Pioneers in Immunotherapy



More than three decades ago, Jack Bellevue’s surgeon advised him to go home and get his affairs in order. The physician had excised a melanoma skin cancer from Bellevue’s back and removed 12 lymph nodes under his right arm that indicated the cancer had spread. The diagnosis was metastatic melanoma.

The survival statistics weren’t good. The oncologist didn’t hold out hope that additional treatment could prolong Bellevue’s life past six months. As he does when he tackles any problem, the successful Prudential insurance salesman and member of the Million Dollar Round Table set to work researching. He and Mary Ann, who is now his wife—he wouldn’t ask her to marry him until four years into their relationship when he felt certain he’d defeated his cancer—hit the library at Stanford University School of Medicine near their home.

They learned of Donald L. Morton, MD, and his pioneering work in immunotherapies and vaccines at the John Wayne Cancer Institute—now Saint John’s Cancer Institute—that Dr. Morton cofounded. It was a wise decision. Bellevue became an early example of the tantalizing possibilities of curing cancer with immunotherapy. “The institute was at the forefront of immunotherapy research in an era when there wasn’t a lot known about the potential of this approach,” says Kim Margolin, MD, medical director of the melanoma program at the institute.

Dr. Morton became an early advocate of immunotherapy research around 1960 while working at the National Cancer Institute. He had been struggling to design a vaccine for melanoma using modified melanoma cells. Vaccines are a type of immunotherapy; they take advantage of the body’s natural ability to recognize and attack harmful substances such as infectious organisms or damaged cells. The problem with cancer cells is that the immune system doesn’t recognize them as harmful to the body. Sometimes they’re crafty enough to hide from the body’s natural immune system. Dr. Morton questioned whether another substance could stimulate the immune system to attack the cancer cells. He proposed giving cancer patients partially-inactivated Bacille Calmette-Guerin (BCG)—a bacterial preparation related to tuberculosis that used to be used as a TB vaccine and is still instilled in the bladder for very early stages of bladder cancer.

Many bacteria contain substances that stimulate important cells of the immune system, and they have been incorporated as part of most cancer vaccines. Dr. Morton suggested BCG therapy. In 1990, Bellevue began BCG therapy which, during clinical trials led by Dr. Morton, consisted of injections in the skin near the major lymph nodes. He received monthly BCG treatments and nine different cancer vaccines and was followed by Dr. Morton for six years.

“We were both very hopeful that it was going to be effective,” says Mary Ann Bellevue. “Jack visualized this therapy as eating up the bad cells—like the Pac-Man game.” Thirty-two years later, Bellevue is 92, semi-retired and living in Santa Barbara. He believes the treatment worked; his melanoma never returned. Bellevue and his wife praise Dr. Morton, who died in 2014, and everyone they came in contact with at Saint John’s. “I’m still alive!” he says, noting that his melanoma has not recurred over the three decades since he received immunotherapy and vaccines.

Did the experimental treatment work for Bellevue? Or was he one of the lucky people who happened to land on the upside of the survival odds? “His original doctor wasn’t wrong about his prognosis—he was quoting a statistic that there was a high risk of the cancer coming back,” Dr. Margolin says, adding that the clinical trial was an important step to take. “Some people do well despite the odds. That’s why it’s so important to support research and offer patients the option of innovative treatments. ”About 10 years after Bellevue received immunotherapy at Saint John’s,

Dr. Morton tested a refined vaccine called Cancer Vax. In the clinical trial, the outcomes were similar for vaccine with BCG and BCG alone. Around the same time, Dr. Morton, a surgical oncologist, was reporting on the sentinel lymph node evaluation procedure he developed that revolutionized surgical treatment of melanoma and breast cancers. With the technique, a blue dye is injected into the site of a patient’s tumor, and the dye travels to the most prominent lymph node, called the sentinel node.

This node is most likely to be affected if the cancer has spread. Research at Saint John’s, published in the New England Journal of Medicine, revealed that removal of excessive tissue or lymph nodes—a tactic that had been routine to try to control cancer spread—didn’t prolong survival. The possibility of avoiding the removal of multiple lymph nodes is a significant benefit to patients, reducing their recovery time, reducing infection and sparing them the risk of future lymphedema (lifelong swelling caused by the removal of lymph nodes).Various forms of immunotherapy are now the standard of care after surgery to treat melanoma and several other cancers, and immunotherapy agents are also used alone, in pairs or with chemotherapy for patients who relapse. “Melanoma is one of the few diseases that can be cured with immunotherapy after it has spread even as far as the brain,” Dr. Margolin says.

The role of immunotherapy in other cancers remains more limited but is advancing rapidly, particularly in lung, colorectal and kidney cancer as well as in some hematologic (blood) malignancies. There are many immunotherapy agents that work via different mechanisms to augment the numbers and functions of immune cells and thus enhance their ability to identify and attack cancer cells. In the mid-2000s, the advent of checkpoint inhibitors—an immunotherapy that prevents cancer cells from evading the immune
response—was an important turning point.

A surge of approvals of other immunotherapy drugs followed, and the varied mechanisms of these agents as well as the diseases in which they showed activity reflected the astonishing advances in the field. Much more research remains to fully understand the power of immunotherapy—even decades after Dr. Morton’s early work. Dr. Margolin sees research efforts heading in many directions, with none yet identified as a single obvious path for all malignancies.

Adoptive cell therapy, where cells taken from the body or tumor are modified and injected back into the patient’s bloodstream, is a complex but highly promising approach, currently available for hematologic malignancies but likely to be perfected soon for solid tumors, she says.

The complexity of cancer and its treatment is pointing researchers more and more toward personalized care, she says—this is defined as selecting the optimal therapy for each individual patient based on factors unique to their tumor and, if possible, unique to their immune response. Stimulating an effective response of the body’s immune system against cancer might depend on a number of factors, including, for example, certain mutations in the DNA of a patient’s cancer cells, inborn genetic characteristics of the T-cells of their immune systems, and the cells and chemical makeup of the microenvironment of a tumor (including which organ the tumor has spread to).

Researchers at Saint John’s Cancer Institute are conducting clinical trials to identify factors that have prognostic value for customized or personalized immune-based cancer therapies. Exceptional laboratory research also continues at the institute, thanks in part to Dr. Morton’s prioneering work decades ago that included the storage of frozen blood samples, tumor and other tissue samples from cancer patients that could be used to study the immune response.

The specimen repository, one of the oldest and largest melanoma tissue banks in the United States, links directly to patient records and outcomes that can be correlated with their tissue samples. It’s possible today for researchers to thaw and study decades-old samples. Dr. Margolin and others collaborate with laboratory investigators to discover what they can learn from melanoma tissue specimens to enable them to select the most effective therapies. Additional research on immunotherapy at Saint John’s Cancer Institute takes place at the Rosalie and Harold Rae Brown Immunotherapy Cancer Research Laboratory under the direction of Maria Ascierto, PhD. Saint John’s Cancer Institute has remained steadfast in the belief that translational science that links investigational therapy with laboratory science, while sometimes discouraging, is the basis for extraordinary scientific discoveries and clinical advances. However, there is more work to be done before doctors will be able to predict when and how cancer will occur, recur, be treated or be cured. “Everything we know about cancer is statistical—the likelihood that cancer will recur or that a specific treatment will be effective is a probability,”

Dr. Margolin explains. Research today, she says, focuses on methods to more precisely match individuals and groups of patients to effective therapies. That brings the story full circle to patients like Jack Bellevue who have beat the statistical odds, living cancer-free and without long-term toxicities from treatment. Dr. Margolin suggests that studies to determine the characteristics of long-term survivors could provide an understanding of how individual patient and tumor factors plus characteristics of therapies would enable doctors to match patients with effective treatments. That’s personalized cancer immunotherapy, and it’s here to stay.