Immunotherapy Biomarkers and Combinations Needed in CRPC: An Interview With Padmanee Sharma, MD, PhD

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.

Sipuleucel-T requires cells to be taken from patients, sent to the company for processing over a few days, and then sent back to the patients for reinfusion. This also needs to be discussed with patients so that they can understand the process. It’s also important to monitor side effects and toxicities, which tend to be low with this particular therapy. Patients are willing to receive treatments with agents that may potentially improve their survival without adding severe toxicities. We monitor patients after three doses and make decisions about what to do next based on how patients are doing clinically. We just watch. Hopefully, additional trials will be conducted to elucidate mechanisms of action or identify biomarkers that can be measured to tell individual patients how they're doing.

Since sipuleucel-T was approved three years ago, is there new thinking about its place within drug sequencing?

There is currently no sequencing paradigm, but there are several trials looking at sequencing. I’m involved in a trial with Larry Fong at the University of California, San Francisco, that combines sipuleucel-T with anti-CTLA-4. Our trial has two arms: one group takes sipuleucel-T followed by anti-CTLA-4 a day later, and the other group takes sipuleucel-T followed by anti-CTLA-4 three weeks later. We’re trying to identify and understand mechanisms of action by measuring immune system response, and we hope to identify biomarkers associated with combination therapy. The primary endpoints of this trial are safety and assessing the impact of timing on anti-CTLA-4 administration, and, second, to measure response and describe mechanisms of action. There are also combination trials that propose to evaluate sipuleucel-T plus abiraterone and sipuleucel-T plus enzalutamide that will also look at the question of sequencing.

What are the clinical challenges associated with its use in the community setting?

Community oncologists want to make sure that treatment is effective and tolerable, and will not interfere with quality of life. When they’re considering immunotherapy, they may need to make sure a patient has enough lifespan left for the treatment to take effect and provide clinical benefit. Treatments also need to be easy for them to administer in the community setting. Some community offices don't have the facilities needed to get patients’ blood cells for the sipuleucel-T treatment and patients need to travel to a blood donation center.

With anti-CTLA-4, it is still in clinical trial testing for prostate cancer, and it is not available in the community as of yet. Anti-CTLA-4 (ipilimumab) is FDA-approved for melanoma, and community doctors are now understanding how to recognize and treat the side effects and toxicities associated with anti-CTLA-4. There will have to be additional education if the drug becomes FDA-approved for prostate cancer patients, as well. Oncologists who take care of prostate cancer patients will probably have to monitor these patients more closely than they have had to with previous therapies such as hormonal therapies, and this may necessitate a change in how the clinic functions. There is also the question of insurance coverage. Doctors will need to know whether the patient fits the criteria checklist to enable insurance reimbursement.

What are the major unknowns at this point about immunotherapy’s efficacy?

Immune responses are complex and involve many different cell types including dendritic cells, natural-killer (NK) cells, T-cells, B-cells and many others. All of these play distinct roles within an immune response. Some of the things that we need to understand include how T-cells traffic, infiltrate into tumors, and function to kill tumor cells. We still don’t understand why some patients have T-cells that infiltrate into tumors while others don’t. This may have to do with how T-cells interact with other cells, such as dendritic cells. We usually don't have access to sufficient tumor tissues to study these processes. We know a lot about mice, but not about humans. In some studies, we’re analyzing tumor tissues from patients, and then using that information to study mechanisms in mice. We’re hoping that these translational studies will help us piece together the puzzle and get a better idea about what makes up an effective antitumor immune response in humans.

What new targets and novel immunotherapeutic approaches are on the horizon?

The next immunotherapy agent that has shown great promise in the clinic is an antibody that blocks another “off switch” on T cells known as PD-1 (programmed death-1). Anti-PD-1 antibodies have been tested in phase I clinical trials and have shown promise in patients with melanoma, renal cell carcinoma, and lung cancer. In a small number of patients with CRPC, anti-PD-1 did not seem to work, but we may need to test more patients to have a better understanding of the role of anti-PD-1 in this tumor type.

Now we’re looking at combination therapies with both anti-CTLA-4 plus anti-PD-1. This is a promising combination that has already shown dramatic clinical responses in a phase I clinical trial with melanoma. But, since these agents stimulate T-cells to work regardless of tumor type and they don't target a particular tumor, this combination may be a promising treatment for all cancer patients, including patients with CRPC.

Can you describe a couple of clinical trials that you think are likely to shed new light on treatment?

The phase III clinical trial with anti-CTLA-4 (ipilimumab) in patients with CRPC previously treated with chemotherapy was recently reported, and it did show that some patients derived benefit, but the trial had a P value of 0.053 for its primary endpoint of OS, which means that we have to go back and carefully look at that trial to understand why some patients did well with treatment while others did not. Another phase III trial is evaluating anti-CTLA-4 (ipilimumab) in patients with CRPC who have not received chemotherapy, and it will hopefully provide important information regarding efficacy of anti-CTLA-4 in patients with CRPC. We’re also hoping that the combination of sipuleucel-T and anti-CTLA-4 in our trial will give us some hints about types of immune responses generated as a result of the combination and possibly association of these immune responses with clinical data.