Where Einstein Meets Edison

The Cancer “Vaccine”

The Cancer “Vaccine”

Sep 14, 2010

$93,000 is a lot of money, but this tidy sum is the cost of a full treatment with Dendreon’s new prostate cancer therapeutic vaccine, Provenge™[1].  The new treatment, recently approved by the FDA[2], is indicated for use in minimally symptomatic, hormone refractory (androgen-independent), metastatic prostate cancer.  In such seriously ill patients, this is often the last weapon a doctor has to try and help fight the spreading cancer.  But with a median increase in survival time of only four months and at such a cost, it remains to be seen how health insurance coverage will accommodate it.

            Much has been made of this new approval, both with respect to the scientific and clinical precedence and the economic impact on the Seattle biotechnology industry.  But much of the associated fanfare may have been somewhat misleading, especially for the non-scientific community.  Multiple news sources reported the approval of a new cancer vaccine[3].  And while such a statement is strictly true, it is not like more traditional vaccines.  Unlike Merck’s Gardasil, which primarily vaccinates against human papillomavirus and secondarily prevents several forms of cervical cancer, Provenge is designed to directly vaccinate against cancer.  The two drugs also differ in their utility; Gardasil is used for prophylaxis while Provenge will be used therapeutically.  So unfortunately, you won’t be able to get an injection of Provenge as a teenager and then never have to worry about getting prostate cancer.  While there is no reason that Provenge couldn’t be used as a prophylactic, there wouldn’t be much sense in it.  The cell-based treatment is specific for a particular prostate cancer antigen, so if someone were to receive a prophylactic treatment they would simply prevent a tumor with that particular antigen from arising, rather than preventing cancer in general.       

            Provenge, sipuleucel-T, is the first approved activated dendritic cell-based therapy[4].  Administered as an infusion bag for intravenous drip, the patients own dendritic cells are isolated and then treated in vitro with an engineered cancer antigen, PA2024, which is designed to induce uptake and display in the major histocompatibility complex by the dendritic cells.  PA2024 is composed of prostatic acid phosphatase, a protein antigen expressed on prostate adenocarcinomas, recombinantly fused to granulocyte-macrophage colony-stimulating factor.  The primed immune cells are then put back into the patient where they can activate the body’s own immune system, specifically cytotoxic T lymphocytes that then attack tumor cells throughout the body.

            Approval for this new treatment came on the heels of a follow up phase III clinical trial requested by the FDA[5].  In this most recent study, a total of 225 patients from 27 clinical centers were divided into two groups and administered either Provenge or placebo.  The key results showed that across all patients, 36-month survival was increased from 15% to 33%, and median survival was increased from 18.9 to 23.2 months.  Some might be skeptical of the analysis of clinical success compared to placebo, especially in cancer patients, but note that these patients have often already failed other treatment methods and that the increased survival time is relatively pain-free, since the only major side effects of Provenge are chills, fatigue, fever, and back pain (occurring in greater than 20% of patients).  From this perspective, a placebo control is more realistic from a patient quality of life perspective than a debilitating chemotherapy.

            But why don’t our dendritic cells do this for us already?  The answer is because of immune dysfunction and immune evasion in cancer.  Directly related to the function of Provenge is the abnormal differentiation of dendritic cells as a result of tumor-derived factors in the bone marrow[6].  A general lack of mature dendritic cells is compounded by major histocompatibility complex class I presentation of tumor antigen by immature dendritic cells and myeloid cells in the absence of stimulating cytokines, resulting in T-cell tolerization.  Furthermore, even when CD8+ T-cells are activated by primed dendritic cells, as with Provenge, the local tumor environment can provide sufficient suppressive signal to neutralize the cells by preventing degranulation and the release of interferon and granzyme[7].  This is likely the reason that the median enhancement of survival provided by Provenge is not greater than it is.  So there is room for improvement of this newly approved therapy.  One potential approach would be a co-treatment with recombinant cytokines enhancing the activation and proliferation of the cytotoxic T lymphocytes, for example, engineered IL-2[8].  For now, Dendreon will have its hands full trying to roll out Provenge on a larger scale and getting it approved in other countries.

It’s been a pretty long journey for Dendreon and Provenge; the company was originally founded in 1992 by Sam Strober and Ed Engelmann out of Stanford as Activated Cell Therapy.  In 1995, Chris Henney took over as CEO, renamed the company and moved it to Seattle, WA.  The company went public (NASDAQ: DNDN) in 2000 with a $45 million IPO, not exactly a mountain of money for a company that estimates it spent upwards of $1 billion in the research and development of Provenge.  The good news is that at the price of a full treatment and with current manufacturing capability, revenues should approach $200 million in the first year and are projected to reach $2 billion per year once additional facilities come online[9].

Dendreon’s pipeline contains similar therapeutic vaccine products targeting different antigens associated with other tumor types, specifically lung and colon cancers with the carcinoembryonic antigen and breast and ovarian cancers with the Her2/neu antigen.  Other therapeutic cancer vaccine developers like Antigenics (Lexington, MA) and Oncothyreon (Seattle, WA) can be more optimistic and hope that Provenge has opened the floodgates for their own vaccines that target other antigens.  Now that Provenge is approved, we should hope for more successful clinical outcomes so that a positive precedence will be maintained for the future approval of other treatments in this class.

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[1] Dendreon. http://www.dendreon.com

[3] Richwine L.  UPDATE 3 – US FDA OKs Dendreon’s prostate cancer vaccine.  http://www.reuters.com/article/idUSN2919838820100429

[4] US Patents 7560104, 7414108, and 5976546.  http://www.uspto.gov

[5] Higano CS, Schellhammer PF, Small EJ, et al.  Integrated Data From 2 Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trials of Active Cellular Immunotherapy With Sipuleucel-T in Advanced Prostate Cancer.  Cancer (2009)  3670-3679

[6] Gabrilovich D.  Mechanisms and functional significance of tumour-induced dendritic-cell defects.  Nat. Rev. Immunol. (2004) 4:941-952

[7] Anderson MJ, Shafer-Weaver K, Greenberg NM, Hurwitz AA.  Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer.  J Immunol. (2007) 178:1268-76

[8] Rao BM, Driver I, Lauffenburger DA, Wittrup KD.  Interleukin 2 (IL-2) Variants Engineered for Increased IL-2 Receptor α-Subunit Affinity Exhibit Increased Potency Arising from a Cell Surface Ligand Reservoir Effect.  Molecular Phramacology (2004) 66:864-869

[9] Timmerman L.  Dendreon Sets Provenge Price at $93,000, Says Only 2,000 People Will Get it in First Year.  Xconomy – Seattle (4/19/2010)

 

Christopher M. Pirie, PhD

About

Scientist & Co-founder, Manus Biosynthesis";s:15:"profile_teambio";s:432:"Dr. Pirie is a scientist and co-founder at Cambridge, MA based Manus Biosynthesis. Chris earned his PhD in Biological Engineering from MIT in 2011 where his thesis research was focused on therapeutic protein engineering and he was a recipient of the NSF Graduate Research Fellowship. Also while at MIT he served on the Institute Committee on Intellectual Property and served as a writer and editor for the Entrepreneurship Review.";s:11:"profile_bio";s:1019:"He received his Bachelors degree, cum laude with college honors, in Bioengineering from the University of Washington where he studied intracellular drug delivery. In addition to his academic research he has served as a student representative to the Institute Committee on Intellectual Property where he helps guide MIT policy on important IP issues like open source publishing and patent reform. While at Washington he served on the Bioengineering Curriculum Committee pushing for improved course work in molecular transport and mathematical modeling. Born in the San Francisco Bay Area, he grew up in Seattle and now lives in Cambridge. As a life sciences editor and writer for MITER he sources primarily research focused articles with tangential, intellectual excursions into ideas on venture capital and technology translation. Chris enjoys sailing the Charles River, reading classic literature and astrophysics books, traveling to places other people only read about, and BASE jumping off the Green Building.