TAKING OUT TUMORS WITH THEIR OWN DNA: Genetic research has shown cancers to be nearly as diverse as the individuals they colonize. But new drugs, targeted to specific tumors, are starting to make cancer killing a very personal endeavor. Image: ISTOCKPHOTO/HENRIK5000
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The first discovery of a cancer gene marker—the BRAF oncogene for melanoma and colorectal malignancies—back in 2002 changed the way many researchers thought about cancer treatment. Rather than approach the disease based on what region of the body it stemmed from, scientists began to identify cancers in terms of their genetic signatures. Researchers now recognize more than 200 kinds of cancer—all genetically unique.
And pinpointing a genetic signature, such as EGFR mutations in lung cancer or HER2 mutations in breast cancer, can guide therapy decisions. Narrowing the treatment to a particular tumor cell type makes for a more effective—and less harmful—oncolytic approach. But a new class of cancer therapy is going even further by combining targeted treatments with personalized immune therapy.
The first of these therapies to be approved by the U.S. Food and Drug Administration, Provenge, hit the U.S. market in April, delivering a personalized punch to patients' prostate tumors. Provenge, and other immunologically based treatments under development do not prevent disease the way the HPV (human papillomavirus) vaccine staves off cervical cancer by using a weakened or dead virus. Instead, the vaccines use killed autologous tumor cells from the patient to activate the immune system.
Treating cancer immunologically is a "truly personalized therapy," says Larry Kwak, a professor and chair of the Department of Lymphoma/Myeloma at the University of Texas M. D. Anderson Cancer Center. "Every cancer cell is heterogeneous from a genetic standpoint," Kwak says. "We had about 140,000 patients diagnosed with lymphoma, leukemia or myeloma in America in 2009. We'd require a separate vaccine for each person," he says.
"Even though you have two patients with the same kind of lymphoma, the immunological signature is different. You have to treat each patient's tumor cells individually," he adds.
Arming the immune system
Kwak and his group have developed a vaccine using this individual immunological approach to treat follicular lymphoma, the most common of the nonaggressive non-Hodgkins lymphomas. The drug uses a double-barreled approach, packing cytotoxic agents, along with creation of a strong idiopathic (patient-specific) immune response.
To create the individual vaccine, a receptor protein is extracted from the patient's malignant B cell lymphocytes and purified in large amounts. This idiopathic protein is added to an adjuvant growth factor, keyhole limpet hemocyanin (KLH)—a protein derived from a giant sea mollusk found off the California coast—known to provoke a strong immune response. Added to the mix is a delivery agent, granulocyte-macrophage colony-stimulating factor (GM-CSF), that promotes the production of white blood cells; the vaccinal mix is then injected back into the patient. Because the vaccine causes the body to mount an immune response directed against a unique tumor, the therapy is much more effective than gene-targeted or more general chemotherapy alone.
Results for the first of the drug's Phase III clinical trials showed that in combination with targeted therapy, median time to relapse for patients receiving the vaccine was 44.2 months, whereas those who received the placebo went an average of 30.6 months before relapse. At least one patient has been in remission for more than a decade. The vaccine, called BiovaxID, is undergoing further phase III clinical trials, sponsored by Biovest International, Inc.*
Other personalized cancer vaccines are in the research pipeline, including a melanoma vaccine being developed at Massachusetts General Hospital (MGH) as well as a bladder cancer vaccine.
Picking the right patients
Despite the successes of these tailored immunological attacks on follicular lymphoma, not every lymphoma patient is likely to be a good match for the treatment. The method falls down in the presence of proliferative disease or a malignancy that has not already responded to chemotherapy.
"Minimal disease state is key," Kwak says. "We don't have success giving the vaccine against well-established tumors." Big tumors, or several tumors dispersed throughout the body, present an overcapacity problem. The body can only create a finite number of antibody-producing white blood cells in a given time period. The more tumor cells there are—and the more rapidly they're dividing and proliferating—the more antibodies are needed. And the immune system cannot always keep pace.
Because the individually tailored vaccine method is so different from mass-manufactured vaccines—those developed to combat infectious diseases such as smallpox—the search continues for a viable production model. Although some companies can manufacture the customized vaccines, getting volumes up to an efficient level has been a challenge so far.