Moon Shot confronts challenges of multiple cancers driven by HPV
Clayton Boldt, Ph.D.
According to the Centers for Disease Control and Prevention, the human papillomavirus is responsible for roughly 33,700 new cancer cases each year, including cancers of the head and neck, the cervix, genitalia, anus and rectum. While there is a safe and effective vaccine available to prevent the majority of these cancers, incidence rates for HPV-related cancers continues to rise, increasing the need for new treatment approaches.
The HPV-Related Cancers Moon Shot® is committed to developing a more complete understanding of the biology and immune environment across all HPV-related cancers in order to develop novel therapies that can improve outcomes and lessen side effects associated with current standards of care.
The effort is part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Ann Klopp, M.D., Ph.D., associate professor of Radiation Oncology, is one of the co-leaders of the Moon Shot® team. Together with Michael Curran, Ph.D., associate professor of Immunology, Klopp leads the Moon Shot’s efforts to identify and overcome barriers to utilizing immune-based therapies for treating HPV-related cancers. She spoke with Cancer Frontline about their work.
Q: The HPV-Related Cancers Moon Shot is unique in that it’s not focused on a single cancer type. How is the Moon Shot approaching the challenge of improving outcomes for patients with HPV-related cancers?
A: It is definitely a unique challenge of the HPV-Related Cancers Moon Shot. One thing that we've done to overcome that challenge is to engage leadership with expertise that spans across diseases. I focus on gynecologic cancers, and Dr. Myers and Dr. Gillison are focused on head and neck cancer, the most common HPV-related malignancies. Physicians with expertise in anal, penile, vaginal and vulvar cancers are also engaged to make sure we take the broad view that we need to across HPV cancers.
Interestingly, there already exist many commonalities in the treatment of HPV-related cancers. From a radiation oncology standpoint, the treatment paradigm is quite similar across HPV diseases. Nearly all locally advanced HPV cancers are treated with a similar paradigm of radiation and chemotherapy. This common therapeutic background creates an opportunity to go across diseases and understand the drivers that distinguish radiation-sensitive from resistant cancers.
Q: What are the primary focus areas for the Moon Shot team?
A: When we got started, we took a step back and looked for the unique opportunities and identified the most pressing problems in HPV cancers, with an aim to let the biology drive our agenda. We came up with three flagships for focusing our Moon Shot projects.
The first is looking at targeting pathways specifically influenced by the HPV viral proteins. We think there is really an opportunity here, and so far there haven't been any treatment strategies that have successfully exploited the very specific biology of HPV cancers. In particular, the E6 and E7 proteins disrupt the cell cycle and the apoptotic response, in addition to other tumor-promoting activities which may create unique opportunities for therapeutic intervention. Thus, our first flagship is aimed at figuring out how to target pathways that are disrupted by these HPV viral proteins, either through small molecules or immunologic approaches.
Our second Moon Shot flagship project focuses on overcoming barriers to generating an effective immune response to HPV cancers. Because HPV cancers all express unique viral antigens and these tumor cells rely on the presence of that antigen to maintain their malignant state, these are theoretically the ideal cancers for immunotherapy. Immunotherapy has been approved for many HPV cancers and has improved outcomes in some cases. However, the rates of response have lagged behind expectations given the antigenic nature of these cancers. A critical goal of the Moon Shot is to discover the mechanisms by which the tumor is able to evade the anti-tumor immune response and how to more effectively exploit the presence of these tumor-specific antigens.
Finally, our third flagship focuses on tissue banking across diseases. We recognize that creating an integrated database across so many disease sites and departments is a real challenge. We’ve designed a new tissue collection study that will have multiple cohorts to collect across each cancer type and integrate those all into one resource. We are actively working with the Moon Shots platforms to analyze these specimens and make the resulting data available to all investigators. Our hope is to create a resource that will help advance discoveries in the field.
Q: You’re leading an effort to overcome barriers to using immunotherapy for HPV-related cancers. What are current challenges to using immunotherapy?
A: Checkpoint inhibitors do improve outcomes in metastatic head/neck cancers and gynecologic cancers, but provide just incremental improvements in survival. One of the important questions we want to answer is ‘Why don’t these work better?’ We know that the viral proteins are present in all of these tumors, and they’re all foreign, so we would expect to see a pretty effective immune reaction. Despite this, immunotherapy fails in the vast majority of cases.
Q: How is your team going to work to identify and overcome these barriers?
A: One of the ways we’re trying to answer these questions is to specifically study the immune populations that recognize those HPV proteins. Using new technologies, we are studying the T-cell populations that recognize HPV antigens in an effort to determine if they are absent, fail to infiltrate tumors, or are exhausted. Alternatively, we plan to investigate whether HPV+ cancers are, in fact, failing to present these antigens in a way that the immune system can effectively recognize.
Our hope is to utilize this unique tissue analysis resource we’re generating to understanding the tumor microenvironment of both standard of care and immunotherapy patients, and how differences between patients in responses to subsequent therapies can be traced back to differences in either their tumors and/or their microenvironments.
First then, we’re working to answer the question of why immunotherapy isn’t currently working and then, we will use that information to drive the next generation of trials. Those may encompass new antibody approaches alone or in combination with therapeutic vaccines. Either way, a critical first step is our ongoing development of improved assays to understand the immune response to HPV+ cancers, which is our current focus.
Q: What project are you most excited about at the moment?
A: Taking advantage of the MD Anderson resources to do these serial analyses of HPV+ cancers under treatment. In patients treated with radiation, we’re learning that radiation works so well for HPV+ cancers because it’s increasing the number of activated T-cells within the tumor. That’s something we haven’t been able to show before we were able to do these in-depth assays using small samples of the tumors that we can acquire non-invasively. So now, we can see that the patients that respond well are the ones who are getting clonal T-cell expansion in their tumors. The question is how can we get everyone to have that response? That’s where we’re focusing now – trying to understand the underlying mechanisms by which radiation is promoting these de novo anti-tumor T cell responses.
Q: How is your work enabled by the Moon Shots Program and its infrastructure?
A: The Moon Shots Program has been incredibly helpful to provide funding for this type of comprehensive research. You must have funding in order to collect and bank the large number of samples required for this type of cross-site analysis, you need the resources to do an in-depth biological analysis and then you have to have adequate biostatistics resources to analyze the data effectively. Only with all those things can you really get the kind of information about why treatment works in some and doesn’t work for others.
Having this level of resource support has been a key enabling factor allowing us to take an unbiased approach to these scientific questions. You can really open it up, ask the fundamental questions you’re interested in and let the real science drive your research. That is why this is such a great opportunity, and why the Moon Shots Program and the platforms have been so important to us.