Padmanee Sharma, MD, PhD
The field of immunotherapy continues to evolve with heightened interest in vaccines, dendritic cell therapies, and immune checkpoint inhibitors. To characterize these new treatment strategies, we interviewed Padmanee Sharma, MD, PhD, a member of the Investigational Drug Steering Committee (IDSC) for the National Cancer Institute’s Clinical Trials Working Group, and an associate professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, on new drugs and emerging trends for patients with castration-resistant prostate cancer (CRPC). OncLive: What are the various approaches to immunotherapy that now exist?Sharma:
Immunotherapy initially focused on methods for activating T-cells to recognize the tumor antigen. These include cytokines, peptide vaccines, or vaccines encompassing entire antigens or whole tumor cells. We have tried vaccinations, as with infectious disease, but this has not worked well. So over the past decade, we have been looking at other ways to harness the immune system.
Immune checkpoint targeting agents represent a new approach. T-cells have “on and off switches” that control how they work. For a long time, we were concentrating on only the “on” switches. Now, we understand that we also have to block the “off” switches so that T-cells can do their jobs. Jim Allison identified a critical “off” switch known as CTLA-4 (cytotoxic lymphocyte antigen-4), and he showed that antibodies blocking CTLA-4 could lead to tumor rejection in mice. Ipilimumab, an antibody directed against human CTLA-4, is a new immune checkpoint agent given as an intravenous infusion in the outpatient clinic, which makes it easy to administer. Ipilimumab was the first agent to show an improvement in OS in a phase III clinical trial with melanoma patients, and was FDA-approved as a standard-of-care treatment for melanoma in 2011. It is now in clinical trials with lung cancer, prostate cancer, and also pancreatic cancer.
Since anti-CTLA-4 targets a T-cell-specific molecule, and not a tumor-specific molecule, it is a promising new way to treat many different tumors. In some patients, anti-CTLA-4 therapy can lead to measurable changes, such as decrease in tumor size on CT scans or decrease in PSA (in individual patients). But, we still need to figure out why some patients respond to anti-CTLA-4 and others don't. Also, after treatment with anti-CTLA-4, some T-cells destroy normal tissue, which causes side effects, and so we need to balance the response between T-cells attacking tumor cells and T-cells attacking normal cells. If we see toxicity, we treat with corticosteroid therapy. The most important outcome with anti-CTLA-4 is that the survival benefit tends to last for years and in some cases, we have seen clinical benefit that has lasted over 10 years without any further therapy. There are two phase III trials with anti-CTLA-4 in CRPC that were recently conducted. One trial evaluates anti-CTLA-4 in postchemotherapy patients who are older and more fragile, and the other is testing it in earlier-stage patients who have not yet received chemotherapy.Where does immunotherapy now figure in CRPC treatment, and how do we measure its effectiveness?
Following surgery, radiation, and chemotherapy, immunotherapy has been a dream in oncology for a long time. We have vaccinations for infectious diseases and should be able to harness the immune system to treat cancer but, to date, have not been able to show a critical benefit. Things began to change with the introduction of sipuleucel-T, which demonstrated in two trials that it could prolong overall survival (OS). This was a first. However, it was curious that we did not see progression-free survival (PFS) or changes in CT scans or prostate-specific antigen (PSA). How we measure the effectiveness of sipuleucel-T in individual patients remains a conundrum; the mechanism of action is not clear. We have no idea how individual patients will respond to it, and we usually will continue treatment on the basis of whether patients are feeling well and tolerating the drug. The agent met a hallmark measure of improving OS, and that’s very important. We need to have very frank discussions with patients about what we can’t monitor in terms of CT scans or PSA.