Turning the immune system against metastatic breast cancer
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 MD Anderson Cancer Center are using various techniques to boost the body’s immune system. Clinical trials of many of these therapies are already underway.
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 of Surgical Oncology. “For a very long time, breast cancers were not thought to be immunogenic,” she said. “But data published in the past two years have shown that there are immune cells, including T cells, in breast tumors. This suggests that breast tumors do indeed produce an immune response.”
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., professor of Breast Medical Oncology. “In breast cancer we still haven’t had the kinds of breakthroughs like the recent successes of immunotherapy drugs and vaccines in melanoma and prostate cancer, 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, such as interferon or interleukin-2, to benefit breast cancer patients,” said Debu Tripathy, M.D., chair of Breast Medical Oncology. “But with advances in therapeutic vaccines, immune checkpoint inhibitors and other immunotherapies, 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 Ibrahim, who led a randomized trial of the sialyl-Tn–keyhole limpet hemocyanin (STn-KLH; also called Theratope) vaccine in the 1990s. The STn-KLH vaccine was derived from MUC1, a mucin expressed on the surface of a large proportion of breast cancer cells. The study didn’t 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.
In collaboration with the U.S. National Cancer Institute, Ibrahim 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. 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). James Murray III, M.D., professor of Breast Medical Oncology, 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.
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., adjunct professor 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.
“Both vaccines were safe and stimulated an immune response,” 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, 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.
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., associate professor 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,” Litton said. “In several national trials, we’ve had people with triple-negative breast cancer whose responses have lasted for years.”
The responses to checkpoint inhibitors in patients with triple-negative breast cancer are particularly encouraging, Tripathy said, because these patients have limited treatment options. Triple-negative breast cancers tend to have more genetic mutations than other breast cancer subtypes, and these mutations generate abnormal or overexpressed proteins that may present targets for immunotherapy.
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 who did not respond to initial standard neoadjuvant treatment. 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 chemo and offer alternative treatments.
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 chemo. “These patients have a higher risk of developing metastatic disease and dying of their disease later,” 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 anti-tumor immune response started by standard-of-care chemo, is led by Naoto Ueno, M.D., Ph.D., professor 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, 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.”
Read more about MD Anderson clinical trials using immunotherapy to battle high-risk breast cancer on the Oncolog website.