, implies that leaving lymph nodes intact until after immunotherapy could improve efficacy against solid tumors, which now respond to only a small percentage of these newer forms of treatment. Most immunotherapies solely try to reactivate T cells in the tumor, where they frequently become fatigued fighting cancer cells as well. This can play an important role in driving positive responses to immunotherapy.
Yet, the current studies indicate that allowing the medication to activate the immunological response of the lymph nodes is beneficial.
This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment,” said Matt Spitzer, Ph.D., an investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study. Lymph nodes are often removed because they are typically the first-place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.
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“Immunotherapy is designed to jump-start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.
Aim for the Lymph nodes, not the Tumor
Researchers have largely been working under the assumption that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes. “That study changed our understanding of how these therapies might be working,” said Spitzer.
Rather than T cells in the tumor being boosted by immunotherapy, he believes T cells in the lymph nodes are the source of T cells circulating in the blood. These circulating cells can then enter the tumor and kill cancer cells. After demonstrating that undamaged lymph nodes can reduce cancer’s grip in mice, Spitzer’s team wanted to determine if the same was true in human patients. Because of the high number of lymph nodes in those locations, they decided to create a trial for patients with head and neck malignancies.
The experiment included 12 individuals whose cancers had not yet spread beyond the lymph nodes. Normally, such individuals would have surgery to remove the tumor, followed by other therapies if necessary. Instead, patients were given a single cycle of atezolizumab (anti-PD-L1), an immunotherapy medicine manufactured by Genentech, the trial’s sponsor. Spitzer’s team analyzed how much the medication triggered the patients’ immune systems a week or two later.
After immunotherapy, each patient’s tumor and adjacent lymph nodes were surgically removed and analyzed to see how the immunotherapy affected them. The researchers discovered that following immunotherapy, cancer-killing T lymphocytes in the lymph nodes began to activate.
They also discovered a larger number of immune cells in the patient’s blood. Spitzer attributed some of the trial’s success to its design, which allowed the team to collect a large amount of data from a small number of patients by examining tissue before and after surgery and doing extensive analysis.
“Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.” That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.
Metastases Inhibit Immune Response
Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases or second cancer growth. “No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”
Spitzer speculated that the medication may have reduced the activation of T cells in these metastatic sites. If this is the case, it may help explain why some immunotherapy therapies fail. Yet, the therapy stimulated enough T-cell activity in the metastatic lymph nodes to consider leaving them in for a short time until treatment is completed.
“Removing lymph nodes with metastatic cancer cells is probably still important, but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer. A subsequent goal of the current trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. Researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.
“My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” Spitzer said. Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.
Reference :
- Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes – (https://www.cell.com/cell/fulltext/S0092-8674(23)00164-2)
Source: Medindia
