environment and scientific and technological capacities. Two ongoing transitions influence and even distort the problem of universal access to medications: the epidemiologic transition to an increasing burden of chronic non-communicable diseases; and the growing role of biotechnology products (especially immunobiologicals) in the pharmacopeia. Examples from Cuba and Brazil are used to explore what can and should be done to address commercial, regulatory, and technological aspects of assuring universal access to medications.
KEYWORDS Biotechnology, biological products, clinical trials, drug costs, economics, pharmaceutical, pharmaceutical preparations, intellectual property, patents, access to health care, world health, Cuba, Brazil
Introduction CIMAvax EGF is a therapeutic anticancer vaccine developed entirely in Cuba and licensed in Cuba for use in adult patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). The vaccine is based on active immunotherapy by which an individual’s immune response is manipulated to release its own effector antibodies (Abs) against the epidermal growth factor (EGF).
Objective Review pre-clinical and clinical research conducted during development of CIMAvax EGF, primarily studies published by Cuban investigators in international peer-reviewed scientific journals.
Methods An automated search for “vaccine” and “EGF” was conducted in PubMed, resulting in 17 articles published by Cuban authors between January 1, 1994 and September 30, 2009. Main findings were described and discussed, along with unpublished preliminary findings of an initial ongoing phase III clinical trial.
Results Articles reviewed describe five phase I/II and one phase II clinical trials conducted in Cuba in 1995–2005. A non-controlled 1995–1996 study resulted in the earliest published scientific evidence of the feasibility of inducing an immune response against autologous EGF in patients with different advanced stage tumors. Subsequent controlled, randomized trials included patients with advanced stage (IIIB/IV) NSCLC. The 2nd and 3rd phase I/II trials differentiated immunized patients as poor antibody responders (PAR) and good antibody responders (GAR), according to their anti-EGF antibody response, and confirmed greater immunogenicity with Montanide ISA 51 adjuvant in the vaccine formulation, as well as the benefits of low-dose cyclophosphamide treatment 72 hours before the first immunization. The 4th phase I/II trial found increased immunogenicity with an increased dose divided in 2 anatomical sites and also established correlation between Ab titers, serum EGF concentration and length of survival. In the first 4 phase I/II trials and the phase II trial, vaccine was administered after chemotherapy (ChTVV schedule). In the 5th phase I/II trial, longer survival and increased immunogenicity were achieved using a VChTV schedule and dividing the vaccine dose in 4 anatomical sites. The phase II clinical trial confirmed results of earlier studies as well as the mild-to-moderate adverse event profile associated with CIMAvax EGF. Longer survival was observed in all vaccinated patients compared to controls, and the difference was significant (p <0.05) in the group aged <60 years.
Conclusions CIMAvax EGF’s benefits in earlier NSCLC stages and in other tumor locations, as well as in patients unfit for chemotherapy, need to be evaluated. Evidence of the vaccine’s safety for chronic use also needs to be systemized.
Key words: Epidermal growth factor, EGF receptor, non-small-cell lung carcinoma, lung cancer, vaccine therapy, immunotherapy, cancer vaccines
Introduction Nimotuzumab, developed in Cuba, is a humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life.
Objective Describe nimotuzumab’s safety profile and clinical benefits in terms of disease control and survival in pediatric patients with progressive or recurrent primary brain tumors who were included in an expanded access program.
Methods An open, prospective clinical study was designed. Between December 2005 and December 2007, 22 patients were included, all of whom had an histological and/or radiological diagnosis of progressive or recurrent primary brain tumor, classified as high-grade malignant glioblastoma (n=6), diffuse brain stem glioma (n=6), ependymoblastoma (n=5), low-grade glioma (n=4), or thalamic tumor (n=1); life expectancy of at least 4 weeks; and a Karnofsky or Lansky Performance Status score of ≥50. Nimotuzumab was administered on a 100 mg weekly intravenous infusion schedule for 6 to 8 weeks, followed by a bi-weekly maintenance phase, as long as there was no deterioration in the patient’s functional capacity. Therapeutic protocols were followed for administration as monotherapy or in combination with chemotherapy and/or radiotherapy. All patients received clinical and imaging follow-up.
Results Nimotuzumab was well tolerated in all therapeutic modalities, even with prolonged exposure. A minority of patients reported slight or moderate adverse events, such as vomiting, mucositis and chills, as classified by the Common Terminology Criteria for Adverse Events (CTCAE). The disease was controlled in 64% (14/22) of patients; 6-month and 1-year survival rates were 82% and 64%, respectively; average survival was 20.3 months and median survival, 19 months. Recovery of neurological functions and improvement in general status were notable in patients who attained control of the disease.
Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. These results indicate further studies of this product are warranted.
Keywords Central nervous system neoplasms, brain neoplasms, brain cancer, biological therapy, immunotherapy, monoclonal antibodies, EGF receptor, child mortality, nimotuzumab.
A national cancer program is essentially a population health initiative that goes beyond satisfying the demand for health services to propose modifying specific objective indicators in a defined population through interventions that have a scientifically grounded probability of success.
In the case of malignant neoplasms, the three “gold standard” indicators are age-adjusted specific mortality, age-adjusted incidence, and average 5- or 10-year survival rates. All other frequently used indicators—such as stage distribution at time of diagnosis, participation in early diagnostic interventions, intensity of public health education efforts, and coverage of chemo- and radiotherapy services, among others—are valid to the extent they are predictors of the three “gold standard” indicators.
Vaccination programs have been successful in Cuba, whatever metrics are used to evaluate them: the population is protected against 13 diseases, well beyond WHO goals; illnesses such as polio, diphtheria, whooping cough and others have been eradicated; and even hepatitis B is slated to disappear. How can these results be explained? Certainly strong political will, a society based on justice and solidarity, the concept of health and education as human rights, and a health system accessible to all, are paramount. Without these, no technology would make a difference.
