Although the cure rate for breast cancer has risen steadily in recent decades, recurrent or metastatic disease remains difficult to control. To fight metastatic breast cancer and forestall the recurrence of high-risk primary disease, researchers at The University of Texas MD Anderson Cancer Center are using various techniques to boost the body’s immune system. Clinical trials of many of these therapies are already under way.
Recent research findings have sparked interest in the role of immunotherapy in breast cancer treatment, said Elizabeth Mittendorf, M.D., Ph.D., an associate professor in the Department of Surgical Oncology. “For a very long time, breast cancers were not thought to be immunogenic,” she said. “But data published in the past 2 years have shown that there are immune cells, including T cells, in breast tumors. This suggests that breast tumors are indeed immunogenic.”
Breakthroughs in immunotherapy against other types of cancer have encouraged research of its use against breast cancer. “The understanding of immunology in cancer is progressing very fast,” said Nuhad Ibrahim, M.D., a professor in the Department of Breast Medical Oncology. Citing the recent successes of immunotherapy drugs and vaccines in melanoma and prostate cancer, Dr. Ibrahim said, “In breast cancer we still have not had those kinds of breakthroughs, but there are definitely leads.”
Those leads have encouraged researchers to explore multiple avenues. “As much as we’ve always been fascinated with pushing the immune system, there has never been enough response to older immunotherapies, like interferon or interleukin-2, to benefit breast cancer patients,” said Debu Tripathy, M.D., a professor in and chair of the Department of Breast Medical Oncology. But with advances in therapeutic vaccines, immune checkpoint inhibitors, and other immunotherapies, he said, “We’ve finally crossed that threshold.”
“The early studies of immunotherapy with vaccines in patients with metastatic breast cancer did not meet their primary objective of improving overall survival, but we learned a lot from these studies,” said Dr. Ibrahim, who in the 1990s—along with James Murray III, M.D., a professor in the Department of Breast Medical Oncology—led a randomized trial of the sialyl-Tn–keyhole limpet hemocyanin (STn-KLH; also called Theratope) vaccine. The STn-KLH vaccine was derived from MUC1, a mucin expressed on the surface of a large proportion of breast cancer cells. The study did not meet its goal of extending progression-free survival for patients with metastatic breast cancer. However, in a post hoc analysis, the vaccine appeared to improve survival outcomes for patients who had previously been treated with tamoxifen.
Dr. Ibrahim, in collaboration with the U.S. National Cancer Institute, recently completed a trial of an anti-MUC1, anti–carcinoembryonic antigen vaccine combined with costimulatory molecules and given with docetaxel. The study’s report is under peer review.
OPT-822 is a carbohydrate vaccine similar in structure to the STn-KLH vaccine. Early studies of OPT-822 demonstrated prolonged overall survival in a subset of patients with metastatic breast cancer, especially when patients received low-dose cyclophosphamide. These findings led to a multicenter trial that recently completed enrollment. Dr. Murray is MD Anderson’s principal investigator for the trial, in which patients with metastatic breast cancer received low-dose cyclophosphamide with the OPT-822 vaccine along with the lipid adjuvant OPT-821 or placebo. The results are currently being analyzed.
Of the breast cancer vaccines, the farthest along is E75 (nelipepimut-S, NeuVax), a peptide vaccine that is derived from human epidermal growth factor receptor 2 (HER2). Dr. Murray led a small phase I clinical trial of E75 combined with granulocyte-macrophage colony-stimulating factor (GMCSF) in patients with metastatic breast or ovarian cancer. Although HER2-specific immune responses were generated in most patients, no antitumor responses were observed, possibly because of the large tumor burden in the population studied.
“A general consensus at MD Anderson is that for vaccines to be successful against breast cancer, they need to be given in patients with low-volume disease, and that means giving them in the adjuvant therapy rather than the metastatic disease setting,” said Dr. Mittendorf, who also served as a principal investigator of early trials of the E75 vaccine.
Dr. Mittendorf is now the principal investigator of two multicenter trials of the E75 vaccine as adjuvant therapy for patients with HER2-positive breast cancer at high risk for recurrence: a phase III trial that has completed enrollment and a phase II trial of the vaccine plus trastuzumab that is currently enrolling patients.
GP2 and AE37
Two other HER2-derived peptide vaccines, GP2 and AE37, are under investigation as adjuvant therapy in an ongoing study that has completed enrollment. The GP2 vaccine—which resulted from research led by George Peoples Jr., M.D., an adjunct professor in the Department of Surgical Oncology—has greater immunogenicity than E75 and binds to both human leukocyte antigen (HLA)-A2 and HLA-A3. AE37 contains more than 10 amino acids, allowing for a broad range of immune stimulation in patients. AE37 was shown in preclinical studies to significantly enhance HER2-specific CD4-positive “helper” T cells.
Patients included in the ongoing adjuvant therapy study had a high risk for recurrence because of lymph node involvement or other factors such as high levels of HER2 expression; however, patients with HER2 immunohistochemistry scores indicating HER2-negative or borderline status were also included in the study. Because the two vaccines bind to different major histocompatibility complex class molecules, patients in the study were sorted according to their HLA status before randomization. Those who were positive for HLA-A2/A3 were randomly assigned to receive GM-CSF with or without GP2; those who were negative for HLA-A2/A3 were randomly assigned to receive GM-CSF with or without AE37.
Dr. Mittendorf presented the primary analyses of the study’s GP2 and AE37 arms in 2014 at the American Society of Clinical Oncology’s Breast Cancer Symposium and its Annual Meeting, respectively. “Both vaccines were safe and stimulated an immune response,” Dr. Mittendorf said. “AE37 had its strongest efficacy in patients with triple-negative breast cancer, and we’re developing a trial of the vaccine for these patients. GP2 had its strongest signal in HER2-positive patients who had received trastuzumab.”
E39 and J65
The E39 vaccine is derived from folate binding protein, which is expressed on the surface of most breast and ovarian cancer cells. Studies performed at MD Anderson demonstrated that E39 produced a robust immune response in ovarian cancer patients; however, whether this response would exhaust the immune system and prove counterproductive was not known. To determine the optimal strategy for using the vaccine, Dr. Mittendorf and her colleagues have begun a clinical trial at MD Anderson in which patients with breast or ovarian cancer receive E39 and J65, an attenuated version of E39, on various dosing schedules. Patients are randomly assigned to receive monthly injections according to one of three regimens: six injections of E39, three injections of E39 followed by three of J65, or three injections of J65 followed by three of E39.
“This trial will determine whether it’s better to come in hard with E39 for a few doses and then give J65 to soften the blow or start soft with J65 and ramp up slowly to E39,” Dr. Mittendorf said.
Immune checkpoint inhibitors
The relatively new class of drugs that inhibit immune checkpoints—cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and the PD-1 ligand (PD-L1)—has extended survival for patients with metastatic melanoma and has been found to be effective against several other types of cancer, including breast cancer.
Jennifer Litton, M.D., an associate professor in the Department of Breast Medical Oncology, has been an investigator on early trials of anti–PD-1 and anti–PD-L1 antibodies as well as two trials combining an anti–CTLA-4 antibody with an anti–PD-1 antibody in patients with metastatic breast cancer. “We didn’t see the huge numbers of responses we’ve seen with other breast cancer therapies, but the few patients who did respond had long-lasting responses,” Dr. Litton said. “In several national trials, we’ve had people with triple-negative breast cancer whose responses have lasted for years. That’s the game-changer.”
The responses to checkpoint inhibitors in patients with triple-negative breast cancer are particularly encouraging, Dr. Tripathy said, because these patients have limited treatment options. Triple-negative breast cancers tend to have more genetic mutations than do other breast cancer subtypes, and these mutations generate abnormal or overexpressed proteins that may present targets for immunotherapy. For example, a recent study by Drs. Mittendorf and Litton and their colleagues found that 20% of triple-negative breast cancers expressed PD-L1. “Triple-negative breast cancer may be a little more immunogenic than other subtypes,” Dr. Tripathy said, “and that may be an opportunity.”
Dr. Litton agreed. “Almost all of the checkpoint inhibitor trials we have in the planning stages are for patients with triple-negative breast cancer,” she said. Although most of these trials are for patients with metastatic disease, researchers are eager to learn whether checkpoint inhibitors can play a role in other settings.
Of particular interest is a clinical trial of the anti–PD-L1 antibody MPDL3280A with nanoparticle albumin-bound paclitaxel in patients with triple-negative breast cancer that did not respond to initial standard neoadjuvant treatment. Dr. Litton, the trial’s principal investigator, said the trial is part of a new MD Anderson program to identify patients whose cancer does not respond to standard chemotherapy and offer alternative treatments (see Triage Program for Triple-Negative Breast Cancer, below).
Researchers are also planning a large trial of the anti–PD-1 antibody pembrolizumab as adjuvant therapy in patients with triple-negative breast cancer who have residual tumor cells in the breast or lymph nodes after neoadjuvant chemotherapy. “These patients have a higher risk of developing metastatic disease and dying of their disease later,” Dr. Tripathy said. Patients in the study will be randomly assigned to standard follow-up care with or without pembrolizumab.
In addition, a clinical trial of pembrolizumab will soon begin enrolling patients with inflammatory breast cancer, which is uncommon but aggressive. The trial, which aims to determine whether pembrolizumab can sustain the antitumor immune response started by standard-of-care chemotherapy, is led by Naoto Ueno, M.D., Ph.D., a professor in the Department of Breast Medical Oncology and executive director of the Morgan Welch Inflammatory Breast Cancer Program.
Although the survival effects of checkpoint inhibitors in breast cancer patients remain largely unknown, Dr. Litton is optimistic. “I think we’re only scratching the surface,” she said. “I think we’re going to see combinations of different immunotherapies as well as how to trigger an immune response in a greater percentage of breast cancer patients.”
Other immunotherapy approaches
“Our immunotherapy studies have moved from just vaccines to include checkpoint inhibitors and other immunotherapy strategies,” Dr. Mittendorf said. “And as an institution, we have the opportunity to do more.”
For example, Dr. Ibrahim is the principal investigator at MD Anderson for an ongoing multi-institutional trial of the oral immunostimulant indoximod with taxane-based chemotherapy for patients with HER2-negative metastatic breast cancer. Indoximod inhibits the indoleamine 2,3-dioxygenase pathway, which suppresses T cell activity.
Also under investigation are agents that block the action of interleukin-8 (CXCL8), which has an immunomodulatory effect and is associated with breast cancer growth and metastasis. A trial of one such agent, reparixin, which binds to the CXCL8 receptor CXCR1, is underway at MD Anderson and other institutions.
Preclinical studies of promising therapies also are underway. For example, Dr. Mittendorf said, Laurence Cooper, M.D., Ph.D., a professor in the Division of Pediatrics, is investigating the use of T cells modified with chimeric antigen receptors (see “Sleeping Beauty” Technique Modifies T Cells to Treat B Cell Malignancies, OncoLog, May 2014) against triple-negative breast cancer.
Also on the horizon are studies of antiphosphatidylserine antibodies, which have been shown to improve the activity of taxanes against breast cancer. Likewise, studies are being planned of agents that stimulate the activity of natural killer cells and therefore may enhance the response to standard breast cancer drugs such as trastuzumab and toll-like receptor agonists.
As researchers continue to elucidate the role of immunotherapy against breast cancer, clinical trials are increasingly becoming available for patients with metastatic disease and those with difficult-to-treat subtypes at high risk of recurrence. “There are trials that are open or in the process of opening for patients with triple-negative breast cancer,” Dr. Tripathy said. “The field is moving rapidly, and we hope that immunotherapy can prevent recurrences.”
For more information, contact Dr. Nuhad Ibrahim at 713-792-2817, Dr. Jennifer Litton at 713-792-2817, Dr. Elizabeth Mittendorf at 713-792-2362, Dr. James Murray at 713-792-2817, or Dr. Debu Tripathy at 713-792-2817. To learn more about ongoing clinical trials at MD Anderson for patients with breast cancer, visit www.clinicaltrials.org.
OncoLog, July 2015, Volume 60, Issue 7
Triage Program for Triple-Negative Breast Cancer
Triple-negative breast cancers—those that do not express estrogen receptors, progesterone receptors, or HER2—have about a 50% chance of responding to standard neoadjuvant chemotherapy. For patients whose cancer does not respond and who therefore are at higher risk for recurrence, researchers at MD Anderson Cancer Center have developed a triage program to find an appropriate experimental treatment.
At MD Anderson, patients with triple-negative breast cancer undergo genomic testing and then begin standard neoadjuvant chemotherapy. Dr. Litton said the triage program is similar in design to the I-SPY 2 TRIAL (see Novel Trial Design Streamlines Development of Breast Cancer Therapies, OncoLog, April 2015), except that patients begin treatment right away instead of waiting 2–3 weeks for the results of the genomic tests. When the results arrive, physicians also have clinical data that indicate whether the cancer is responding to standard chemotherapy.
“In the triage protocol, we can look at the early response and, for patients whose cancer is responding, we continue standard therapy and observe them; these patients will likely do well,” Dr. Litton said. “But we know that patients whose cancer does not respond to those initial doses of first-line treatment have only a 5% chance of a complete pathologic response to standard second-line treatment, and these patients are assigned to a clinical trial based on the results of the genomic tests. We’re in the process of opening a series of phase II trials of new treatments—including immunotherapy—for triple-negative breast cancer.”
Dr. Litton said that MD Anderson is the only institution in the United States to offer such a program for patients with triple-negative breast cancer.