By Jennifer Van Brunt
In the future, doctors may well view today's cancer treatment protocols as nothing short of barbaric. In modern medicine's war on cancer, the usual approach is to hit the malignant growth hard and fast. The plan is to destroy the cancer with surgery (when possible), massive doses of chemotherapeutic drugs and radiation -- before the patient, too, becomes poisoned. This heavy artillery may, in fact, obliterate the malignancy. Or it may only hold the cancer at bay for a few precious weeks or months or even years. But in the meantime, it does nothing at all to improve the patient's quality of life. In fact, the opposite is often the case.
No wonder, then, that the many presentations centering on clinical advances in biotherapies for cancer got such a rousing reception at this year's annual meeting of the American Society of Clinical Oncology (ASCO) in Los Angeles. For the first time, the clinical evidence points toward a kinder, gentler means to attack cancer. It's becoming clear that biologics can be combined with chemotherapy -- in doses that are not noxious -- for treating cancer, and that the outcome is good for the patient.
"I saw a paradigm shift at the ASCO meeting," explained Alain Schreiber, president and CEO of San Diego-based Vical Inc. "There's a better understanding of the immune system and the biology of tumors."
The new philosophical approach to treating cancer holds that "it's quite all right to keep tumors in check [rather than try to kill them outright with high-dose chemotherapy ] to provide not only a clinical benefit but also a better quality of life for the patient," Schreiber said.
In fact, for many types of tumors, this approach might mean that doctors can prolong the time to recurrence of a tumor for the life of the patient. Thus, many oncologists have come to believe that patients can learn to live with cancer, just as AIDS researchers are now beginning to believe it may be possible to live with that terrible disease, too.
There are dozens of potential cancer vaccines in the clinic at the present time, but only a few have progressed beyond the earliest stages of proof of safety to demonstrate some sort of efficacy. At the far end of the spectrum, Ribi ImmunoChem Research Inc. (NASDAQ:RIBI) of Hamilton, Mont., has applied for marketing approval in Europe and Canada for its Melacine melanoma vaccine. New York-based ImClone Systems Inc. (NASDAQ:IMCL) recently started international Phase III trials with BEC-2, its anti-idiotypic monoclonal antibody product for treating small cell lung cancer. And Vical has initiated two advanced trials for its lead oncology vaccine as well as a host of earlier stage trials for other products under development.
Vical (NASDAQ:VICL) announced in mid-May that it had initiated registration trials (Phase IIIs as well as an expanded Phase II trial) of Allovectin-7, its most advanced product candidate, for treating metastatic melanoma. At the same time, the company also started Phase II trials of its second cancer vaccine, Leuvectin, for metastatic renal cell carcinoma.
In early June, Vical, of San Diego, released data from a Phase I/II clinical trial of Leuvectin for treating prostate cancer. And in early July, the company started a Phase I/II trial on a new DNA vaccine for metastatic melanoma in collaboration with Steven Rosenberg at the National Cancer Institute of the National Institutes of Health in Bethesda, Md. This vaccine contains a gene for the modified melanoma antigen gp100; the initial trial will test whether intramuscular or intradermal administration of the potential vaccine is more effective.
Vical's vaccines rely on its naked DNA technology, which is a gene transfer approach using plasmids. The plasmids, which are DNA segments whose ends are attached together to form a highly stable closed loop, contain the gene encoding the protein of interest as well as short segments of DNA (flanking sequences) that control the rate and location of protein expression. Naked DNA, which is most effective for intramuscular gene delivery, can be used to deliver the gene for essentially any protein or hormone -- a facet that Vical's long-term partner Merck & Co. Inc. has taken to heart. The Whitehouse Station, N.J., company has licensed Vical's technology for many different applications over the last several years. In September 1997, Merck (NYSE:MRK) got rights to use naked DNA technology to deliver genes for several undisclosed growth factors. Prior to that, in 1991, the pharmaceutical giant had taken out a license to use the technology for vaccines for seven infectious diseases: influenza, HIV, herpes simplex virus, hepatitis B and C, human papilloma virus and tuberculosis.
Vical has numerous licensees to its technology, big pharma and biotech companies alike. In fact, the company holds three fundamental U.S. patents: One covers the use of naked DNA for the expression of therapeutic proteins when administered by direct intramuscular injection. Another is specific for the use of naked DNA to develop vaccines. And the third covers the delivery to any tissue of lipid-mediated naked DNA constructs that stimulate an antibody response.
In one of its most recent deals, Vical signed on fellow biotech firm Centocor Inc. in February 1998; the Malvern, Pa., company (NASDAQ:CNTO) intends to use the technology to develop gene-based therapeutic vaccines for treating certain cancers.
Vical's potential vaccine Allovectin-7 consists of the gene for HLA-B7, a human leukocyte antigen marker that plays a key role in strong immune responses, complexed with lipid and suspended in a water-based solution. The product is injected directly into the tumor; the cancer cells take up the product and then express the HLA-B7 surface marker. It's thought that this process alerts the patient's immune system to seek out the tumor cells -- which are now marked as being "non-self," or foreign -- and set about destroying them.
The Phase III trials, which are open-label, will combine Allovectin-7 with standard chemotherapy in patients with unresectable, metastatic melanoma not previously treated with chemotherapy. The expanded Phase II trials, on the other hand, are designed to confirm the efficacy of Allovectin-7 in the defined patient population that benefited the most in earlier Phase IIs -- patients with metastatic, refractory melanoma that has not yet spread to multiple internal organs.
In the expanded Phase II trial, the objective is a clinical partial response or complete response -- with a duration of at least four months -- in at least 15 percent of the evaluable patients. In the Phase III trial, the objective is a greater relative clinical benefit for the patients taking drug than for those receiving chemotherapy only. Endpoints include either an improvement of at least two months in the median time to disease progression with no decrease in the rate of objective clinical responses or an improvement of at least 15 percent in the rate of objective clinical responses with no decrease in the median time to disease progression. The goal of the therapy, then, is not so much to cure the cancer per se, but to slow its progression and improve the quality of life for the patient.
Leuvectin is also a lipid-DNA complex; the active ingredient is the gene for interleukin-2, a protein that is known to stimulate the immune system. Once again, the putative vaccine is injected directly into the tumor, whose cells take up the DNA and subsequently express the protein. This is thought to stimulate the patient's immune system to attack and destroy the tumor cells.
Vical and its various academic collaborators have proved that the technology can bring the gene to the cell and that it stays there long enough to stimulate an immune response, Schreiber explained. "We clearly saw from the first trials on that this goal was being achieved," he explained. But interestingly, the immune response doesn't necessarily correlate with the clinical response. "The best immune response we saw was in colorectal cancer, but there was no tumor shrinkage," he said.
"Is the product only going to work in the types of tumors that are the current focus of our clinical trials?" Schreiber pondered. Perhaps the company has just been lucky in its choices -- metastatic melanoma, head and neck cancer, kidney cancer and B-cell lymphoma. "We know, then, that an immune response is necessary" but it might not be sufficient. "We do know that the triggered immune response is antigen- and tumor-type specific, but we don't completely understand the other factors that are necessary [for a clinical response]," he said. But in the end "what matters is that the treatment provides a clinical benefit to the patient."