DrugWatch

Cancer edge towards success

➜ Richard Harrop* and Stuart Naylor*

A number of cancer vaccines are now entering the final stage of clinical development. Are vaccines finally on their way to enjoying mainstream success in the oncology arena?

ver the past decade, vaccina- cines that have such a safety profile such as renal cancer and , tion strategies for the treat- may be readily integrated into current yet they offer only modest benefits and O ment of cancer have been standard-of-care regimens, particularly frequently lead to toxic side-effects. investigated with renewed vigour, per- in the first-line setting where combi- In between these two approaches haps catalysed by a greater under- nation strategies prevail over lie cell-based therapies, in which whole standing of tumour immunology and monotherapies. tumour cells or cell extracts are used as the clinical successes achieved with the immunogen. While tumour-specific and cytokine- TARGETED VS NON-SPECIFIC immune responses may be induced, based therapies. However, before vac- Cancer can broadly the precise target(s) of the response is cines become fully integrated into the be divided into two categories: not usually known. Furthermore, arsenal of weapons currently used to tumour-specific and highly-targeted immune responses against other com- treat cancer, they must show not only products, for example vaccines or mon tissue antigens may also be efficacy but also safety and limited or antibodies that target a specific induced. Despite the lack of fine no toxicity. Recently, a number of tumour antigen, and therapies which specificity of the immune response cancer vaccines have moved into the modulate the immune system in a induced and the labour involved in the stages of development where clinical non-tumour-specific way. An example production of autologous, cell-based benefits and good safety profiles can of the latter is BCG, which has been therapies, a number of products have be determined convincingly. used for many years in the treatment completed Phase II and Phase III tri- Reports from a number of Phase II of bladder cancer and has been als with promising results. and Phase III studies suggest cancer shown to provide superior benefits The explosion in the identifica- vaccines are not only well-tolerated over chemotherapy regimens in tion of tumour-associated antigens but that they are also meeting clinical patients with a high risk of progres- (TAAs) in multiple cancer types endpoints, ranging from significant sion. While the precise mode of which occurred in the 1990s repre- tumour responses to improvements in action of the treatment is not known, sented a critical phase in the ability to median survival time. Results from it is accepted that it has an effect on apply tumour immunology research to such trials build on a significant body the immune system. the development of of Phase I clinical data which suggest Likewise, the cytokines IL-2 strategies. This discovery enabled the that, in general, this class of thera- (interleukin 2) and IFNa (interferon α) development of targeted treatments peutic is safe and that the attributed have found widespread use in the and allayed some of the safety concerns adverse event rate is low. Cancer vac- treatment of different malignancies, over the deleterious autoimmune

First published in issue 145 of Scrip Magazine May 2005. © T&F Informa UK Ltd 2005. Reprinted with permission of PJB Publications *Richard Harrop is director of clinical immunology and Stuart Naylor is vice-president of biological systems at Oxford BioMedica, based in Oxford, UK

28 ■ CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 DrugWatch KAREN KASMAUSKI / CORBIS CONTRASTO KAREN KASMAUSKI A number of studies suggest cancer vaccines are not only well-tolerated but meet clinical endpoints reactions that can result from less enjoyed a renaissance in the treat- (trastuzumab), Mylotarg (gemtuzum- specific approaches. The successful ment of different cancers, and there ab ozogamicin), Zevalin (ibritumomab targeting of specific tumour antigens are currently eight therapeutic anti- tiuxetan), Bexxar (tositumomab), in vivo has been exemplified by the bodies approved by the Food and Erbitux (cetuximab) and Avastin use of monoclonal antibodies. Drug Administration (FDA) for sale (bevacizumab) achieved total sales in Although they failed to live up to their in the US. Campath (alemtuzumab), excess of US$3 billion in 2004. promise in the 1980s, they have since Rituxan (rituximab), Herceptin While the success of monoclonal

CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 ■ 29 DrugWatch

antibody therapies cannot be denied, established convincingly. However, tive of confirming recent findings so other targeted approaches are now clinical responses including tumour that FDA approval of Provenge may waiting in the wings, including vacci- shrinkage, disease stabilisation and be sought. nation. Unlike monoclonal antibodies, improvements in time-to-disease pro- Other immunotherapies have led which are usually delivered as a bolus gression are being reported in con- to positive results in subsets of treat- infusion, a ’s therapeutic trolled trials. And more importantly, ed patients, for example, antibody potential has to be transduced statistically significant increases in responders in Aphton’s Phase II trial through multiple biological steps patient survival have been detected of Insegia in colorectal cancer within each patient before any clinical (see Table). patients, or in multiple, open-label benefit is realised. This offers both For example, in June 2004, Aphton Phase II studies including CancerVax’ advantages and disadvantages over the Corporation of Philadelphia trials of Canvaxin in melanoma. In more direct effects of infused mono- announced the results of a Phase III the latter study, retrospective analyses clonal antibody therapies. On the pos- trial of Insegia, a synthetic peptide, showed treatment with Canvaxin, itive side, a vaccine-based approach: similar to a portion of the hormone which consists of irradiated cancer • Induces a broad polyclonal cellular Gastrin 17, linked to the diphtheria cell lines, significantly improved sur- and humoral immune response toxin. The study compared Insegia vival of patients with stage IV • Leads to a response of potentially with placebo in patients with melanoma. The median overall sur- greater longevity, requiring fewer advanced pancreatic cancer and vival time of 268 patients with the injections demonstrated a statistically signifi- cancer, who received Canvaxin fol- • Does not require ‘humanisation’ of cant increase in patient survival time; lowing the surgical removal of their the immune response, unlike the use 150 days for patients receiving the tumours, was 42.4 months compared of monoclonal antibody therapies, vaccine compared to 83 days for to 14.3 months for 170 historical con- which are usually of murine origin those on placebo. trol patients who did not receive the • Costs less And in February 2005, Seattle- vaccine. However, success is dependent on based Dendreon announced encour- Furthermore, a Phase IIb study of the induction of a potent and ‘appro- aging results for its immunotherapy Canadian firm Biomira’s BLP25 lipo- priate’ immune response in a patient product Provenge – autologous den- some vaccine, a synthetic MUC1 group that may be immuno-compro- dritic cells loaded ex vivo with a peptide encapsulated in a liposome mised. Furthermore, an efficacious recombinant fusion protein consisting delivery system, has shown encourag- response may take a month or more to of the TAA prostatic acid phosphatase ing improvements in overall survival induce. Despite these drawbacks, a linked to GM-CSF (granulocyte/ in non-small-cell diverse array of cancer vaccines has macrophage colony-stimulating fac- (NSCLC) patients – although it did not made the transition from pre-clinical tor). It was reported that treatment quite attain statistical significance – research to clinical development over with Provenge significantly improved and it has been granted fast-track the past 5–10 years. The positive survival in men with asymptomatic, approval by the FDA. results now being observed in the clin- metastatic androgen-independent Another candidate is TroVax, a ic owe much to a greater understand- (hormone-refractory) prostate based on the TAA 5T4 deliv- ing of the immune system, the timing when compared to placebo. ered by the attenuated vaccinia virus, and method used to deliver the thera- According to the final three-year MVA (modified vaccinia Ankara), peutic antigen(s) and the increased intent-to-treat analysis of the ran- under investigation by Oxford sensitivity of monitoring tools. domised Phase III study, patients BioMedica in the UK. receiving Dendreon’s investigational A recent announcement reported THE MAIN CONTENDERS product showed a 4.5-month interim data from two Phase II clini- Given the time and money required improvement in median survival time cal trials in which TroVax was admin- to take a product from pre-clinical and a more than three-fold increase istered in combination with research to pivotal Phase III clinical in survival after 36 months compared chemotherapy to patients with late- trials, only a small number of cancer to patients receiving placebo. This is stage colorectal cancer. vaccines have to date progressed to now being followed up with a second Immune responses specific to the stage at which efficacy can be Phase III , with the objec- antigen 5T4 were observed in 100%

30 ■ CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 DrugWatch

of patients who were suitable for tic is a difficult one. Scientifically, the realistic expectation in patients with analysis. This observation is particu- adjuvant setting, in which disease large tumour burdens or with rapidly larly encouraging given that a retro- burden is minimal, may well repre- growing cancers. spective statistical analysis of data sent the optimal slot to detect clinical Despite the challenges, this is an collated from a Phase I/II study benefits. However, it requires a bold exciting time for the cancer vaccine showed a highly significant correla- decision to commit to this type of investigational arena. Results from tion between the strength of 5T4-spe- study, because large patient numbers some of the Phase III trials, such as cific immune responses and time-to- are required and clinical endpoints studies on Canvaxin, GVAX and disease progression. are protracted. Financially, this trans- PANVAC-VF should be available this The following immunotherapies are lates to trials that are exceptionally year or early 2006. also in late-stage clinical develop- expensive to conduct and that take If the primary objectives are met, ment: Oncophage from Antigenics in many years to yield results, and this is product registration could follow New York, PANVAC-VF from problematic, especially for biotech within a year or two. Therion Biologics in Cambridge, companies. The selection of both Furthermore, important advances Massachusetts, and TG4010 (MVA- indication and setting, whether adju- are being made in the search for sur- MUC1-IL2) from Transgene in vant, first-line or second-line treat- rogate markers and the ability to pre- Strasbourg, France. ment, has to balance the speed in dict whether individual patients are reaching clinical endpoints with the likely to respond to a specific treat- TEMPERED EXPECTATIONS time needed for the immune ment. Such information will help to Cancer vaccine strategies are often at response to become effective in ‘dis- refine the design of clinical trial pro- odds with classical clinical develop- ease management’. tocols and target patients who are ment approaches. For example, they The expectation that vaccines more likely to gain benefit from the are usually trialled in potentially will cure cancer may have to be tem- immunotherapy. Subsequently, it is refractory patient groups in which the pered in certain indications and set- hoped that cancer vaccines will soon ability to galvanise an immune tings. While tumour regressions have become commonplace alongside sur- response may well be compromised. been observed in a number of clinical gery, chemotherapy and radiotherapy And the decision as to where a cancer trials, stabilisation of disease leading for the treatment and management vaccine is best placed as a therapeu- to enhanced survival may be a more of cancer.

SELECTED CANCER VACCINES IN LATE-STAGE CLINICAL DEVELOPMENT

Company Product name Indication Trial stage Trial status Survival benefit Antigenics Oncophage Renal Phase III Part I closed Not yet available Aphton Insegia (G17DT) Pancreatic1 Phase III Completed Increase in overall survival2 Pancreatic Phase III Completed Yes (statistically significant) Colorectal Phase II Completed Increase in overall survival2 Biomira Theratope Breast Phase III Completed None BLP25 NSCLC Phase IIb Completed Yes (but not statistically significant) CancerVax Canvaxin Melanoma Phase III Closed Not yet available3 Cell Genesys GVAX Prostate Phase III Active Not yet available Dendreon Provenge Prostate Phase III Completed Yes (statistically significant) Onyvax Onyvax-P Prostate Phase II Closed Not yet available Oxford BioMedica TroVax Colorectal Phase II Closed Not yet available Renal Phase II Active Not yet available Therion Biologics PANVAC-VF Pancreas Phase III Active Not yet available Transgene TG4010 NSCLC Phase II Active Not yet available

NSCLC – non-small-cell lung cancer 1With/without chemotherapy 2In antibody-positive patients 3Encouraging open-label Phase II studies

CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 ■ 31 DrugWatch

Green is the new black

➜ Edzard Ernst*

It enhances survival in ovarian and prostate cancer patients and protects their hearts against damage from chemotherapy drugs. Could green tea be a new wonder drug?

Japan, 5.5 billion bottles currently, research into the health survived for longer than three years, of green tea were con- aspects of green tea is buoyant. the figure was only 48% for the IN sumed last year. Yet in Studies in test tubes show that the abstainers. The authors of this study Europe, green tea is drunk by few. ingredients of green tea inhibit therefore believe that “increasing the Which is a pity, because it is probably tumour growth and cause the death consumption of green tea ... may the healthiest choice. Like black tea, of cancer cells. In animal experi- enhance epithelial ovarian cancer green tea is made from the leaves of ments, green tea impedes the devel- survival.” Another analysis found the tea plant Camellia sinensis. The opment of chemically induced can- similar effects for sufferers of difference is essentially that, for cers. Some green tea ingredients prostate cancer. black tea, the leaves are fermented, seem to enhance the effect of anti- Antioxidants in green tea are not while for green tea they are not. cancer drugs. Other compounds pro- only important for cancer, they might Green tea therefore contains plenty tect our organs against the damage also play a role in cardiovascular dis- more chemicals called polyphenols. that cancer drugs can have, for ease. Regular green tea consumption These are powerful antioxidants with instance, on the heart. Taken along- normalises lipid metabolism, reduces exotic names, such as catechins, epi- side chemotherapy, green tea could blood pressure, slightly lowers body catechin, catechins gallate and epi- maximise the benefits of such drugs weight, stabilises glucose metabolism gallocatechin gallate. It is these and minimise their risks. in diabetes patients, and might even ingredients that may make green tea These effects may be valuable for neutralise some effects of smoking. good for our health. a range of cancers. Importantly, they Collectively these effects are likely to Years ago, epidemiologists noted are supported not just by one or two amount to a significant protection that cancer rates in populations that investigations, but by dozens of stud- from heart disease, stroke and other consume green tea were lower than ies from around the world. cardiovascular problems. expected. We should not get too But the proof of the pudding is in However, clinical trials are again excited about such findings. For the eating. scarce. A Japanese team observed instance, tea drinkers could also be Do we have data from clinical tri- 203 patients who underwent a coro- avoiding things that cause cancer or als, or is all this based on lab experi- nary angioplasty. Of these, 109 had have a lifestyle that protects them. ments? So far few such studies have coronary artery disease while the rest But encouraging results about green been completed. A rare exception is a had normal coronaries. Patients with tea kept coming in and eventually prospective investigation from China normal coronary arteries consumed formed a compelling body of evi- of 254 women with ovarian cancer. significantly more green tea com- dence. The curiosity snowballed and, While 78% of the green tea drinkers pared to those who had diseased

*Edzard Ernst is professor of complementary medicine at the Peninsula Medical School at the universities of Exeter and Plymouth. © Guardian Newspapers Limited 2005

32 ■ CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 DrugWatch TIZIANA AND GIANNI BALDIZZONE / CORBIS CONTRASTO TIZIANA In a Chinese study, 78% of green tea drinkers, but only 48% of abstainers, were alive at three years coronary arteries. The authors were of green tea, a word of caution. All news is that green tea is delicious and optimistic: “The more green tea these findings are encouraging but, refreshing. The bad news is that to patients consume, the less likely they to be sure, we really need the results match the dose used in the research are to have coronary artery disease.” of clinical trials. These will take a studies, you need to drink up to 12 Before you rush out to buy a car load while to come through. The good cups a day.

CANCER WORLD ■ SEPTEMBER-OCTOBER 2005 ■ 33