Dendritic Cells: The Cancer Vaccine Era

Have you ever wondered about how the body defends itself from invasions and attacks from harmful pathogens while working to produce life long & robust immunity? Or what about those complex diseases we hear so much off on that TV Show “House”?

Well, Ralph M. Steinman was similarly curious. Steinman not only found the answer, but he was awarded the 2011 Nobel Prize in Physiology/ Medicine for discovering dendritic cells (DC), cells which serve as the directors of your body’s defense system.  Steinman’s finding elucidated what once was enigmatic, while simultaneously unifying separate fields within immunology (innate & adaptive), and he has transformed the way scientist and doctors look at complex diseases such as cancers and autoimmune disorders. Steinman, a professor of Immunology and senior physician at The Rockefeller University, used his Nobel Prize winning knowledge in an attempt to treat his own pancreatic cancer. Alas, he tragically died after a four year battle against the disease, even as his work has the potential to save countless others.

DCs were first discovered in 1968 as Langerhans cells(specialized DC of the skin). According to the Laboratory Cellular Physiology and Immunology, Steinman’s discovery came while studying the induction of immune responses in a major lymphoid organ, a known site for the generation of immature progenitor cells into mature lymphocytes. There, he noticed the presence of a group of cells scientist had regarded as being either macrophages or accessory cells. However, from Steinman’s previous work & experience with phages and immunity, his analysis of the cell convinced him he had stumbled across a distinct class.

Further examination of the role of DCs revealed that they were able to direct and coordinate both innate (non-specific) and adaptive (leading to specificity) immune responses. Precursor DCs patrol the blood stream, like sentinels, while immature DCs reside in tissues. Both forms are positioned and poised for the capture of foreign infectious antigens. After attacking and absorbing the foreign invaders, DCs migrate to lymphoid organs. Simultaneously they undergo phenotypic & functional maturation, and, in what I like to call the “3 Ps,” process, package, and present pathogen antigenic patterns , i.e. molecular structures, on their cell surface. The cell extends from its body, long tentacle like structures. This enables the DC to capture foreign cells and then communicate effectively (using these molecular patterns) with T-cell lymphocytes. Thanks to the DC’s “alarm”, T-cells are activated, proliferate, and differentiate into Natural Kill cells which attack and degrade infected cells.

A robust feature of DCs are their ability to induce differentiated T-cells to acquire “memory” of these antigenic patterns for prolong periods. This allows a rapid response in the case of similar and future attacks. This also allows the immune system to “remember” an immunologic historical library of diseases.

Another interesting and vital task of DC is its capacity to induce T-cells into Helper cells which in turn stimulate B-cells to transform into Plasma cells. Plasma cells are the body’s biological factory for the manufacturing of antibodies which neutralize the invading pathogen.

According to the Food and Drug Administration, DCs have been recognized as an immune therapy that harnesses the body’s own defense mechanisms to fight cancers. In patients of compromised or suppressed DC activity, studies on tumor cells have shown that if DCs can be extracted from the body, presented with antigens of the disease in treatment, and reinfused into the patient’s blood stream, tumors caused by the disease reduce in size and immunity against that disease is acquired. As a result, today there are 49 completed and 116 current clinical trials which utilize dendritic based cell therapies in the treatment of cancers such as prostate, ovarian, glioblastoma, melanoma, lymphoma, and renal cell carcinoma. The crowning jewel of which is the development of a cancer vaccine, which has had great success. The Food and Drug Administration (FDA), on April 29, 2010, approved the first ever cancer vaccine, a treatment that trains the body’s own immune system to fight cancerous tumors in the prostate. The treatment cost about $93,000 per patient and is available in 50 cancer treatment centers across the U.S. The vaccine, called Provenge (generic name sipuleucel-T), was developed by a Seattle-based biotech company, Dendreon Corporation. Lori Valigra, Mass High Tech correspondent, writes that “Vaccines represent a relatively new approach to fighting the spread of cancer, having appeared in the last decade” (see previous link).  Valigra explains that the underlying doctrine “is similar to a vaccine for a disease like measles: an injection in the arm induces an immune response that helps the body fight a particular pathogen, in this case, a cancer. An effective immune response would then shrink tumors and extend lives.”

Figure 2: Generation of Dendritic Cells in a Patient
http://www.fz-juelich.de/ibt/cell/matured-dendritic-cells
(Cell Culture Technology Group, Research Centre J�lich, Public Relations (�A), 52425 J�lich, Germany)

Hailed as the “dawning of the vaccine era,” Thomas Davis, MD, senior vice president and chief medical officer at Celldex Therapeutics Inc. Davis noted,

“a critical turning point for cancer vaccines was the discovery by Drs. Ralph Steinman and Zanvil A. Cohn [co-discoverer] at Rockefeller University in New York of dendritic cells, which are pivotal to the immune system. The cells don’t work well in patients with cancer. There’s still a lot we do not know, but we are getting a better sense of how dendritic cells work and how cancer suppresses them.”

http://www.masshightech.com/stories/2011/06/20/weekly11-Cancer-vaccines-make-progress-in-combating-disease.html

In the past doctors were limited to traditional chemotherapeutical drugs, but with the approval coming from FDA for developing DC based therapies, we are indeed harnessing the body’s natural biological and immuno-regulatory agents to cure illnesses. Dr. Edgar Engleman, one of the innovators of Provenge, believes that the approval of this new form of treatment may in fact “herald a new wave of cancer treatments that will not necessarily come with the many negative side effects typically associated with chemotherapy and radiation therapy.”

While a complete cancer vaccine may be years away, discoveries such as Steinman’s often take years to come to their full fruition. Just as Pierre and Marie Curie could not have know the place of radiation in our lives today, so too are the possibilities of dendritic cell therapy. Dr. Steinman is no longer with us, but the knowledge he has left about how the body defends itself from invasions and attacks from harmful pathogens while working to produce adaptive immunity will forever be a part of our lives in the 21st century and beyond.

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