Scientists Padmanee Sharma, MD, PhD The University of Texas at MD Anderson Cancer Center Houston, TX CRI Investigator Tests New Prostate Cancer Immunotherapies Modern methods of detection and treatment mean that many prostate cancers are now found earlier and can be treated more effectively. Prostate cancer is the second leading cause of cancer-related deaths in men. In 2009, more than 27,000 men in the United States fell victim to this disease. However, there is cause for hope: if prostate cancer is detected early and treated, survival rates can approach 100 percent. Early detection of prostate cancer, however, does not necessarily mean a patient requires treatment. Some prostate cancers are aggressive and more likely to spread, while others remain localized and grow very slowly over time, if at all. Treatment may impart its own side effects, including impotence and incontinence, so it is important that doctors understand the biology of each patient’s particular cancer before deciding whether to pursue treatment. “Watchful waiting,” where doctors monitor a patient’s cancer over time without medical intervention, is often sufficient in cases of nonaggressive cancers. Researchers are therefore looking for molecular markers that would help them to predict disease aggressiveness in order to select which patients should undergo treatment versus patients that should not. Padmanee Sharma, MD, PhD, is a CRI-supported physician scientist in the Departments of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center, Houston, Texas. Her translational research focuses on learning how to apply immune-based therapeutic strategies to manipulate components of the human immune system to lead to tumor regression. She designs and conducts clinical trials of cancer vaccines and other immune-based treatments. She also conducts laboratory research on collected patient samples as part of her ongoing studies aimed at understanding how immunotherapy affects the immune system and tumor biology. She shares data from her studies with the network of CRI/LICR Cancer Vaccine Collaborative researchers, which helps to advance our global efforts to develop the most effective immune-based approaches to cancer treatment. Can you describe your clinical trials? Dr. Sharma: The first was a Phase I clinical trial of a NY-ESO-1 DNA vaccine for prostate and lung cancer patients. NY-ESO-1 is a protein marker found on cancer cells that CRI/LICR Cancer Vaccine Collaborative trials have shown is a good cancer vaccine target. In this vaccine construct, we loaded genes coding for NY-ESO-1 onto gold particles that we then injected directly into the skin cells of cancer patients. It is an alternative DNA delivery platform to using viral vectors. My group focused on the impact of that vaccine on prostate cancer patients. We published the data from that trial in Clinical Cancer Research in March of this year1. In that study, we learned that this vaccination method is effective at stimulating an immune response against the NY-ESO-1 tumor antigen. However, disease progressed in most of the patients, disappointingly, but the immunological data we gathered provided a great deal of insight. We learned that the poor clinical outcome in these patients was likely due to the action of regulatory T cells, which can inhibit anti-tumor immune responses. Future immunotherapy strategies need to combine methods that enhance desired T cell responses against cancer while limiting regulatory T cell responses. Another trial with which I am involved deals with an immunotherapy strategy that blocks an intrinsic regulatory molecule on T cells known as CTLA-4. It’s a much larger, Phase 3 trial testing an antibody (Ipilimumab) against CTLA-4 in prostate cancer patients. The anti-CTLA-4 antibody was discovered by CRI Scientific Advisory Council Associate Director Jim Allison, who is now at Memorial Sloan-Kettering Cancer Center. He proved he could “take the brakes off the immune system” in mice treated with anti-CTLA-4 antibody, thus leading to tumor rejection. A number of clinical trials in humans since then have shown that anti-CTLA-4 can override an inhibitory pathway and lead to enhanced anti-tumor immune responses, which in some cases has led to durable complete regression of disease in treated patients. The Phase 3 clinical trial with anti-CTLA-4 in prostate cancer patients is expected to begin accrual within the next 1 to 2 months. We initially obtained data regarding the immunological impact of anti-CTLA-4 on tumor tissues and peripheral blood by conducting a pre-surgical clinical trial in bladder cancer patients. Male bladder cancer patients undergo surgery to remove both the bladder and prostate. Some patients will have incidental prostate cancers while others will have non-cancerous prostates. This allowed us to study the impact of anti-CTLA-4 on bladder tumors, prostate tumors, and non-cancerous prostate tissues. Our studies, published in the Proceedings of the National Academy of Sciences,2,3 identified a subset of effector T cells that express a molecule known as inducible costimulator (ICOS), which we are now investigating in our ongoing studies as a biomarker and/or target for cancer immunotherapy. The advantage of this “neo-adjuvant” setting (pre-surgical) is that we can measure the immunological impact of therapy on tumor tissues from treated patients. This is in contrast to studies, for instance, that give immunotherapy to patients with metastatic disease, which is a setting that has limited access to tumor tissues for immunological studies. With this pre-surgical trial, we can analyze both blood and tumor tissues from patients for immune monitoring. By identifying biomarkers in tumor tissues that correlate with biomarkers in blood, we hope to detect relevant biomarkers that could be helpful in monitoring patients with metastatic disease who receive this therapy. We are currently conducting a pre-surgical trial in which we give anti-CTLA-4 in combination with a standard treatment, such as hormonal therapy, to patients before they undergo surgery. This trial will allow us to study the immunological impact of combination therapy on tumor tissues and blood. What is the importance of immune monitoring in these trials? Dr. Sharma: In order for an immunotherapy to lead to clinical benefit, it must first have an effect on the immune system. Monitoring allows us to determine whether an immunotherapeutic strategy led to changes within the immune system that indicate appropriate activation and mobilization to tumor tissues. Many cancer trials look only at the effect of therapy on clinical outcome. Clinical benefit is at the end of the line in terms of seeing an impact of therapy, and there’s a lot happening immunologically in the middle between vaccination and clinical endpoint that we need to monitor to understand whether the immunotherapeutic agent “has hit its target”. Monitoring shows us not only whether a therapy is or isn’t successful at effecting an anti-tumor immune response, but also shows us what that response is, specifically—which immune cells are responding, how many, how are they behaving, and how long do they remain active. This gives us clues for making our therapies more effective down the road. How are you studying the immune response? Dr. Sharma: T cells are the major cellular players during an anti-tumor immune response. They travel through the body to find their target and can actually get into the tumor to effectively kill cancer cells. There are various kinds of T cells—helper, killer, regulatory, etc. We are looking for differences in T cell subsets and function between pre-therapy blood and tissue samples versus post-therapy blood and tissue samples. It is important to study both the blood and the tissue samples. Changes in the blood show us whether the therapy stimulated a T cell response. Changes in tumor tissues reveal whether T cells were able to traffic into the tumors. Both of them together give us the full picture of which specific T cells are able to engender successful anti-tumor responses. What are the challenges to vaccination against prostate cancer? Dr. Sharma: One challenge in the prostate cancer field is selecting the right patient population for vaccination. Not everyone is going to respond to a particular therapy, and our studies are trying to determine who will be more likely to benefit and who will not with certain therapies. My colleagues and I have been trying to determine whether the best impact would be to give immunotherapy to patients with early stage disease or with later stage disease, for instance. We are also trying to determine how to identify patients who may have a bad reaction to certain immunotherapies to avoid unnecessary risk. The other challenge is deciding what endpoints to look at in the clinical study. Every clinical trial is set up with specific goals in mind, which may include immunological endpoints (was the therapy safe and well tolerated, did it generate the desired immune response, etc.), and clinical endpoints (was there improvement in the patient’s course of disease, does the therapy impact survival, etc.). Immune responses may take a longer time to work than standard chemotherapy approaches. The body needs time to build a sufficient immune response, so our trials have to take this into account before we can assess clinical endpoints. The problem is that years of patient follow-up gets expensive, and it means a promising therapy might have to wait for years before we’ve gathered enough data to get it approved. We are looking for surrogate immunological biomarkers that could help us predict how well a patient is likely to respond to a therapy. Establishing these biomarkers could help us get new therapies approved quicker. What attracted you to being a scientist and then pursuing a career in immunology? Dr: Sharma: I’ve always been excited by science and medicine and was hooked after my first biology class in high school. I chose to pursue a career in science and medicine because it gives me a chance to help patients, sometimes simply by being there to explain things during the course of a difficult situation, and to develop research that can have an impact on patient care. When I was in my undergraduate program at Boston University, I took my first immunology course and was fascinated by the concept of how the immune system can keep adapting to recognize and fight off any pathogen or tumor cell that comes its way. I completed a M.D/Ph.D program with my Ph.D studies conducted in immunology and then pursued medical oncology fellowship at Memorial Sloan-Kettering Cancer Center with my post-doctoral research work conducted in Dr. Lloyd Old’s lab. During that time, I had the opportunity to see how my understanding of immunology could be applied to the clinical setting. I worked with Dr. Dean Bajorin in the clinic and Dr. Old in the lab to study samples from bladder cancer patients for particular tumor antigens. This work later led to a clinical trial with the NY-ESO-1 full-length protein vaccine in the adjuvant setting after bladder cancer patients were treated with surgery. In 2004, I joined MD Anderson and have established my own laboratory to continue studies on the human immune system and the development of immunotherapy strategies to treat cancer. In your view, how promising is immunotherapy for prostate cancer? Dr. Sharma: It’s very promising and I think within the next few years it’s a strategy we’re going to see become an approved and acceptable modality for the treatment of prostate cancer patients, the same as chemotherapy, radiation therapy, or surgery. Immunotherapy will have to be integrated into the treatments we currently use in the clinic because it’s beginning to prove itself to be clinically beneficial to patients. Dendreon’s Provenge vaccine in prostate cancer, for example, has been shown to confer survival benefit in a Phase 3 clinical trial. We’re still trying to understand how that particular immunotherapy works, and that’s where immune monitoring will help. Anti-CTLA-4 antibody is another promising immunotherapy strategy and hopefully the Phase 3 clinical trial will provide positive data that will lead to its approval for prostate cancer. Based on data from recent and ongoing clinical trials, I am very encouraged to say that immunotherapy will quickly become another treatment that can be offered as part of the standard of care for prostate cancer patients. Reference Publications 1 Gnjatic S, Altorki NK, Tang DN, Tu SM, Kundra V, Ritter G, Old LJ, Logothetis CJ, Sharma P. NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells. Clin Cancer Res. 2009 Mar 15;15(6):2130-9. Epub 2009 Mar 10. 2 Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, Logothetis C, Sharma P. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14987-92. Epub 2008 Sep 25. 3 Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, Sun J, Jungbluth AA, Troncoso P, Logothetis C, Sharma P. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2729-34. Epub 2009 Feb 6. Originally published January 31, 2015.