Leaving lymph nodes intact could increase efficacy of cancer immunotherapy
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Sparing lymph nodes until after immunotherapy treatment may result in improved antitumor immune response among patients with cancer, according to a study published in Cell.
“This study helps clarify how immunotherapies work and where the reservoir of cells is that is responding to the therapies, so we can think about developing better immunotherapies that harness those cells in the lymph nodes,” Matthew H. Spitzer, PhD, an investigator for Parker Institute for Cancer Immunotherapy and Gladstone UCSF Institute of Genomic Immunology, told Healio. “It also demonstrates that if there’s ambiguity about whether a person has lymph node metastasis or not, it might be better to give them immunotherapy prior to surgery so you can activate those T cells and keep them in the body.”
Spitzer spoke with Healio about how a study in mice encouraged him to conduct a human study and how these findings could change the standard of care in cancer treatment.
Healio: What inspired you to conduct this study?
Spitzer: A number of years ago, we found in mouse models that immunotherapies activated T cells from outside of the tumor microenvironment, which at the time was surprising. When we did those studies, the prevailing notion in the field was that immunotherapies reactivated exhausted or dysfunctional T cells already present in the tumor. The reason for thinking that was that tumors with more T-cell infiltration tend to respond better, and T cells in the tumor tend to express the targets of the therapies, like PD-1.
What surprised us in these mouse models was that with immunotherapies, T-cell proliferation was only being sustained outside the tumor and not within the tumor, including in tumor-draining lymph nodes. When we did some experiments to get at the importance of these cells — by either taking them away or adaptively transferring them — we found that if we blocked egress of immune cells from lymph nodes and prevented them from leaving, the immunotherapy stopped working. Conversely, if we isolated those activated T cells from outside of the tumor from the lymph nodes and transferred them to mice with the same kind of cancer that hadn’t been treated with immunotherapy, those T cells could provide tumor control. That prompted us to then ask whether similar biology is happening in human patients. Do we see T cells in lymph nodes responding to immunotherapy in patients? That was the genesis of this project.
Healio: How did you conduct your study in humans?
Spitzer: This originated as a small clinical trial supported by Genentech, and the clinical principal investigator of the trial is Alain P. Algazi, MD, a medical oncologist here at UCSF, with Patrick K. Ha, MD, a surgical oncologist and chief of our head and neck surgery practice, and Lawrence Fong, MD, who leads the cancer immunotherapy program at the UCSF Helen Diller Family Comprehensive Cancer Center. We had a hypothesis, based on the mouse data, that what was going on in the lymph nodes probably mattered. That led to some excitement about opening this neoadjuvant clinical trial. Patients received either one or two cycles of atezolizumab (Tecentriq, Genentech), which is an anti-PD-L1 antibody, shortly before their surgery. Because of the short treatment course, it didn’t delay surgery for these patients.
Twelve patients were enrolled in the arm of the trial where we gave anti-PD-L1 as monotherapy, either one or two cycles prior to surgery. Then the patients had their tumors surgically removed, as well as neck dissection to remove the lymph nodes, as part of the standard of care. That gave us the opportunity to see what the therapy does in lymph nodes and in the tumor.
We found that when lymph nodes are still present when a patient receives immunotherapy, T cells in the lymph nodes respond and help to drive cellular response to that immunotherapy.
We are hoping that will make an impact clinically. If we can initiate a good T-cell response in these patients before surgically removing the tumors, the hope would be that those T cells prevent tumor recurrence, because now you have a good source of memory T cells left in the body that would recognize those cancer cells if they were to come back. These neoadjuvant clinical trials have also been very impactful in terms of our understanding of the biology, because they give us the opportunity to see what’s happening at the cellular and molecular level in patients who receive these treatments.
Healio: What is next in your research on this?
Spitzer: We’ve extended the clinical trial and have another treatment arm enrolling patients. This trial looks at combination immunotherapy. We see this as an opportunity to build a platform to study how different types of immunotherapies lead to different types of immune responses. Hopefully, this will enable us to identify treatment strategies that activate these T cells and lymph nodes broadly across all patients with head and neck cancer. That’s one ongoing area that we are very excited about — continuing the clinical trial activity but evolving the treatments to understand which are doing the best in this particular indication.
We also found that in patients who had metastatic lymph nodes, the T-cell responses in those lymph nodes were significantly inhibited compared with patients who didn’t have metastases in the lymph nodes. That has led us to ask what we can do to rescue those responses in patients who had metastatic lymph nodes. Based on our observations, specific pathways are keeping those cells in check and not allowing them to respond. We are looking at whether we could intervene to drive stronger T-cell responses in those metastatic lymph nodes. That is another ongoing area of interest for us.
Healio: Do you think this could lead to changes in the standard of care regarding the timing of removing lymph nodes in these patients?
Spitzer: It could. It provides good evidence that giving even one cycle of immunotherapy before taking out the lymph nodes has a real effect. So, if you’re considering giving immunotherapy, it could mobilize these T cells in the lymph nodes and activate them. There’s an opportunity to shift clinical practice. In breast cancer, for example, there has been a movement over the last few decades away from complete axillary lymph node dissection toward sentinel lymph node biopsy to see if there’s evidence of metastasis, before taking out all the lymph nodes. So, I think strategies like lymph node-sparing when there is no clear evidence of lymph node metastasis can potentially be beneficial.
For more information:
Matthew H. Spitzer, PhD, can be reached at the Spitzer Lab, UCSF, 513 Parnassus Ave., Box 0552, San Francisco, CA 94143; email: matthew.spitzer@ucsf.edu.
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