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.



As for treating other cancers, some, including most pancreatic and colon cancers, remain difficult to treat with a personalized vaccine because of their biochemical profile. Drugs used in targeted gene therapy operate by inhibiting one or more cellular processes. But pancreatic and colon cancers are almost always associated with a KRAS gene mutation. The KRAS oncogene activates the PI3K enzyme pathway (involved in cell growth, proliferation and survival) and the MEK/MAPK pathway (a process that governs the way growth factors bind to the cell surface). In the KRAS mutation the oncogene is effectively always turned on, making it impossible to alter cellular processes it activates.



"In general, cancers like pancreatic cancer that almost always have a KRAS gene mutation have been quite refractory. That would of course change overnight if there were a promising way to molecularly target KRAS abnormalities," says Daniel Haber, director of the MGH-East Cancer Center.



For patients who respond well to these vaccines, however, cancer could become manageable, even if it's not curable, Haber says.



To be considered as a candidate for immune treatment, cancer patients must first undergo a successful course of targeted chemotherapy. This means that only patients who have responded to conventional treatment are eligible. Patients in clinical remission—whose tumors have disappeared or are significantly reduced in size—are given a course of immune treatment after a six-month rest period following chemotherapy. In the most successful of the Phase III lymphoma clinical trials, the course of treatment consisted of seven immunizations given over 24 weeks.



Although a standardized treatment protocol has not yet been developed—and it will probably vary according to the type of cancer involved—managing patients who respond to the vaccine promises more hope than does treatment with gene-targeted chemotherapy alone. It's the next bridge on the path to a cure. Theoretically, patients who have responded to one course of autologous vaccination could respond very well to a booster vaccination, if need be, somewhere down the road, or as planned maintenance therapy to prevent relapse.



Adapting ahead of cancer

Another big challenge looming ahead for personalized cancer immunotherapy is the disease's adaptability. "Cancers evolve in response to therapy," Haber says. "Even promising targeted therapies are limited by the development of drug resistance."



Even novel attacks on cancer can end up as an arms race. Controlling cancer rests on clinicians' ability to monitor changes in their patients. If one treatment becomes disease-resistant, catching it quickly and changing strategy can make all the difference to patient's prognosis.



Nevertheless, trying to develop new therapies based on what treatments will look like in the coming decade is a nearly impossible task, points out Michael Stratton, joint head of the Cancer Genome Project and professor of cancer genetics at the University of London's Institute of Cancer Research, who has been working on developing finely targeted cancer treatments since identifying the BRAF oncogene in 2002.



"Here it is the 10th anniversary of the human genome, and I have PhD students in my lab who say 'I can't understand how an old man like you possibly worked on this stuff before the genome was decoded. Why did you even bother?'" he says. But Stratton is convinced that in a few years time, once the full pattern of the cancer genome is revealed, his next group of students will ask the same question about the present state of research. "These are transformative times," he says. "Some pathways to the answers are clear. Most aren't."

*Correction (6/30/10): This sentence was edited after posting. It originally erroneously stated that the National Cancer Institute sponsored BiovaxID's development and that Genitope Corp., and Favrille, Inc., were involved in the phase III clinical trials.