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Why is treating cancer so complex?

Author: Laurie Wertich

“The way I see it is that I became sick at the right time," explains Dick Rogers. The 68-year-old chief financial officer from Methuen, Massachusetts, was diagnosed with an aggressive form of multiple myeloma in 2010 and has since undergone several different types of treatment. Today he’s in remission, and he attributes his current state of health to the ever-evolving advances in cancer treatment.

“I’m one of the fortunate people around—one of the survivors,” Dick explains. But his remission didn’t come easily. In fact, it was the result of a complex series of treatments that Dick humbly refers to as a “difficult process.” The process has involved about nine months of chemotherapy, an autologous stem cell transplant that kept him in the hospital for more than a month, and finally a clinical trial that’s evaluating an immunotherapy agent used after stem cell transplantation in multiple myeloma. Dick’s treatment experience exemplifies the reality of treating cancer today: it’s complicated.

Cancer is complex

So, why is treating cancer so complex? The short answer is because cancer itself is complex. David Avigan, MD, director of the Hematological Malignancy and Bone Marrow Transplant Program at Beth Israel Deaconess Medical Center Dana-Farber/Harvard Cancer Center, explains that there are multiple pathways involved in cancer. In other words there are several things that can go wrong in order for cells to become malignant and develop into cancer. The process varies from cancer to cancer and from individual to individual. As a result, the treatment must vary as well.

The evolution of cancer treatment

To understand the complexities of cancer treatment, it helps to understand how treatment has evolved in recent years. “The standard way that we’ve approached treating cancer until now has been about using chemotherapy drugs that will attack rapidly dividing cells,” explains Dr. Avigan. “That process is not terribly selective because it affects all rapidly dividing cells and causes some serious collateral damage in the process, such as hair loss and mouth sores and others.”

This approach has its drawbacks— namely side effects, lack of selectivity, and tumor resistance to chemotherapy drugs over time. These drawbacks have led to the development of targeted therapies, which attack specific tumor cells. “We started asking, ‘What are the critical pathways?’ ‘What goes wrong when a cell becomes malignant?’” Dr. Avigan explains. “This led to the idea of targeted therapies and trying to personalize treatment. Individual tumors may have unique qualities. If we understand that, we can be more thoughtful and directed with therapy.”

Targeted therapy has revolutionized cancer treatment, but it is not without problems. “The problem with this approach is that there is a lot of redundancy in the ways that tumors develop—meaning it’s not usually just one thing that goes wrong,” Dr. Avigan says. In other words the targeted approach may address one pathway but miss five others.

Striking a balance

According to Dr. Avigan, to be successful a cancer treatment needs to be broad enough to treat cancer from several different angles yet specific enough to target it. The attempt to strike that balance is what can make cancer treatment so complex— but that hasn’t stopped Dr. Avigan and his colleagues from trying.

Dr. Avigan specializes in tumor immunotherapy and its incorporation into bone marrow transplantation. In an effort to give myeloma patients a more powerful weapon against cancer, Dr. Avigan and his team have begun a clinical trial, funded by the Gateway for Cancer Research, that includes an antibody and a custom vaccine that they hope will amplify the body’s cancer-fighting immune response. The two-part trial will involve multiplemyeloma patients who’ve undergone a stem cell transplant.

Participants in the first cohort will receive an antibody to observe its effect on the programmed death-1 (PD-1) pathway. Cancer uses the pathway to inhibit the body’s helpful T-cell functions to avoid immune overactivity against cancer. Tumors typically take over the pathway to create a suppressive response to them. The goal is for the antibody, a myeloma drug designed to block the body’s PD-1 pathway, to help create a stronger, more durable immune response.

The second cohort about to begin will use the antibody along with a personalized vaccine to teach the immune system to recognize the myeloma as foreign, attack the cancer cells, and improve its work against cancer. The personalized vaccine will be created by taking cells from patients’ myeloma and inserting the cancer protein into their dendritic joint cells, the immune- stimulating cells. Whole myeloma cells will be used to generate dendritic cells with myeloma protein to create vaccines that will simultaneously target both individual and multiple cells, making it more effective.

The clinical trial is a prime example of a complex—and potentially invaluable— cancer treatment. “We wanted to design a vaccine that would stimulate an immune response against cancer cells but not healthy tissue,” Dr. Avigan says. “We wanted it to be broad enough to attack cancer and targeted enough to not affect the rest of the body.”

Dr. Avigan explains that the immunotherapy treatment is a nuanced process. They want to teach the immune system to see and attack cancer cells but leave other cells alone. The trick is to target multiple pathways. If they are too successful at blocking the PD-1 pathway, they run the risk of creating autoimmune disease—so it’s a matter of finding just the right balance.

The trial is unique in several important ways: It is novel in the idea of using a cancer vaccine to educate and use a patient’s immune system to recognize and attack cancer cells; it is a patient-specific vaccine that uses the entire myeloma cell and captures all the unique features of an individual’s tumor; and it combines a specific vaccine from a patient with the antibody pathway.

Early results of the study are promising. Patients are experiencing only minimal side effects and no autoimmune response. Researchers are also seeing a good immune response and good T-cell recognition in patients, even in those who have undergone a lot of treatment before participating in the trial. Patients are also converting to full response from a partial response. Dr. Avigan hopes that they are able to keep patients’ disease at a low level longer and that patients feel well enough to work and live life. “The hope is that we can teach patients’ immune systems to recognize cancer as foreign and use the vaccine to target the leftover disease and cure it by targeting it,” he says.

He is grateful to the Gateway for Cancer Research for helping make the clinical trial possible. “Efforts at developing targeted therapies for patients involve a tremendous amount of research and preclinical work,” he says. “Trials are possible only with funding. Gateway has helped a lot in terms of resources and has played a critical role in helping bring the trial forward.”

“The bottom line is that science and medicine are incremental, but that’s okay and you get where you need to go,” Dr. Avigan continues. “The treatment of multiple myeloma is a perfect example of this process: chemotherapy is too broad; highdose therapy and transplantation create a donor immune response; and targeted agents have increased options and helped prolong survival. Now we’re attempting to incorporate an immune-based strategy that can target residual disease.

“I don’t know that we have exactly the right answer, but there is a community of people trying to ask the right questions,” Dr. Avigan concludes. “The general idea of combining modalities and trying to target and use the immune system is a powerful lever to create effective and somewhat broad—but at the same time selective—treatment. That combination has a lot of promise.”

Complexity is not a barrier

As cancer treatment evolves and becomes more nuanced, patients like Dick reap the benefits. The clinical trial he is currently participating in is rather a bonus package for him. “I’m happy to participate, and I’m hopeful about the results of the clinical trial,” he says. “Hopefully, it will benefit me—and if not me, then it will benefit someone else in the future.”

Dick says the clinical trial is much easier than his previous treatment regimen, but it was all worth it. “You have to have a goal,” he insists. “My goal is to dance with my two granddaughters at their weddings. That is the reason I went through it. Now I’m in remission, and I feel ecstatic about it.”

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