Biotech Values

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Cancer vaccines' bumpy road
Signals (16 May 2006)



By Jennifer Van Brunt
What used to be a relatively esoteric line of research – immunotherapy for cancer -- has become mainstream. In fact, there are so many companies and institutions involved in various aspects of cancer vaccine research that the Albert B. Sabin Vaccine Institute has organized the Cancer Vaccine Consortium to help accelerate the development and licensure of these immunotherapies. Some biotech firms have been investigating cancer vaccines for decades now, and the lessons they've learned over time inform the burgeoning field as it moves forward.

Researchers have been hard at work on developing means to harness the body's own immune system to fight cancer for decades now. Yet, it's widely believed that not one single cancer vaccine has made it to market.

Strictly speaking, that may be true, since there is no approved vaccine aimed directly at cancerous cells. Yet, if you consider the fact that infection with hepatitis B virus (HBV) can lead to severe liver damage, including liver cancer, then, indeed, a cancer vaccine has been on the market for a long time already. In fact, there are handful of HBV vaccines: The first two FDA-approved recombinant vaccines, which incorporate the virus' surface antigen S, are Merck & Co. Inc.'s Recombivax HB (approved in July 1986) and GlaxoSmithKline plc's Engerix-B (approved in September 1989). On a global basis, a number of other HBV vaccines exist, including ones developed by Savient Pharmaceuticals Inc. and Sanofi Pasteur.

Absolute protection
Meanwhile, an as-yet-experimental vaccine directed at another virus – human papillomavirus (HPV) – is set to make history as the first vaccine approved for treating cervical cancer, the second most common cause of death in women worldwide. And what a vaccine. In large clinical trials, Merck's Gardasil (quadravalent human papillomavirus types 6, 11, 16 and 18) has been shown to prevent 100 percent of cervical pre- and non-invasive cancers associated with HPV types 16 and 18. As it turns out, these two HPV types account for about 70 percent of cervical cancer cases. The large Phase III study followed originally uninfected women who had received the vaccine for two years following enrollment, and compared them with a placebo group. No cases of cancer were found in the vaccine group; 21 cases were found in the placebo.


Selected cancer vaccines in late-stage development Company Vaccine name Type/description Cancer target Developmental status
Antigenics Oncophage Patient-specific vaccine; heat shock protein gp96 and associated peptides isolated from patient's tumor then injected back under skin to elicit cellular immune response Renal cell carcinoma Phase III (trial halted on insufficient data 3/06)
Biomira Theratope Synthetic mimic of sialyl Tn attached to carrier protein KLH Metastatic breast cancer Missed 2 primary endpoints in Phase III trial in women with metastatic breast cancer (6/03): statistically significant benefit in women on hormonal therapy following chemotherapy, but Biomira will not pursue further without partner
CancerVax Canvaxin Non-patient-specific tumor cells (from three irradiated cell lines) Stage III and Stage IV melanoma (post-surgical adjuvant treatment) Product was not able to demonstrate a significant survival benefit over placebo in Phase III trials (4/05; 10/05; 3/06)
Cell Genesys GVAX Non-patient-specific vaccine consisting of two prostate cancer cell lines, genetically engineered to secrete GM-CSF Metastatic, hormone refractory prostate cancer Two Phase III trials underway (GVAX +/- Taxotere and prednisone)
Dendreon Provenge (sipuleucel-T) Patient-specific dendritic cell-based vaccine that targets prostatic acid phosphatase Metastatic, androgen-independent prostate cancer in asymptomatic men Two Phase III trials completed; rolling BLA submission expected to begin 1H:06; Fast Track status granted 11/05


It's almost unheard of for a vaccine (or any drug, even) to be 100 percent effective, but that's what the data from Merck's vast trials indicate. (The overall Phase III program involves over 25,000 people in 33 countries.) But that's not all: Gardasil also contains viral coat proteins from HPV types 6 and 11, which together account for about 90 percent of genital wart cases. According to results presented at the ICAAC meeting in December 2005, Gardasil also proved 100 percent effective in preventing external genital lesions in women. The vaccine has actually been tried in younger individuals, too, including boys and girls as young as 10.

Merck submitted its BLA to the FDA in December 2005, and it's scheduled for review sometime in early June 2006. If anyone thinks it's going to be turned down, they're not talking. Au contraire: Analysts are predicting that Gardasil could become a blockbuster, and the stark statistics back that up. Cervical cancer kills 290,000 women worldwide every year. In the U.S., about 10,000 new cases were diagnosed last year, and 3,700 deaths resulted. Moreover, it's thought that about 20 million men and women in the U.S. are infected with HPV, and about 1 million cases of genital warts occur annually.

The only caveat: Since this vaccine will most probably be approved for use in preventing genital warts and the like, as well, it brings up moral issues for parents as to whether to inoculate pre-adolescent girls and boys for a sexually transmitted virus. (For background reading on the development of Gardasil, see the Signals article, "The Burden Of STDs.")

More good news
Merck may be the first to market with its cervical cancer vaccine, but GSK isn't far behind. The British company has developed its own version of the vaccine, called Cervarix, which differs from Merck's in that it targets HPV types 16 and 18 only. Thus, Cervarix is cancer-specific, and does not target genital warts at all.


In clinical trials, this vaccine, like Merck's, was able to demonstrate 100 percent protection from infection by both HPV types as well as protection from associated precancerous lesions. As well, the vaccine's effects are long-lasting: In a follow-up study published in The Lancet, researchers found that Cervarix was 100 percent effective over 4.5 years against precancerous lesions associated with HPV types 16 and 18. As well, antibodies to HPV types 16 and 18 were found in over 98 percent of the women in this study for up to 4.5 years, indicating a sustained response to the vaccine. This demonstration of Cervarix' long-term protection gives it a potential competitive advantage over Gardasil, where the long-term data aren't yet available.

GSK submitted a marketing application on Cervarix to the European Agency for the Evaluation of Medicinal Products in March 2006 and expects to submit a BLA to the FDA by the end of this year. It's certainly lagging Merck's vaccine through the regulatory maze, but will Cervarix be able to grab market share based on its capacity for long-term protection?

That there are now two candidate vaccines to prevent cervical cancer is extremely exciting news for women everywhere – that each seems to be 100 percent effective in preventing the disease is nothing short of miraculous.

However, these successes have not carried over to any of the vaccines in development to treat (rather than prevent) cancer. As we shall see, the path for these vaccine candidates has been anything but smooth.

Shocker
In fact, it appears that devising an effective cancer vaccine is every bit as tough as developing any other therapy – if not more so. For, in most cases, scientists are creating products intended to stimulate the immune system to attack a resident tumor. That's a tricky business in and of itself, not to mention the fact that, in many patients, the immune system is already weakened by the presence of the disease.

Over the decades, there have been many attempts to create effective cancer vaccines – and many failures. But we're finally at the point where more than a handful of vaccine candidates have progressed through early- and mid-stage clinical trials and now stand poised to score in pivotal trials. (A select group of late-stage candidates are included in the tables in this article.)


Some of them will disappoint even now. And, as Antigenics Inc. learned earlier this year, surprises can come from the least expected places. In fact, in this case, it's not clear what the underlying data actually said.

Antigenics' cancer vaccines (Oncophage and AG-858) are based on heat shock protein technology and are designed to reprogram the immune system to target cancer cells. In particular, it's thought that heat shock proteins (a.k.a. stress proteins) play a role in triggering an immune response by presenting antigens on the surface of diseased cells, which essentially "tag" those cells for destruction. To make a vaccine, Antigenics isolates a heat shock protein (gp96 in the case of Oncophage) and its associated peptides from an individual patient's tumor. When the heat shock protein-peptide complexes are injected back into the patient's skin, they stimulate a cellular immune response that is supposedly powerful enough to kill the cancer cells from which the complexes were derived.

Selected cancer vaccines in late-stage development Company Vaccine name Type/description Cancer target Developmental status
Favrille FavId Patient-specific; recombinant idiotype conjugated to KLH, then combined with GM-CSF Follicular B-cell non-Hodgkin's lymphoma (in treatment-naïve patients and in those who have received Rituxan therapy) Phase III (enrollment completed 1/06); Fast Track status granted 1/06
Genitope MyVax Patient-specific; recombinant idiotype protein conjugated to KLH; GM-CSF added as adjuvant Follicular non-Hodgkin's lymphoma (following chemotherapy) Phase III (enrollment completed; Data Safety Monitoring Board recommended continuation of trial 7/05)
GlaxoSmithKline Cervarix Human papillomavirus types 16 and 18 vaccine, formulated with adjuvant AS04 Cervical cancer MAA submitted 3/06; BLA expected before YE:06
Merck &Co. Gardasil Quadrivalent human papillomavirus types 6, 11, 16 and 18 recombinant vaccine Cervical cancer BLA submitted (12/05); BLA accepted for filing; FDA grants fast track status (2/06)
Therion Biologics PANVAC-VF Two vectors (fowlpox and vaccinia) plus GM-CSF Metastatic pancreatic cancer (in patients in whom chemotherapy is ineffective) Phase III (enrollment completed 2/06)


Oncophage, which has been tested in various cancers, has been tested in Phase III clinical trials for renal cell carcinoma and metastatic melanoma. The results, although they lean in the right direction, are not overwhelmingly positive. In preliminary results from the melanoma trial, for instance, the company reported that median survival improved by more than 50 percent in patients treated with Oncophage as compared to those who received the physician's choice of treatment, but the difference was not statistically significant. Antigenics is now conducting a final analysis of these results.

Preliminary results from the kidney cancer trial, unfortunately, were hard to interpret. As reported in late March, the study did not meet its primary endpoints, but that was because the number of events (defined as recurrence of cancer following surgery or death prior to recurrence) was insufficient for analysis. An independent panel determined that the number of events that occurred was actually quite a bit lower than the number of events reported by the investigators. Apparently some of the patients should have been disqualified from the analysis because surgery had not eliminated all traces of disease, a requirement for enrollment in the trial. The analysis did trend in favor of Oncophage for recurrence-free survival but against it for overall survival – a mixed message that hopefully will become clear once the company finishes a detailed analysis of the results.

Meanwhile, Antigenics has stopped all its late-stage clinical programs, shifted its focus to preclinical and Phase I studies, and restructured to reduce its burn rate. And, we still don't know whether Oncophage works or not.

Try, try again
Sometimes, it takes an advanced clinical trial in a large patient population to identify exactly which of those patients will actually benefit from an experimental therapy. It's an expensive and time-consuming way to go about it, but picking out a subset of patients might actually help the sponsoring company to win regulatory approval for its product the first time around. Or not.


CancerVax Corp., for instance, seemed to have a potential winner with Canvaxin, which it was testing in patients with advanced-stage melanoma. Unfortunately, the product, which is a non-patient-specific vaccine, failed to provide a survival benefit first in patients with Stage IV melanoma and then in patients with less-severe Stage III melanoma.

And Biomira Inc.'s vaccine candidate, Theratope, did not meet either of its endpoints – time to disease progression and overall survival – in a Phase III trial in women with metastatic breast cancer. However, one subset of patients – women taking hormones following chemotherapy – appeared to derive some survival benefit. The company confirmed this finding, which it determined was statistically significant, but decided not to proceed further without a partner.

Has any company developing a cancer vaccine had an easy time of it?

First to market?
If everything goes smoothly from here on, Dendreon Corp. could be the first company to market a therapeutic cancer vaccine. The company's prostate cancer vaccine Provenge, which targets the prostate cancer antigen prostatic acid phosphatase (PAP, found in 95 percent of prostate cancers), is a patient-specific dendritic cell-based immunotherapy that is designed to stimulate a T-cell response. The patient's own dendritic (antigen-presenting) cells are isolated, incubated with the PAP antigen, then administered back to the patient.


The FDA awarded Provenge fast-track status for use in treating asymptomatic men with metastatic, hormone-independent prostate cancer. In Phase III studies, the vaccine did not provide a statistically significant benefit in time to disease progression in the overall intent-to-treat population, but a benefit was seen in the subgroup of patients with Gleason scores of seven and less, i.e., those whose cancers are intermediate- to low-risk. A trial in this subset is still ongoing. However, analyses of several Phase III trials demonstrated that Provenge provided a statistically significant survival benefit in the overall patient population of men with advanced prostate cancer – and that finding will form the basis of the BLA that Dendreon intends to submit this year.

Manufacturing twist
Not every company chooses survival as a primary endpoint, though. Favrille Inc., for instance, has chosen time to disease progression in its pivotal trial. The company has completed patient enrollment in a Phase III clinical trial of its cancer vaccine FavId. This product, a patient-specific immunotherapy, is being tested in patients with follicular B-cell non-Hodgkin's lymphoma (NHL), subsequent to therapy with Rituxan.


This particular vaccine consists of a recombinant protein made from a patient's tumor-specific genes (in this case, antibody genes), linked to the carrier protein KLH and injected with GM-CSF, a general immune stimulator. Interestingly, it's produced in insect cells rather than bacteria or mammalian cells,

According to Daniel Gold, Favrille's founder and CSO, producing patient-specific vaccines this way was a technological hurdle in the past, but the company feels its production method is rapid, reliable and amenable to automation. "We use a recombinant approach to make enough product," he said. "Insect cells are very efficient in making recombinant proteins." There's another advantage, too: Insect cells add different sugar groups to recombinant proteins than mammalian cells do. For a therapeutic protein, this isn't desirable, since the product will be recognized as foreign, but "for a vaccine it's a big advantage," Gold explained, because dendritic cells will readily take it up and process it.

As noted, all the patients in Favrille's Phase III trial received Rituxan prior to vaccine treatment. Of patients diagnosed with NHL, "100 percent will have Rituxan at some point," he said. Thus, it just makes sense to start them off this way. However, "Nobody is cured by Rituxan alone in follicular NHL. There's an extended benefit with the vaccine."

Although the trial is fully enrolled, it will be some time before the results are known. Data for the secondary endpoint, overall response to the combined therapy, will be available in the late summer or early fall, Gold said. "We know about 50 percent of patients will go into some form of remission after Rituxan, We picked response as an endpoint because in the Phase II trial we saw that about 30 percent of the patients had an improvement in response following vaccine treatment."

Off the shelf
While quite a few firms have elected to create personalized vaccines, Cell Genesys Inc. has opted to make off-the-shelf vaccines that can be used by all patients. But it wasn't always that way, for the company started with individualized cancer vaccines. It used to modify a patient's own tumor cells ex vivo with the gene for GM-CSF, lethally irradiating the cells and then injecting them back into the patient. But no more.


The firm's now using an immunotherapy which consists of irradiated whole tumor cells (from two cell lines) together with a human antibody (from Medarex Inc. and Bristol-Myers Squibb Co.) that stimulates the immune system to treat patients with hormone refractory metastatic prostate cancer. The two Phase III trials are still enrolling patients The trials are designed to show that treatment with GVAX plus the antibody provides a survival benefit.

According to Stephen Sherwin, chairman and CEO, "we initially tested both patient-specific and non-patient specific vaccines in parallel. Then last year we decided to focus only on cell-line-based vaccines." And the prostate cancer vaccine candidate was the first non-patient-specific program that the company focused on. "We did about five different Phase II trials in a total of 200 patients," Sherwin said. And two of those, in men with advanced prostate cancer that is hormone refractory and metastatic, "provide support for the Phase IIIs," he added. The hope in the Phase III trials is to show that the GVAX vaccine "can improve on Taxotere's [survival] benefit."

With help from my friends
There's another company that's been doing clinical trials on cancer vaccines about as long as Cell Genesys – Therion Biologics Corp. of Cambridge, MA. Surprisingly, this firm has been able to protect its private status from 1991, and apparently has no aims of going public. Still, even with what many say would be limited resources, the firm has been able to conduct an incredible number of clinical trials with its cancer vaccines. That's because it's had the solid support of the National Cancer Institute (NCI), which has been very instrumental conducting these trials. Over 13 years, the company has conducted more than 30 clinical trials with about 1,000 patients, mainly through its relationship with the NCI.


Therion has now completed enrollment of patents in a Phase III trial in metastatic pancreatic cancer. The patients have already failed treatment with gemcitabine, so this is a second-line therapy. The company uses a prime-boost regimen (PANVAC-VF), which means that the initial vaccinia--expressing shot, which targets carcinoembryonic antigen (CEA) and mucin-1 (found on over 90 percent of pancreatic tumor cells) -- was followed by a fowlpox dose. The vaccine also incorporates a triad of co-stimulatory molecules (B7.1, ICAM-1 and LFA-3) which are supposed to sustain a targeted immune response against the tumor cells. As well, the firm uses GM-CSF as a general immune system stimulator. The results, based on early-stage trials, indicate that men with pancreatic cancer may derive long-term benefits from these vaccinations which, very importantly, means living longer.

According to Thomas Schuetz, Therion's chief medical officer, "PANVAC-VF is the 6th or 7th generation of cancer vaccines based on CEA. One of the things we learned, and learned more than once, is that a heterologous prime boost regimen works the best… It gives the best immune responses and generates T-cell immunity."

Lessons learned
Since some companies have been trying to create cancer vaccines for decades already, researchers have learned some valuable lessons – but they also realize that they've got a ways to go. "The major thing we're still learning is how to effectively stimulate the immune system against itself," Favrille's Gold said.


Another major point is to treat patients earlier in their disease, if at all possible. For instance, follicular B-cell non-Hodgkin's lymphoma is a slow-growing disease, Gold explained. "It takes many months to mount an immune response, but we have time in this disease." That's in contrast to pancreatic or prostate cancer, for instance, which are much more aggressive and leave relatively little time for the immune system to respond to a vaccine. "We should be using vaccines when a patient's immune system is optimal, as a first-line therapy," Gold said.

Most obviously, perhaps, is the fact that just about every vaccine maker has opted to add GM-CSF to the mix. The first company to hit on this approach to stimulating the immune system was Cell Genesys, of course. Over time, "people began to understand what GM-CSF does in the body," Sherwin explained. "It's one of the most potent stimulators of dendritic cells." And, since dendritic cells are just the ones you want one your team if you're trying to stimulate the immune system, this approach is a natural.

"Today, the question is why you would not use GM-CSF," added Therion's Schuetz.

"The whole concept of stimulating the immune system has been around for a long time," Sherwin said, but "there have been more failures than successes." However, over the last decade or so, "we understand more about the immune response and we've got more insight into what targets are better than others for immune therapy," he added.

"The cancer vaccine field can no longer hide behind the generation of immune responses," said Therion's Schuetz. "We now have to show that the vaccines do more than that." Like prolong survival, perhaps.

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