As researchers continue to study and better understand oncological outcomes, new, innovative treatments are being explored. One such treatment, of which the results were published in the Journal of Clinical Oncology in February 2022, involves an experimental form of immunotherapy (2022; doi: 10.1200/JCO.21.02170). This ongoing clinical trial demonstrated that there exists the potential for a patient's own tumor-fighting immune cells to be used to treat people with metastatic breast cancer. If proven effective, this approach could become a revolutionary last resort for terminally ill cancer patients.
Led by researchers at the National Cancer Institute's (NCI) Center for Cancer Research, this trial took an individual's lymphocytes and used them to treat their cancer specifically by targeting the unique mutations comprising the cancer. Study leader Steven A. Rosenberg, MD, PhD, Chief of the Surgery Branch in NCI's Center for Cancer Research, explained that tumor-infiltrating lymphocytes (TIL) are able to target the cancer cells that possess specific proteins presented on their surface. These neoantigens are produced when mutations occur in the DNA of a tumor, although their effectiveness in breast cancer has been less clear as this type of cancer presents fewer neoantigens than others.
"There are currently over 600,000 patients that die of cancer each year here in the United States, despite the best applications of the major treatments, [such as] surgery, radiation, and chemotherapy," said Rosenberg. "We have been working on methods to stimulate the body's immune system to fight disease for decades. We described interleukin-2 therapy (the first FDA approved immunotherapy for cancer) and the first patients who received their own immune lymphocytes that were genetically modified to recognize CD19, a molecule on lymphomas, an approach that received FDA approval in 2017."
Study Details
To expand upon this previous work, Rosenberg and his colleague, Nikolaos Zacharakis, PhD, sought to use this trial to determine if clinicians could identify effective immunotherapies for patients with the solid epithelial cancers that result in 90 percent of all cancer deaths. His team identified the antigens that are being recognized inside the patient's body to develop immunotherapies targeting these antigens.
"We've developed techniques over the years to utilize a patient's own lymphocytes as a 'living drug,' isolating those lymphocytes that have anti-tumor activity, growing them outside the body, and then giving them back under appropriate conditions," Rosenberg explained.
Using these techniques, Rosenberg's team additionally sought to determine if an immunotherapy approach could lead to tumor regressions in patients with metastatic epithelial cancers, such as breast cancer. Demonstrating the trial's potential, researchers found that one woman with metastatic breast cancer who was treated as part of a trial in 2018 had complete tumor shrinkage, known as a "complete response" ongoing now over 5 years later.
Across the remainder of trial participants, 28 of 42 women (67%) with metastatic breast cancer generated an immune reaction against their cancer. Further, the results stated that, upon using this approach to treat six women, half then experienced measurable tumor shrinkage.
"To perform this treatment with lymphocytes, we resect the tumor deposit sequence, the expressed genes in the cancer, and normal tissue to identify all the mutations that are present in that cancer," Rosenberg explained. "We know that the T cells recognize the products of these gene mutations. It's somewhat ironic that the very genes that cause the cancer can turn out to be the targets for treating the cancer."
At this stage, researchers are able to identify the T cells within a patient that can recognize these cancer antigens, which are the products of mutations in the patient. Those are the cells that are then ultimately grown to treat patients. Rosenberg noted that, as it turns out, researchers are able to obtain these cells from inside the tumors themselves, because the tumor is a sink in the body for the immune lymphocytes.
"When lymphocytes circulate through the tumor, they enter the tumor stroma so we can obtain about 100-fold purification of the tumor reactive cells," he explained. "We call them tumor infiltrating lymphocytes, or TIL."
Also, during the trial, researchers utilized whole genome sequencing to identify mutations in tumor samples from the 42 women with metastatic breast cancer (whose cancers had progressed despite all other treatments). The researchers then isolated TILs from the tumor samples and, in lab tests, tested their reactivity against neoantigens produced by the different mutations in the tumor. Overall, 28 women had TILs that recognized at least one neoantigen. All the neoantigens identified were unique to each patient. These results were especially exciting as most available immunotherapies, such as immune checkpoint inhibitors, have presented limited effectiveness against HR-positive breast cancers (making up the majority of breast cancers).
For the six women treated, the researchers took the reactive TILs and grew them to large numbers in the lab. They then returned the immune cells to each patient via intravenous infusion. All the patients were also given four doses of the immune checkpoint inhibitor pembrolizumab before the infusion to prevent the newly introduced T cells from becoming inactivated.
After the treatment, tumors shrank in three of the six women. One is the original woman reported in the 2018 study, who remains cancer free to this day. The other two women had tumor shrinkage of 52 percent and 69 percent lasting 6 months and 10 months, respectively. However, some disease returned and was surgically removed. Those women now have no evidence of cancer approximately 5 years and 3.5 years, respectively, after their TIL treatment.
"We've only treated six patients with this approach," Rosenberg noted. "This is something that deserves extensive study, and we are now making a major commitment to treat patients with this approach to not only to see how effective it is, but to attempt to improve the results with it."
His team of researchers acknowledged that the use of pembrolizumab, which has been approved for some early-stage breast cancers, may raise uncertainties about its influence on the outcome of TIL therapy. However, they said treatment with such checkpoint inhibitors alone has not led to sustained tumor shrinkage in people with hormone receptor-positive metastatic breast cancer.
"This research shows that the immune system can recognize breast cancer, and that the lymphocytes that recognize the antigens resulting from the mutations can cause cancer regression. Now we need to improve it and apply it to a larger number of patients," Rosenberg said.
Rosenberg added that, with the anticipated opening early this year of NCI's new building devoted to cell-based therapies, he and his colleagues can begin treating more individuals with metastatic breast cancer as part of the ongoing clinical trial. He noted this new immunotherapy approach will be used for people with other types of solid cancers as well.
"The most important thing now is to treat additional patients to get some idea of how often it works, and why it works in some people and not others," Rosenberg shared. "Based on that understanding, we will continue to attempt to develop improvements in this adoptive cell immunotherapy approach."
Lindsey Nolen is a contributing writer.