The Molecular Immunology Center is a campus of concrete and stone buildings with dark-tinted windows set against palm trees and pink tropical flowers. The buildings are imposing and seem to stretch endlessly along the flat terrain of Havana, Cuba. The research institute, like most buildings in Cuba, is just a few minutes’ walk to the Atlantic Ocean coastline. Inside the research and development building, investigators are working on creating 18 new cancer immunotherapy treatments from vaccines to monoclonal antibodies to synthetic cytokines. A few buildings down, in an almost 50,000–square foot manufacturing plant, a positive pressure air gradient system whirs, and stirred tank bioreactors clank in continuous motion. It is here that the CIMAvax-EGF, a therapeutic vaccine used to treat non–small-cell lung cancer (NSCLC), is manufactured, formulated, and packaged into 40-L sterile bulk bags.
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Shown is the old city of Havana.
The Molecular Immunology Center, also called the Center of Molecular Immunology or Centro de Immunologia Molecular, was founded in the early 1990’s and the research that eventually led to CIMAvax-EGF began almost immediately, spurred by Cuba’s high rate of lung cancer–related deaths (at the time the second leading cause of death and the leading cause of cancer mortality in the country).
The vaccine works by stimulating a patient’s own immune system to make antibodies against epidermal growth factor (EGF), which depletes circulating EGF levels and prevents EGF from binding to its receptor. “The epidermal growth factor receptor (EGFR) is a well-known oncogene. Its overactivation can induce malignant transformation of a normal cell, signaling inhibition of apoptosis, cell proliferation, angiogenesis, metastasis, and tumor-induced proinflammatory and immunosuppressive processes,” wrote Dr. Pedro Rodríguez and his associates at the Molecular Immunology Center in Cuba (MEDICC Rev. 2010;12:17-23).
“The EGFR signaling and transduction pathway can be efficiently interrupted by EGF deprivation, direct specific mAb [monoclonal antibody] receptor inhibition, or low-molecular-weight molecules competing intracellularly with adenosine triphosphate for the receptor’s tyrosine kinase activity site, with negative repercussions on cell proliferation and, consequently, on tumor development. Inducing EGF deprivation by active immunotherapy is an emerging concept developed by Cuban researchers that involves manipulating an individual’s immune response to release its own effector antibodies against EGF, thereby reducing tumor size or preventing its progression,” the investigators wrote.
Early preclinical studies for vaccine formulation began in Cuba in 1992. Over the next few years, researchers perfected the vaccine’s formula: EGF along with two immunopotentiating molecules, an adjuvant called Montanide ISA 51 and the virulent protein P64k from the microbial organism Neisseria meningitidis (Ann Oncol. 1998;9:431-5; Ann Oncol. 2003;14:461-6).
Together, the adjuvant and the virulent protein activate the immune system while the overabundance of EGF in the body directs antibodies to be made specifically against EGF and not virulent protein P64k. Although some antibodies bind the EGF introduced by the vaccine, other antibodies target cancerous cells where EGFR is overexpressed.
NSCLC was selected “because of its frequency and because EGFR is overexpressed in tissues during development and progression of lung neoplasms,” reported the investigators.
Subsequent clinical trials focused on fine-tuning administration route, dose, dosing interval, optimal combinations with other established therapies, and reducing vaccine-related side effects, which include fever, chills, nausea, headache, asthenia, and tremor.
Researchers found that administering the vaccine in “high but fractioned dose[s] in multiple anatomical sites (such as the 2 deltoid and 2 gluteal regions), thereby bringing the EGF vaccine closer to regional lymph nodes and synergizing the immune response” resulted in the best patient outcomes. In addition, significantly better patient outcomes were achieved when the vaccine was administered before and after chemotherapy.
By 1995, Cuban researchers had successfully completed five separate phase I/II clinical trials and one phase II clinical trial.
Pooling the results from the various clinical trials, non–small-cell lung cancer patients who received the vaccine and who were under the age of 60, lived an average of 4-6 months longer than patients who did not receive the vaccine or were older than 60.
By 2009 “more than 700 patients [had] received the vaccine over the years, many of them in seven clinical trials in Cuba, Canada, and the U.K.,” reported an online Cuban newspaper, Cuba Headlines.
It wasn’t until September 2011 that Cuban researchers officially began distributing the vaccine to Cuban citizens.
“The drug could turn the cancer into a manageable, chronic disease by generating antibodies against the proteins, which triggered the uncontrolled cell proliferation,” Dr. Gisela Gonzalez of the Center of Molecular Immunology said in an interview in 2009 following the official launch of the vaccine.
Today, ongoing clinical trials continue in Cuba and are also underway (at various stages) in several other countries, including the United States. The vaccine still has a long way to go before it can be hailed as a true “cancer cure,” a sentiment that many American publications expressed and one that the researchers at Roswell Park Cancer Institute who are leading the U.S. clinical trials are vehemently trying to quell. Nonetheless, the now global reach of CIMAvax may mark a promising paradigm shift in the field of oncology.