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April 29, 2010 was a significant date in the history of cancer treatment with the FDA's approval of Dendreon's (NASDAQ:DNDN) Provenge for advanced prostate cancer. That date did not mark the beginning of the immunotherapy approach to fighting cancer; however, it did legitimize the class of therapies. Although not a perfect treatment due to costs and an initial overall survival increase of "only" about 4 months, this was the pharmaceutical sector's first successful venture into immunotherapy, which utilizes the patient's own immune system to recognize and then mount an attack against cancer tumors.

One of the most difficult characteristics to deal with in fighting cancer is the body's failure to recognize the cancer cells as dangerous or foreign. Bacteria and viruses have substances on their surfaces such as proteins that are very different from a person's cells, and are seen as invaders and attacked by the human immunity system. Most cancers, although different in many ways from normal cells, are not different enough from normal cells for our immune system to actually recognize. Cancer cells do have characteristics that differentiate them from normal cells in the proteins found on the surfaces of cancer cells that are either unique to the cancer cells or in much greater number (higher expression) than normal cells. These proteins are called antigens and are the key to the immunotherapy approach to fighting cancer. The entire concept of the immunotherapy approach to fighting cancer stems from teaching the body through some means to recognize cells with the antigens specific to the cancer, and then attacking and destroying these cells. Unlike chemotherapy, radiotherapy and resection, the body may "remember" what these cancer cells look like and attack any recurring or new cancer cells with the same antigen signature and attack them, thus invoking a much more sustained prevention of the recurrence of the cancer in the future.

Provenge's First-Generation Activated Monocytes

At the heart of Provenge's technology are the therapy's dendritic cells. Through the process of leukophoresis, blood is withdrawn from the patient and the plasma containing peripheral blood monocytes (to create dendritic cells from) is removed. The remaining portion of the blood is returned to the patient who is promptly allowed to recover and/or go home. Since the therapy will be targeting cancer cells with PAP (prostatic acid phosphatase) expression, found in 95% of prostate cancer tumors, the extracted cells are subsequently exposed to and cultured with PAP and granulocyte-macrophage colony-stimulating factor cytokines (GM-CSF) to form a recombinant antigen PAP-GM-CSF. The end products are activated antigen presenting cells (APCs) capable of initiating a T cell response against any cells having the PAP expression. The dendritic cells (now activated monocytes) are then returned to the patient (must be done within 18 hours of manufacture). This process is repeated in two week intervals for a total of three treatments.

DCVax's Second-Generation Purified Dendritic Cells

With the same concept in mind as Provenge's dendritic cells, Northwest Biotherapeutics (NASDAQ:NWBO) takes the approach one step farther. First, CD34+ progenitor cells are mobilized from the bone marrow by treating the patients with G-CSF. The resulting cells are then extracted through leukophoresis. The CD34+ progenitors are then purified and subsequently cultured. Rather than against one antigen, as in Provenge, the cells are cultured in the presence of the tumor lysate (GBM for their most advanced trial). The cells, as reintroduced into the patient, have a larger APC target group rather than only PAP, and the dendritic cells produced are more mature. The phase I trial for glioblastoma was impressive, with a median overall survival of 33.8 months relative to 14.6months with the current standard of care. However, painfully slow enrollment of their phase II-turned-phase III trial for glioblastoma patients appears to be causing investor anxiety, as the company hasn't been very forthcoming with updated enrollment figures, and DCVax was strangely absent from ASCO this year.

ICT-107's Third Generation Purified Dendritic Cells with IL-12

ImmunoCellular Therapeutics' (NYSEMKT:IMUC) ICT-107 has been gaining more investor, and most likely, large pharmaceutical interest lately, with their phase I trial for newly-diagnosed glioblastoma. Building on advances made throughout the industry and adding their own twists, the company is building its patent portfolio and protecting its intellectual property with its third generation dendritic cell therapy to combat GBM and a host of other cancers. While also utilizing purified dendritic cells and multiple antigens, the dendritic cells produced are more mature and express high levels of the cytokine interleukin (NYSE:IL)-12, which yields a stronger T-cell response to cells containing the targeted antigens. Adding to the therapy's possible additional indications in the future is the number of antigens that ICT-107 targets including HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2.

While DVax has been showing some efficacy in prostate and GBM cancers, ICT-107's plausible future indications include any cancers with the targeted antigens. Adding another twist in the treatment approach, ICT-107 also addresses the cancer stem cells [CSC] as well. These CSC's are thought to be behind the recurrent nature of many cancers. CSC's are much more resistant to traditional cancer treatment such as radiotherapy and chemotherapy as they are more similar in nature to normal cells and don't have the phenomenal growth rate that typical cancer cells have that make them more susceptible to those regimens. CSCs normally survive the traditional treatments, and live to start the next generation of cancer cells, often much more resistant to the treatment that killed the first generation cancer, and thereby, creating a much more difficult cancer to treat.

What Next?

Provenge is and will remain controversial. It has secured its place in history as being the FDA's first approval of an immunotherapy approach to fighting cancer. The biotech sector and cancer treatment made a mighty step with the validation of this type of treatment. Dendreon may be years away from profitability and needs to make large improvements in cost cutting, marketing and manufacturing efficiency to improve their bottom line. However, patients needing the treatment should be finding insurance and reimbursement issues subsiding as improvements are made in the process. Impatient shareholders are apparently as concerned as the author is about the status of Northwest Biotherapeutics' DCVax. The company greatly needs to find a way to speed up enrollment and be more transparent with its enrollment updates rather than omitting such information in their recent press releases.

ImmunoCellular Therapeutics' major catalysts are behind them with ASCO and 4/5 year data on their phase I GBM data mostly revealed with substantial improvement over the standard of care for GBM. Investors and healthcare providers will be eagerly anticipating phase II data as that trial progresses and updates are provided. The company's growing intellectual property and large potential target patient set for ICT-107 and their preclinical pipeline will likely prove to be substantial in the future if the phase II ICT-107 proves successful. Real or perceived success in ICT-107 could prove to a huge catalyst by legitimizing its safety and efficacy both for GBM and a host of other cancers. Still a lower market capitalization company at $150 million, Big Pharma rumors are likely coming as the company continues to advance ICT-107 and proves that its intellectual property is worthy of licensing or acquisition. The use of dendritic cells has rapidly improved and advanced since Provenge's approval. ICT-107's third generation therapy is likely not the pinnacle of the immunotherapy approach but does represent substantial hope for cancer sufferers and substantial value to shareholders if the phase II data shows even a portion of the efficacy of the phase I success. If it does, ASCO 2013 and ASCO 2014 headlines are being written right now in ImmunoCellular Therapeutics' third generation DC approach, ICT-107.

Source: Dendritic Cell Evolution: Investment Potential