Engine of Hope

From Turning Point 2018

By Robert Levy

Elizabeth Mittendorf, MD, PhD, vividly recalls her thoughts as she examined a woman with breast cancer at Walter Reed National Military Medical Center in 2002. The patient had been treated for breast cancer 15 years earlier, but now the disease had returned in her chest wall.

"I wondered why her immune system let her down," says Dr. Mittendorf, a breast cancer surgeon who now directs the Breast Immuno-Oncology Program at the Susan F. Smith Center for Women's Cancers. Her curiosity spoke to an interest in immunology that would eventually spark an unorthodox turn in her career as a surgical oncologist.

The notion that cancer is more than a matter of faulty genes propelling chaotic cell growth – that it also requires complicity or inadequacy on the part of the immune system – was not scientifically fashionable at the time. Only in the past few years have doctors learned to offer therapies that help the immune system foil cancer.

The most established of these agents are immune checkpoint inhibitors, which free the immune system to conduct a full-scale offensive on tumors. In clinical trials and standard treatment, the drugs have produced headline-grabbing results – generating remissions in substantial percentages of patients with Hodgkin lymphoma, melanoma, glioblastoma, kidney, lung, or bladder cancers, and a range of other malignancies. In a recent study in patients with metastatic triple-negative breast cancer, chemotherapy plus a checkpoint inhibitor was clearly superior to chemotherapy alone. It is likely that this study will lead to an FDA approval for such treatments.

If women's cancers are conspicuously absent from that list, it doesn't mean checkpoint inhibitors have no hope of succeeding against them – only that the results of initial testing of these drugs weren't as impressive for breast and gynecologic cancers as for other types. In fact, researchers say, there's every reason to believe that women's cancers will prove to be as responsive to checkpoint inhibitors as other cancers are.

Doubling Up

In the first trials of checkpoint inhibitors in patients with women's cancers, the drugs were used as single agents. The trials produced remissions in less than 10 percent of patients with breast or ovarian cancer.

Conceding that the initial results were "disappointing," Dr. Mittendorf explains that they weren't entirely surprising. Checkpoint inhibitors work by unleashing immune system T cells to attack cancer. "Because breast tumors generally aren't infiltrated by many T cells to begin with, the T-cell attack is likely to be rather meager," she observes.

Tumors that are only sparsely invaded by T cells are said to be immunologically "cold." Research at Dana-Farber focuses on making such tumors "hot," teeming with T cells.

That can be accomplished with drugs or radiation that ravage cancer cells' DNA and create mutations and other abnormalities in key genes. The genetic wreckage causes tumor cells to sprout distinctive new proteins called neoantigens on their surface, attracting the notice of the immune system and sending swarms of T cells into the tumor.

With that in mind, clinician-scientists are leading an array of clinical trials in breast and gynecologic cancers in which checkpoint inhibitors are combined with other therapies capable of making tumors "hot."

In breast as well as gynecologic cancers, the trials encompass a range of subtypes, an array of clinical circumstances, and a variety of drug combinations. In women with ER-positive breast cancer, researchers are testing checkpoint inhibitors in tandem with chemotherapy, radiation, and targeted therapies. They're also investigating whether combinations are useful prior to breast cancer surgery. And they're leading trials of immunotherapy plus other agents for women with HER2-positive or triple-negative breast cancer.

With these and other trials as a foundation, researchers are working to identify patients who are likely to respond to specific combinations. By analyzing blood and tumor tissue from study participants – those who respond to treatment as well as those who do not – "we're working to tease out which patients are likely to benefit from immunotherapy, and why," says Sara Tolaney, MD, MPH, associate director of the Susan F. Smith Center. The decision to test a drug duo in a particular group of patients "is informed by the results of preclinical experiments in laboratory cells lines and animal models," she notes.

If checkpoint inhibitors alone didn't perform as well as investigators had hoped, subsequent research has produced some welcome surprises. A study led by Dana-Farber's Shom Goel, MD, PhD, and Jean Zhao, PhD, found that, in mouse models of breast cancer, drugs known as CDK4/6 inhibitors not only stir up the immune response to cancer but are even more lethal to tumor cells when coupled with checkpoint inhibitors. Their finding led to a clinical trial that is now under way at Dana-Farber.

Most of the clinical trials combining checkpoint inhibitors with other therapies are new and in progress. But the early returns are encouraging. In gynecologic cancer, for example, an early-phase trial led by Panos Konstantinopoulos, MD, PhD, director of Translational Research, Gynecologic Oncology, found that a checkpoint inhibitor and a drug known as a PARP inhibitor were more effective together than either drug alone in women with hard-to-treat ovarian cancer.

Several investigators are testing combination therapies – two or even three agents – in patients with ovarian, endometrial, or cervical cancers. A phase II trial directed by Joyce Liu, MD, MPH, director of Clinical Research, Gynecologic Oncology, matches the checkpoint inhibitor nivolumab with bevacizumab, a drug that dries up tumors' access to the blood supply and, in the process, can fire up the immune system. Trials of other pairings and "triplets" are being planned.

Blazing Trails

For patients, participating in a checkpoint inhibitor combination trial involves a move into uncharted territory. Though the therapies have solid track records as single agents, their joint effect is unpredictable.

In enrolling for a trial of the checkpoint inhibitor pembrolizumab and a targeted therapy in 2016, Barbara Bigelow was mindful of the regimen's potential benefits and its possible side effects. A high school psychologist, the North Easton, Mass., resident had been treated for breast cancer in 2002, only to have it recur, with metastasis to her liver, kidney, and lymph nodes, 13 years later. When her cancer shifted from ER-positive to triple-negative – a rare occurrence – her oncologist, Rachel Freedman, MD, MPH, associate clinical director of the Breast Oncology Center at the Susan F. Smith Center, informed her of the trial.

Bigelow's reaction to the dual therapy was dramatic. She developed anemia, mouth sores, rapid weight loss, severe nausea, and high fever. Her health deteriorated to the point where she had to be put on dialysis and placed in a medically-induced coma for ten days. The crisis, produced by an onslaught of immune system activity, subsided in response to large doses of steroids. (Find a full account of her experience on her blog at barbigwire.com).

Recovery involved extensive rehabilitation therapy, but for the past two years, Bigelow has been off treatment, with no evidence of active disease, and says she "feels great." The extreme side effects she encountered are rare, and doctors have a variety of approaches to deal with those that do arise.

Without minimizing the health crisis she experienced, and its impact on her husband and two grown daughters, Bigelow states that she would "do it again because the eventual outcome was great. It's given me all this extra time with my family.

"I was happy to be in the first group to receive this therapy – to be a pioneer" Bigelow says.