Just a shot in the dark?

Cancer vaccines slow to catch on

Kimberely Sirk
The bane of childhood—the recurring trek to a doctor'soffice to receive vaccinations—is now looked to as a promising approach topreventing and treating certain types of cancers. In fact, one of thosechildhood immunizations—the "hep b" vaccine given shortly after birth—hasprovided protection against liver cancer since 1981.
 
 
Cancer vaccines are medicines that fall under the categoryof biological response modifiers, which work by stimulating or restoring theimmune system's ability to fight invaders that make the body fall ill. Themedicines fall under two broad headings: prophylactic or preventive vaccines,and therapeutic or treatment vaccines.
 
Two types of cancer preventive vaccines are available in theUnited States, and two cancer treatment vaccines are in limited use. Othertreatment vaccines are being studied in labs across the nation.
 
 
A shot of preventionis worth a pound of cure
 
 
Currently, only vaccines to prevent the sexually transmittedhuman papillomavirus (HPV) and hepatitis B (HBV) are approved for use. The HPVvaccines Gardasil (Merck) or Cervarix (GlaxoSmithKline) are used to preventonly specific strains of the virus; those strains are thought to be responsiblefor the majority of cervical cancers. Gardasil also offers protection againsttwo additional types of HPV—those that are implicated in 90 percent of cases ofgenital warts in both men and women, but do not cause cervical cancer. Cervarixoffers protection against the two strains that indicate future cervical cancer,but the drug has shown additional promise in preventing infection from otherstrains.
 
Although the primary indication is to prevent cervicalcancer, recent recommendations suggest that better overall prevention could beachieved if young males also receive the HPV vaccine. The Gardasil vaccine isapproved for these indications in females and males ages nine to 26. Cervarixis approved for use in females ages nine to 25. The vaccines also offer someprotection against other types of genitourinary cancers.
HBV, or what's known as the "hep b" vaccine, works bypreventing chronic hepatitis infections that can lead to liver cancer.
 
 
Attacking cancerswith a needle
 
 
Provenge is an autologous, or patient-specific, vaccine thatis used to treat metastatic prostate cancer. That drug was approved by the U.S.Food and Drug Administration (FDA) in April 2010, and is manufactured byDendreon Corp. It was the first FDA-approved vaccine specifically designed totreat cancer. According to company officials, the vaccine became available inMay 2010; company officials would not share the number of patients who havebeen treated with the drug, which is delivered by infusion.
 
 
A drug of great promise on the horizon is BiovaxID,Biovest's late-stage personalized cancer vaccine for the treatment ofnon-Hodgkin's lymphoma. If approved, BiovaxID would represent the firstnon-immunosuppressive consolidation therapy option for patients with follicularlymphoma. Biovest has on its medical board Dr. Larry Kwak of the University ofTexas MD Anderson Cancer Center, who was recognized by Time Magazine as a 2010 Person of the Year for his decade of workin the area of cancer vaccines. Kwak was unavailable for comment for thisstory.
 
What makes theseshots different? 
 
Think of the traditional influenza vaccines that arewell-publicized each year. The strategy in creating these vaccinations is forscientists to make an educated guess on which strains of the flu will be mostprevalent in a coming season. Then, factories must create enormous quantitiesof this standard formula, and distribute millions of doses of the vaccine priorto the start of the annual flu season. These vaccines contain killed orweakened versions of the annual suspect microbe, or microbes, that areimplicated for that particular year. The body's immune system, whenencountering these microbes, mounts a defense against them, and then"remembers" that particular invader to offer the body protection should thatmicrobe be encountered in the future.
 
Cancer preventive vaccines target infectious elements thatcause or contribute to the development of cancer. Both cancer preventivevaccines and traditional vaccines are based on antigens that are carried byinfectious agents and that are easy for the immune system to see as not normal.
 
 
White blood cells, or leukocytes, orchestrate immuneresponses, and are mainly responsible for circulatory system invaders. Othertypes of leukocytes, known as lymphocytes, provide targeted protection againstspecific threats, whether from a specific microbe or a diseased or abnormalcell. The most important groups of lymphocytes are B cells and cytotoxic Tcells. B cells make antibodies, large proteins that destroy foreign invaders orabnormal cells. Most preventive cancer vaccines stimulate the production ofantibodies that bind to specific microbes and block their function.
 
 
T cells destroy infected or abnormal cells by releasingtoxic chemicals or by causing the dangerous cells to self-destruct.
 
 
Cancer treatment vaccines are designed to work by activatingB cells and T cells and sending them destroy a very specific cancer, doingtheir work by introducing an antigen, which causes a very specific immuneresponse, into the patient. Antigens are also found normally in some cells;those antigens can tell the body that their presence is normal while microbes,which carry antigens that are foreign to the body, can be recognized anddestroyed.
 
 
The complication with antigens that occur in cancer cells isthat they carry both "signatures" of a normal and a malignant cell. Thecancer-associated antigens can then trigger the actions of the B cells and Tcells to attack.
In addition, cancer calls can sometimes mutate to where theantigens that instigate the attack instinct of the killer cells is no longerrecognized. Cancer cells can also be mightier than the T cells that come afterthem.
 
 
Treatment vaccines:All or part of a cure?
 
Cancer treatment vaccines treat cancers that have alreadydeveloped. They are intended to delay or stop cancer cells and tumors fromgrowing, prevent cancer from recurring or kill cancer cells that have not beensuccessfully eliminated by standard cancer therapies.
Producing effective treatment vaccines has proven much moredifficult and challenging than developing cancer preventive vaccines. Toachieve the desired result, cancer treatment vaccines must achieve two goals.First, like traditional vaccines and cancer preventive vaccines, cancertreatment vaccines have to stimulate specific immune responses against thecorrect target. Second, the immune responses must be powerful enough toovercome the barriers that cancer cells use to protect themselves from attackby B cells and killer T cells.
 
 
Dendreon's Provenge is designed to stimulate an immuneresponse to prostatic acid phosphatase, an antigen that is found on mostprostate cancer cells.
 
 
Dr. Candice McCoy, senior medical director at Dendreon, saysin clinical trials, the drug was shown to increase survival by more than fourmonths over a placebo. She adds that the three-year survival rate from Provengeis 31 percent, and with a placebo, the probability of survival in three yearsis 23 percent. 
"Both of those numbers are statistically significant," McCoyadds.
 
 
She continues that Provenge is unique in that it iscustomized to each patient—or what is known as an autologous vaccine.
 
 
"Patients receive three infusions of Provenge," she says."Each dose is created individually for each patient through leukapheresis,where white blood cells are removed from that patient and shipped to one of ourfacilities. They are exposed to an antigen and shipped back to the patient'sdoctor to be administered at two-week intervals, where they are administeredthrough infusion." 

While not able to disclose details about patients, McCoyindicated that Provenge is used across the nation by both urologists andoncologists.
 
Tampa, Fla.-based Biovest is making strides toward apersonalized vaccine for non-Hodgkin's lymphoma, with BiovaxID, but patientswould still need to pair this therapy with traditional chemotherapy forsuccess. 
 
 
Dr. Sattva S. Neelapu works in the same laboratory as Kwakat MD Anderson, and is familiar with the mechanism that BiovaxID uses againstlymphoma.
 
 
"BiovaxID induces both antibody and T cell responses againstthe ideotype (Id), which is the tumor-specific antigen expressed on B celllymphomas such as follicular lymphoma," Neelapu says. "Antibodies induced bythe vaccine can bind to the Id expressed on tumor cells and mediate killing viaother immune cells. T cells induced by the vaccine also recognize Id-derivedpeptides on the tumor and mediate killing by secreting various cytokines andother cytotoxic molecules. Our results suggest that the T cell responses arelikely to be more important than antibody responses for BiovaxID effect."
 
 
The treatment, which is still in Phase III testing, is giventhrough a series of five vaccinations over a six-month period. The companyexpects to apply for approval in the United States, Canada and Europe withinthe next few months.
 
 
Why go after this cancer in particular? Neelapu has somespecific answers: "Follicular lymphoma is historically known to be highlyimmune responsive, and therefore, immunotherapy such as cancer vaccines arelikely to have high chance of success," Neelapu says. "The Id protein isexpressed on the tumor but not in normal tissues. Thus, Id can serve as atumor-specific antigen and an immune response elicited against the Id willtarget the tumor while sparing normal cells."
 
 
Even though this therapy will not cure the cancer in and ofitself, this development is important for testing theories related to potentialfuture success of these vaccines. "Although not curative," Neelapu says,"chemotherapy can induce complete remissions in the majority of patients, andtherefore, follicular lymphoma provides an opportunity to test the hypothesisof whether a cancer vaccine can eradicate minimal residual disease and improveclinical outcome."
 
 
In addition, Bristol-Meyers Squibb Co. recently entered thecancer market with a vaccine to treat advanced metastatic melanoma. The vaccineis known as Yervoy, which received FDA approval.
 
 
The price is … wrong?
 
 
Although Dendreon representatives would not comment on thenumber of patients being treated with Provenge, other published reports suggestthe enormous cost of processing personalized treatments gives doctors andpatients pause.
 
 
Published reports have suggested that the $93,000 price tagfor a course of treatment of Provenge induces sticker shock, and that adoptionof the treatment into wide use has been slow because of it.
 
And any work in the lab is costly and time-consuming, evenif researchers are pursuing a "orphan disease" cure, as in the work of OncoPep,another company, which is as-yet virtual, but associates with the Dana-FaberCancer Center. It is pursuing work toward treating "smoldering myeloma" with acompound it calls PVX-410.
 
 
In addition, as in the case with BiovaxID, patients muststill pair this vaccine with traditional chemotherapy.
 
 
MD Anderson's Neelapu says impressive results in trials holdpromise for treatment vaccines. Developments across this space point to a cleardirection for future research.
 
"I think the positive results from three Phase III vaccinetrials reported recently in three different cancers; the FDA approval ofDendreon vaccine; better understanding of the immune system, in particularimmunosuppressive mechanisms in the tumor microenvironment; and promisingactivity of multiple immune modulators including the FDA approval of ipilimumabhave revived interest in cancer vaccines and suggested that immunotherapy candefinitely improve clinical outcome in a variety of cancers, both hematologicalmalignancies and solid tumors," Neelapu says.
 
 
"We expect to see a lot more cancer vaccine trials in thefuture, particularly combination trials with other immune modulators," Neelapuconcludes. "The combinations are likely to be more effective than single-agenttrials. I think cancer vaccines and other immune modulators are likely to playan increasing role in the fight against cancer."


Kimberely Sirk

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