Target Folate Receptor Alpha in Ovarian Cancer?

As part of our coverage of the 12^th Biennial Ovarian Cancer Research Symposium, being held September 13–15 at the University of Washington in Seattle, we are speaking with Dr. Dmitriy Zamarin, MD, PhD, a medical oncologist who specializes in the care and treatment of women with cervical, ovarian, and other gynecological cancers at the Memorial Sloan Kettering Cancer Center in New York City. At the conference, Dr. Zamarin presented data from a phase II trial at Memorial Sloan Kettering, of a peptide vaccine called TPIV-200 in combination with durvalumab, an anti–PD-1 checkpoint inhibitor antibody, in patients with platinum-resistant ovarian cancer.

-Interviewed by Anna Azvolinsky

Cancer Network: Can you first describe this peptide vaccine, what it targets, and the rationale for its use as a therapy for advanced ovarian cancer?

Dr. Zamarin: Absolutely. One of the limitations of cancer vaccines against shared antigens in different cancers in general is that the overexpression of some of these antigens is restricted to only a subset of tumors. The nice thing about the vaccine against the folate receptor alpha that we are using is that folate receptor alpha is overexpressed in the majority of ovarian cancers. In the metastatic setting, it has been reported that 80% or more of these tumors express folate receptor alpha. In addition, spontaneous immunity against the folate receptor alpha has been previously reported in breast and ovarian cancer patients which suggests that this target can actually be immunogenic.

Overall, the findings suggested that folate receptor alpha is an attractive target for vaccination and generated the rationale for this vaccine. In this case, the vaccine is called TPIV-200 and is composed of five long peptides that each target different regions of the folate receptor alpha. Those specific peptides were previously identified to elicit T-cell responses in breast and ovarian cancer patients that were vaccinated with this product.

These peptides are HLA Class II restricted, which means that there is not much of a restriction of use in specific patients as its estimated that over 85% of women express the HLA that would recognize at least one of these peptides and that eliminates the need to screen for specific HLA expression in the patients to assess their eligibility. In addition, the vaccine includes GM-CSF as an adjuvant to stimulate dendritic cells.

Cancer Network: It sounds like this is not the first clinical trial to use this vaccine. Can you tell us about the design of this trial and also the rationale for combining these two immunotherapy approaches in ovarian cancer?

Dr. Zamarin: Sure. And you are absolutely right, this is not the first trial to use this vaccine. It has been previously tested for immunogenicity in breast and ovarian cancer patients. That study was not designed to look for outcomes, it was designed to test whether patients respond to this vaccine or not. And in that that study, which was published in Clinical Cancer Research a few months ago, vaccination had elicited T-cell responses in virtually every single patient that received the product. This was one of the findings that led us to try this vaccine in patients with advanced ovarian cancer.

That leads me to the design of this trial. Studies with various vaccines in cancer to data have, unfortunately, demonstrated rather underwhelming efficacy results. This is due to the fact that even once tumor-antigen specific T cells are generated via vaccination, these T cells might not be effective in clearing the tumor because of the multiple inhibitor–mechanisms that are present in the tumor microenvironment.

To overcome these mechanisms, there has been development of novel immunotherapy agents over the last few years including immune checkpoint blockade antibodies with those that target PD-1 or PD-L1 being the prime examples. While in some cancer types, such as melanoma, these antibodies are effective as single agents, in ovarian cancer, these anti-PD1 and anti-PDL1 antibodies have unfortunately not been very effective. Only about 10% of ovarian cancer patients respond to these drugs. Studies in animal models have indicated that combinations of tumor vaccines with agents targeting PD1 or PD-L1 can be very effective in instances when single agents don’t work.

In this trial, we decided to use a combination of this folate receptor alpha targeting vaccine and an agent targeting PD1, an antibody called durvalumab. This was a phase II study using a 2-stage design with 27 patients accrued to the first stage and then another 13 patients accrued to the second stage. The decision to proceed to the second stage was based on the response rate in the first stage.

We reported results on the first stage of the trial. This was a very heavily pre-treated patient population who received a median of four prior lines of chemotherapy and 33% of the patients received five or more lines of prior therapy. To provide a historical perspective, patients with platinum-resistant disease and two prior lines of therapy have a median overall survival of approximately 12 months, so ours is a much more heavily pre-treated population in this trial.

Cancer Network: What are the key efficacy and safety results from this trial?

Dr. Zamarin: To start with the safety, this combination treatment was very well tolerated. The majority of the adverse events that were seen on the study were grade I or II and the most common adverse event was a grade I injection site reaction from the vaccine. This was seen in approximately 40% of the patients. Interestingly, this injection site reaction persisted for a long time, even after discontinuation of the vaccination which was probably reflective of an ongoing response to the vaccine. There were only two grade III/IV immune adverse events that were thought to be clinically significant.

One of the patients developed an immune-related thrombocytopenia and a second patient developed type I diabetes. But overall, the treatments were very well tolerated. With regards to the efficacy results, only 1 patient met the criteria for a partial response and 7 patients or 26% exhibited stable disease. Interestingly, several patients had pretty durable disease stabilization with 22% of patients being on the study beyond 24 weeks.

Based on these findings, the study was closed after the first 27 patients because it did not meet the criteria for the response rate that was needed to activate stage II of the study and the number of patients that benefited was, unfortunately, not higher than what would be expected for those patients treated with an anti-PD1 or anti-PD-L1 antibody alone.

Although the population treated on our study were more advanced and heavily pre-treated than those reported in previous studies. As I mentioned, in this heavily pre-treated patient population, the overall survival is expected to be pretty dismal and in prior recent trials of patients with platinum-resistant disease and two prior lines of therapy, the median overall survival was reported to be approximately 12 months.

In our study, what is interesting is that despite the poor response rate, the median overall survival was 21 months which is much higher than we would expect in this patient population. Because this was a single institution study, we had the opportunity to look at subsequent therapies that the patient received and saw significant responses even to standard chemotherapy, often to drugs that patients had already received. 

Many of the patients went on to receive several lines of therapy and had durable benefit from each of these therapy lines. These findings, while from a relatively small cohort, highlight that cancer immunotherapies can make a durable impact on tumor biology even without an objective response and may affect responses to subsequent treatments.

Cancer Network: Is there a next step that is planned for this combination for ovarian cancer patients or either drug on its own? Will there be additional clinical trials conducted? And you mentioned that this vaccine could potentially affect subsequent therapies, so what are the implications of that?

Dr. Zamarin: We are in the process of performing translational studies to delineate whether the responses to the vaccine or the vaccine-immunotherapy combination were predictive of clinical benefit during the trial and perhaps, predictive of the benefit to subsequent chemotherapies.

We are also trying to understand whether the subsequent responses to chemotherapies were affected by the vaccine alone or by the addition of durvalumab. For this, we are looking at other patient populations that have been treated with immune checkpoint blockade alone.

In general, while the vaccine had a relatively modest efficacy in tumor shrinkage on its own, we believe that it does alter tumor biology and it may be that the tumor microenvironment of advanced tumors is resistant to vaccine-specific T cells and that the vaccine needs to be tested in an earlier setting.

We have initiated a trial of this adjuvant TPIV-200 vaccine in ovarian cancer patients that have completely upfront chemotherapy. Basically, these are the patients that have finished chemotherapy and had a partial or complete response after the upfront treatment and then they receive the vaccine as a maintenance therapy. This trial is currently ongoing.

In addition, given our findings of subsequent chemotherapy responses, it would also be prudent to evaluate the vaccine in combination with chemotherapy to see if responses to chemotherapy, or perhaps, the durability of chemotherapy benefit could be improved with this combination.

The findings also suggest that we should continue to prospectively collect information on the patients that discontinue from our immunotherapy trials because we often come across findings that we otherwise would not be able to capture.

Cancer Network: Thank you so much for joining us today Dr. Zamarin!

Dr. Zamarin: Thank you. It was my pleasure.