PLANT SCIENCE
22 AUGUST 2008 VOL 321 SCIENCE
Using Tobacco to Treat Cancer
Charles J. Arntzen
School of Life Sciences and Arizona Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA. E-mail: charles.arntzen@asu.edu
Plant biotechnology brings us closer to personalized therapies as tobacco plants are genetically reprogrammed to produce a vaccine to treat lymphoma.
Tobacco, which has a gained a reputation as a cause of cancer, may soon earn some praise rather than recrimination after being used by McCormick et al. to manufacture patient-specific vaccines against follicular B cell lymphoma (see the figure) (1).
Follicular lymphomas are a subtype of non-Hodgkin’s lymphoma, the seventh leading cause of cancer-related deaths in the United States (2), and are a malignant disease of the lymphatic system that originates from cells of the immune system (lymphocytes). The administration of a tobacco-derived non- Hodgkin’s lymphoma vaccine (a single-chain segment of an antibody protein) in a human clinical trial resulted in immune responses in more than 70% of the patients. A majority of patients showed a cellular immune response, suggesting that the vaccine specifically directs the immune system to attack cancer cells. The study not only demonstrates the safety and efficacy of the plant-made protein, but represents the first time that such responses have been observed using a subcutaneously administered antibody-based vaccine in the absence of a carrier protein (which typically boosts the immune response and has been used in all previous clinical studies). Bayer AG, a major pharmaceutical company, has acquired the supporting data from the new study, and very recently announced the opening of a production facility that will use tobacco to manufacture biopharmaceuticals, the first of which will be a candidate patient-specific antibody vaccine for non-Hodgkin’s lymphoma therapy.
Although the report of McCormick et al. will undoubtedly be appreciated as an advance in immunotherapy for cancer patients, the results will likely generate even greater excitement in the plant biotechnology community. It has been almost two decades since genetically engineered plants were shown to produce monoclonal antibodies or vaccine ubunits (the latter can be antigens that elicit protective antibodies) (3–5). To date, however, only small biotechnology companies have used plant biotechnology to produce protein pharmaceuticals, such as glucocerebrosidase to treat Gaucher disease, lipase to treat cystic fibrosis, a-interferon, lactoferrin, and others (3). Meanwhile, large pharmaceutical companies have watched from the sidelines.
To understand what technical or economic forces have enticed a major player in the pharmaceutical industry into the use of plant biotechnology, one need only look at the strategy for producing a patient-specific vaccine. In the case of non-Hodgkin’s lymphoma, patients are diagnosed through symptomatology, followed by excision biopsies (from either a tumor mass or lymph node where the tumorous B cells predominate). Biopsy materials are used to characterize the specific type of non-Hodgkin’s lymphoma. Because each B cell bears a unique surface immunoglobulin protein, and because a malignant B cell is of clonal origin, the immunoglobulin becomes a specific marker for the tumor of a specific patient (6). Once the specific gene sequences encoding the individual’s tumor immunoglobulin have been determined, the challenge is to find a way to obtain a portion of this very specific immunoglobulin in sufficient quantity and conformation to use it as a vaccine that will trigger the body to attack the malignant B cells bearing this immunoglobulin (and not normal B cells).
Earlier studies had shown that immunization with a complete immunoglobulin protein (composed of four polypeptides, with regions that specify the class of antibody and specific antigen target) induced the desired immune response (7). From a technical standpoint, however, the time between identification of the immunoglobulin gene sequences in a tumor and manufacture of the corresponding protein is slow (many months) and complex. The time delay, in particular, is a severe hindrance to the use of vaccination as a therapy for non- Hodgkin’s lymphoma patients who are newly diagnosed. Rather than wait for a vaccine, these patients are more likely to start conventional (immunosuppressive) chemotherapy even with its negative side effects and uncertainty of durable remissions.
Speed of manufacture turns out to be the key to plant biotechnology’s contribution to non-Hodgkin’s lymphoma vaccine development. The genomic sequences of many plant viruses are known, and molecular tools are available to quickly insert new genes into a viral genome in such a way that virus replication produces a new nonviral protein as a “by product” to virus replication. As reported by McCormick et al., a fragment of the tumor-specific immunoglobulin protein called the autologous single-chain variable domain was incorporated into a virus that infects tobacco. Because the single-chain variable domain must correspond uniquely to the immunoglobulin found on the surface of a patient’s malignant B cell, a unique virus must be engineered for each patient. Once introduced into a tobacco plant, the engineered virus replicates and spreads rapidly throughout the plant, diverts normal cellular metabolism, and turns on production of the proteins encoded by the viral genome, including the single-chain variable domain gene. Even without optimizing or automating production, patient-specific single-chain variable domain protein fragments could be produced under good manufacturing practice (GMP) regulations within 12 to 16 weeks of receiving biopsy specimens (8). The high-risk arena of pharmaceutical development makes it difficult to predict when (or if) a plant-made non-Hodgkin’s lymphoma vaccine will ultimately be marketed, but the production facility investment commitment by a large and experienced pharmaceutical company suggests probability of success.
Academic scientists who have long promoted the use of plant biotechnology as a tool to attack global public health issues and achieve lower-cost protein drugs will learn a valuable lesson if the non-Hodgkin’s lymphoma vaccine is successful: There is more to moving a pharmaceutical product into practical use than simple “cost of goods” arguments. For example, the speed by which useful proteins can be produced in plant systems (such as in patient-specific vaccine production) is also advantageous to companies that wish to rapidly obtain GMP samples for phase I clinical trials. And the fact that each individual tobacco plant is a manufacturing unit provides an infinitely scalable manufacturing platform, with low capital investment for the protein production component of biomanufacturing.
The value of plant biotechnology to global health should not be forgotten, however. Protein drugs are now widely used in the developed world, but economic barriers make most of these new biotechnology products inaccessible to all but the very wealthiest inhabitants of the developing world. It is likely that another opportunity for plant-made pharmaceuticals will come in the arena of “biosimilars” (new versions of biopharmaceutical products) or “generic” versions of existing protein drugs (the latter is often through reverse engineering, in which an existing product is produced in a redesigned manufacturing process), especially as patents on current drugs expire. Cancer therapeutics offer a major opportunity. For example, the monoclonal antibody Avastin (manufactured by Genentech) used to treat colorectal and lung cancer and approved earlier this year by the U.S. Food and Drug Administration for treating advanced breast cancer, costs $84,700 for an average 11-month course of breast cancer treatment (9). It is conceivable that Avastin and a related monoclonal antibody, Herceptin (also manufactured by Genentech), prescribed for women with breast cancers with high expression of the HER2 receptor, could be manufactured using plant biotechnology with considerable cost advantages. Protein-based therapeutics is still at an early stage, and the involvement of plant biotechnology in their production is at an even earlier stage. But the prospects are exciting.
References and Notes
1. A. A. McCormick et al., Proc. Natl. Acad. Sci. U.S.A. 105, 10131 (2008).
2. L. A. G. Ries et al., SEER Cancer Statistics Review, 1975–2005, National Cancer Institute, Bethesda, MD (http://seer.cancer.gov/csr/1975_2005).
3. J. Kaiser, Science 320, 473 (2008).
4. A. Hiatt, R. Cafferkey, K. Bowdish, Nature 342, 76 (1989) .
5. H. S. Mason, D. M. Lam, C. J. Arntzen, Proc. Natl. Acad. Sci. U.S.A. 89, 11745 (1992).
6. W. L. Carroll et al., J. Exp. Med. 164, 1566 (1986).
7. P. A. Ruffini et al., Curr. Gene Ther. 5, 511 (2005).
8. D. Tus., personal communication based on antigen production by Large Scale Biology Corporation.
9. M. Chase, A. W. Mathews, Wall Street Journal, 23–24 February 2008, p. A3. |
