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Steinman’s discovery of dendritic cells has opened up a new class of cancer vaccines

In 1973, Dr. Ralph M. Steinman discovered dendritic cells, a new class of cells that play a critical role in regulating the immune system. His work laid the foundation for future studies validating the importance of these potent immune system guardians. When Steinman was diagnosed with pancreatic cancer four and a half years ago, he turned to dendritic cells in search of a cure.

For this groundbreaking work in immunology, Steinman was named one of three winners of the Nobel Prize in
Medicine on Monday, October 6. Only, he had died in his home three days earlier from progression of his disease.
He was 68.

Steinman’s work helped elucidate the role of dendritic cells. These cells are part of what is called the adaptive immune response, comprising various white blood cells capable of recognizing pathogens, destroying them, and mounting a stronger response in future attacks.

Dendritic cells are called antigen presenting cells; upon engulfing and destroying pathogens such as bacteria or cancer cells, pieces of the pathogens, or antigens, are displayed on the cells’ surface to activate T-cells and sustain the immune response.

Steinman went on to win the 2007 Albert Lasker Award for Basic Medical Research for his work, which eventually paved the way for the development of dendritic cell immunotherapies, particularly as a treatment for cancer helping usher in the era of cancer vaccines.

Steinman himself co-founded Argos Therapeutics, a company focused on dendritic cell based immunotherapies.
The company has projects in lupus, HIV, and cancer, the latter being the most advanced, with a candidate nearing
Phase III.

Putting his theories to the ultimate test, Steinman used his own body as a laboratory for experimental therapies. He was treated with an early cancer vaccine called GVAX developed at that time by Dr. Elizabeth Jaffee at John Hopkins University in Baltimore. Later, he received a vaccine from his own company.

Cancer vaccines work by teaching the immune system to recognize and destroy cancer cells. In the case of
Steinman’s treatments, a couple methods were used. The idea behind GVAX is fairly simple: inactivated cancer cells designed to express a large number of tumor antigens are injected into the patient, stimulating an immune response towards that tumor type.

The vaccine from Argos is somewhat more complicated and is considered a personalized vaccine; a separate treatment is made for each individual. Using the Argos treatment, dendritic cells from Steinman were transfected with the RNA from his own tumor. The cells were then re-injected in him, ready to activate his T-cells with tumor antigens.

It’s impossible to know if his treatments worked, but Steinman certainly beat the odds. The prognosis for pancreatic cancer is dim; one-year survival upon diagnosis is just 20%, and only 4% make it to five years. Most likely, the treatments had some effect, but just not enough.

The first cancer vaccine, Provenge from Dendreon (NASDAQ:DNDN), was approved in April 2010, giving hope to the entire field.  Provenge was approved for the treatment of men with prostate cancer on the basis a four-month survival improvement.  It is a personalized treatment though not quite a dendritic cell vaccine, rather, Provenge consists of patients’ monocytes - dendritic cell precursors.

Others following in Dendreon’s footsteps, like Argos, aim to improve on Provenge by developing treatments based directly on dendritic cells.  Bellicum Pharmaceuticals has an early stage prostate cancer vaccine with Phase I/II results presented at the Genitourinary Cancers Symposium demonstrating tumor shrinkage, PSA decline, and the eliciting of an immune response. A randomized Phase II trial is expected to begin this year.

A bit further along is Immunocellular Therapeutics (OTC:IMUC) with its cancer vaccine for brain tumors.  Their treatment, called ICT-107, consists of dendritic cells loaded with six specific tumor antigens, some found on cancer stem cells.  This allows the dendritic cells to activate T-cells toward both the tumor and tumor-initiating stemcells, which have been shown to be resistant to radiation and chemotherapy.

IMUC’s Phase I trial, though small, demonstrated compelling data.  Of 16 newly diagnosed GBM patients,
OS at 36 months reached 55% in ICT-107 treated patients compared to the historic rate of 16% with standard of care (SOC); median PFS improved to 16.9 months from the historic 6.9 months; and median OS was 38.4 months compared to the historic 14.6 months.

A Phase II multicenter, double-blinded, study of ICT-107 in patients with glioblastoma was initiated this January. Patients in this 102 person trial will be randomized 2:1 to receive either drug or untreated dentritic cells as the control.  The primary outcomes will be overall survival (OS) and progression free survival (NYSE:PFS). An interim analysis will be performed near the end of 2012 with final results coming by the end of 2013.

With multiple dendritic cell vaccine trials ongoing, it won’t be long before we see tangible results. Steinman’s research led to development of the first cancer vaccine; it also set the stage for next-generation technologies with the potential to improve outcomes even more.