Unlike that of other gynecological malignancies, the etiology of cervical cancer is the human papillomavirus (HPV). This fact plays a role in how cervical cancer is perceived as immunogenic: T cells themselves are involved in the immune response and in the control of viral infections and the development of these tumors. In this discussion with i3 Health, Bradley Monk, MD, FACS, FACOG, Professor of Gynecologic Oncology at the University of Arizona and Creighton University, and Ramez Eskander, MD, Assistant Professor of Obstetrics, Gynecology, and Reproductive Science at the University of California San Diego, share their perspectives on immuno-oncology, particularly immune checkpoint inhibition, in the management of cervical cancer.
What was the hypothesis behind beginning to explore immune checkpoint inhibition in the management of cervical cancer, which is an HPV-related carcinoma?
Dr. Monk: The paradigm here is Merkel cell carcinoma. Obviously, the number of cases of cervical cancer is much greater, as is its clinical impact.
The difference between cancers like Merkel and HPV-related cancers, such as cervical, vulvar, vaginal, head/neck, and anal, is that HPV-induced malignancies do not stimulate inflammation. That's why even though the hypothesis is that this presents an opportunity as a virally-driven tumor, if you look at the level of inflammation, of tumor-infiltrating lymphocytes, that number is relatively low. The good news is that the PD-L1 expression is relatively high. The other issue, obviously, is that the tumor mutational burden (TMB) is also low, so the only thing that you have in favor of a biomarker and understanding this biology is the high programmed death ligand 1 (PD-L1) expression.
Dr. Eskander: And that ties in to where we are with many of these diseases and understanding how we can capitalize on immune checkpoint inhibition in their management. In order for us to understand how we are going to be able to advance immuno-oncology in these platforms, we have to better understand the immune environment, including tumor-infiltrating lymphocytes and tumoral inflammation, and we need to identify ways to make these cancers more immunogenic. Whether that will require combinatorial approaches is an area of active clinical investigation.
We have anti–CTLA-4 antibodies. These were initially developed in the melanoma arena, where there have been multiple approvals and established efficacy. In addition, more recently, we have the development and evaluation of anti–programmed cell death protein 1 (anti–PD-1) and anti–PD-L1 antibodies. We understand that these ligands are involved in the immune regulatory system so that in normal conditions, there is a balance between immune activation and inhibition. Unfortunately, cancer has figured out a way to hijack this normal mechanism to its advantage. In cervical cancer, as you stated, we see increased PD-L1 expression, which may be suggestive of a therapeutic opportunity that we could take advantage of.
A multi-specialty team approach is essential, given that immune-related adverse events can be complex in nature. How do you treat your patients?
Dr. Monk: Most cervical cancer patients are treated by gynecological oncologists. For our other tumors, like ovarian cancer, the medical oncologists are involved frequently, but not for the gynecologic cervical cancer patients. If you're a gynecologic oncologist, it's likely that you have limited experience [with immune checkpoint inhibitors]. Feel free to talk to, for example, the melanoma team. The individuals in your cancer center that treat melanoma can help you and guide you. Or you can call Dr. Eskander or me. I don't want you to feel like you're out there on an island using a class of agents that you're not familiar with, and I don't want you to refer these patients. I want the gynecologic community to become familiar with this class of agents and become familiar with the toxicity management because these agents are going to be more and more prevalent in the clinic, and we need to bring them to our patients in a responsible way.
About Dr. Eskander & Dr. Monk
Ramez N. Eskander, MD, is an Assistant Clinical Professor in the Department of Obstetrics, Gynecology & Reproductive Sciences and the Division of Gynecologic Oncology of the Rebecca & John Moores UC San Diego Cancer Center. He has been a recipient of the Padres Pedal the Cause C3 Collaborative Translational Cancer Research Award; a Society of Gynecologic Oncology Shark Bait winner, selected to develop a novel mobile application for the management and treatment of gynecologic malignancies; and a National Cancer Institute Cancer Therapy Evaluation Program Career Development Award, among others. He has authored numerous publications and book chapters on topics related to ovarian cancer, uterine cancer, endometrial cancer, and cervical cancer.
Bradley Monk, MD, FACS, FACOG, is a Professor of Gynecologic Oncology at the University of Arizona and Creighton University. An expert in the multidisciplinary prevention and treatment of vulvar, vaginal, cervical, uterine, fallopian tube, primary peritoneal, and ovarian cancers, he has published over 200 peer-reviewed manuscripts and 30 book chapters. He is President of the Western Association of Gynecologic Oncologists, Co-Chair of the Cervix Committee of NRG Oncology, a Member of the Board of Directors of the GOG Foundation, Inc. (formerly the Gynecologic Oncology Group), and a Member of the Gynecologic Cancer Foundation, among others.