Traditionally, the war on cancer has been waged from the outside in, with therapies such as surgery, radiation, and drugs entering the body from external sources. For more than 100 years, however, a notion has persisted that the most formidable tool against cancer may come from within: the immune system.
The immune system is the body’s defense against disease, but for decades, science’s attempts to use it against cancer have largely fallen short. Today, however, as researchers begin to understand the intricate thrust-and-parry of the immune system’s relationship with cancer, it has become possible to intervene in a way that gives the immune system the upper hand.
The success of a new generation of immune-based therapies has turned skeptics into believers. Melanoma has been driven into long remissions in many patients with an immunotherapy drug first tested by investigators at Dana-Farber. Many cancers, including lung and kidney cancer, have shown themselves vulnerable to immunotherapy agents in Dana-Farber-led clinical trials, as has Hodgkin lymphoma.
Today at the Susan F. Smith Center for Women’s Cancers at Dana-Farber, investigators are testing the mettle of immunotherapy against breast and gynecologic tumors.
Prime Candidates in Gynecologic Cancers
Many new immunotherapy drugs are based on a key insight made by researchers at Dana-Farber and other institutions: Although immune-system cells often recognize cancer cells as dangerous and target them for destruction, many cancer cells carry proteins that ward off the immune cells’ attack. Drugs known as immune checkpoint inhibitors that blunt these proteins are the new stars of immunotherapy.
There are sound biological reasons for believing that ovarian and other gynecologic cancers will prove susceptible to checkpoint inhibitors. Many such tumors have a high “neoantigen load,” meaning they carry proteins that advertise their cancerous nature to the immune system, which can prepare an attack against them. The right immunotherapy could provide an opening for an attack to succeed.
Like most cancers, ovarian cancer comes in several subtypes. The effectiveness of an immunotherapy agent may depend on which subtype it is used for.
“We’re currently learning how and where immunotherapies work best,” says Ursula Matulonis, MD, interim director of the Susan F. Smith Center and medical director of Gynecologic Oncology. “Many of the clinical trials now underway will help us match immunotherapies to the patients who can most benefit from them.”
Matulonis is leading the North American arm of an international trial of the immunotherapy drug pembrolizumab in women with recurrent ovarian cancer. The trial will help determine whether the drug works best if patients have had few previous treatments or many, and whether it’s more effective against platinum-sensitive or platinum-resistant tumors.
So far, immunotherapies have scored only modest success in small, early-stage trials where they’ve been used as solo treatments for ovarian cancer. As a result, many of the newer trials combine immunotherapies with other types of drugs.
In one study involving patients with ovarian cancer resistant to platinum chemotherapy, investigators are teaming the checkpoint-inhibitor drug nivolumab with bevacizumab, a medication that chokes off tumor blood supply.
“Research suggests that some of the same signaling molecules that attract blood vessels to tumors can also hold back an immune system attack,” says study leader Joyce Liu, MD, MPH, of the Susan F. Smith Center. “Blocking these signals with bevacizumab, while also using a checkpoint inhibitor like nivolumab, may further enhance the immune system’s ability to attack the cancer.”
Panos Konstantinopoulos, MD, PhD, has opened a phase 1 study of the immune checkpoint inhibitor pembrolizumab, niraparib, and a drug that prevents cancer cells from repairing damaged DNA. The combination may spur the formation of more neoantigens, further stimulating an immune response.
Konstantinopoulos is also leading a trial of immunotherapy agents for endometrial cancer. It will be open to patients whose tumor cells have “microsatellite instability” and carry a mutation in the gene POLE. (Microsatellites are short, repeated stretches of DNA. The number of such stretches can be off-kilter, or “unstable,” because of DNA repair problems.) “Both of these conditions can lead to a high neoantigen load, which can render the cancer cells highly visible to the immune system,” Konstantinopoulos says. “Our study will examine whether immune checkpoint inhibitors can be effective in this group of patients.”
Exploring Immunotherapies for Breast Cancer
Immunotherapy is already proving to be a promising approach in breast cancer. “Over the past several years, our view of immunotherapy for breast cancer has evolved,” says Eric Winer, MD, director of Breast Oncology for the Susan F. Smith Center. “Today this appears to be one of the most promising treatment approaches, particularly for patients who have the most aggressive tumors.” Triple-negative breast cancer (which lacks three key growth receptors) is a prime target for immunotherapy because it tends to have a relatively high degree of DNA instability and frequently expresses immune-suppressing proteins. Investigators at the Susan F. Smith Center have helped lead a study of immune checkpoint inhibitors in patients with triple-negative breast cancer.
Ian Krop, MD, PhD, director of Breast Clinical Research at the Susan F. Smith Center, was senior investigator for a study showing that the checkpoint inhibitor atezolizumab could prevent the growth of triple-negative cancers for well over a year in some patients. Winer has led several studies of pembrolizumab, including an ongoing international study that could lead to FDA approval of this drug for triple-negative breast cancer.
While the results from the use of checkpoint inhibitors in triple-negative breast cancer looks encouraging, other investigators are exploring the effectiveness of these agents against hormone-driven breast cancers. This is the most common type of breast cancer, but also the least likely to provoke an attack from the immune system.
“The challenge is to intervene in a way that converts a weak immune response in these tumors into a stronger one,” says Sara Tolaney, MD, MPH, who is leading three soon-to-open clinical trials of this approach for women with hormone-sensitive breast cancer. “That will involve combining immunotherapies with other treatments.”
In one phase 2 trial, women will receive chemotherapy and the immune-checkpoint inhibitor pembrolizumab when first diagnosed. “There’s evidence that chemotherapy can make tumors more susceptible to checkpoint inhibitors by activating the immune system,” says Krop, who is helping run the trial. “This trial will help determine whether the combination is effective in patients.”
A second trial will compare the effect of chemotherapy and pembrolizumab to that of chemotherapy alone in patients with metastatic, hormone-sensitive breast cancer. A third will examine the value of radiation therapy in combination with pembrolizumab in patients with hormone-sensitive breast cancer. The hypothesis here is that radiation leads to cell death, which may stimulate an immune response to the tumor. Still another trial will focus on a tandem of pembrolizumab and T-DM1 (a conjugate drug that fuses chemotherapy with tumor-targeting antibody) in patients whose breast cancer carries the HER2 protein receptor.
Additional immunotherapy projects will be aided by a recent $1 million gift from the Carney Foundation.
Leading Edge of the Wedge
For all the promise of checkpoint inhibitors, they represent just one of many ways the immune system may be mobilized to fight cancer. As Kai Wucherpfennig, MD, PhD, chair of Dana-Farber’s department of Cancer Immunology and Virology, notes, the immune system consists of an array of specialized cells and proteins, many of which have anti-cancer potential.
“There are many ways to enhance the immune system’s work,” he says. “These include vaccines that increase the number or intensity of disease-fighting T cells, engineering T cells to hunt down specific tumor cells, using viruses to attack tumors, and harnessing natural killer cells. Mobilizing the immune system will be a very important part of how we treat cancer in the future.”