ORLANDO, FL, USA (UroToday.com) - In this session, Dr. Antonarakis presented interim analysis from a Phase II trial evaluating sequencing of ADT and the immunotherapy “vaccine” sipuleucel-T in 68 men with biochemically-recurrent prostate cancer who were randomized over nine months. Sipuleucel-T and ADT were both well tolerated in these patients.
“Sipuleucel-T is an immunotherapy which is currently FDA approved for patients with metastatic and castration-resistant prostate disease. These patients have what's considered more advanced, aggressive disease. There have been fewer studies looking at sipuleucel-T in patients with less advanced disease. Specifically in this trial, we focused on those patients that have what is known as biochemically recurrent prostate cancer (BRPC) -- these patients have an elevated PSA without evidence of any metastases after local therapy which is typically either radical surgery or radiation therapy. Additionally, these patients have not received hormone therapy. These patients are known as hormone-naïve patients or non-castrate patients. The goal of this study was to see what effect the immunotherapy sipuleucel-T might have in these patients.
Listen to Emmanuel S. Antonarakis, MD speak about the findings
"One of the things that has been unclear is: 'What is the optimal sequencing of vaccines such as sipuleucel-T with standard therapies such as androgen deprivation therapy (ADT)'? Since androgen deprivation is one of the reasonable standards for these patients, we wanted to see whether the effect of the androgen deprivation can be augmented or improved by adding an immunotherapy product. Before we could even do that, we had to first answer the question: 'Does the sequence of the immunotherapy and the hormone therapy matter'? In other words, 'is one sequence better than the other in terms of immune results, and potentially clinical results'?
"We designed a small, randomized phase II study of 68 patients where the key question was not so much whether the combination of hormone therapy plus immunotherapy was better than hormone therapy alone, but rather: 'What is the optimal sequencing of hormone therapy and sipuleucel-T'?
"In both groups of the study, all patients got the sipuleucel-T and the androgen deprivation therapy (ADT). The difference in the two arms was simply the sequencing. In one arm of the study, patients got the hormone therapy first, followed 12 weeks afterwards by sipuleucel-T (which was given by three infusions two weeks apart, according to the FDA-approved label). In the other group, patients got the sipuleucel-T first, and six weeks after the first dose of sipuleucel-T they received the androgen deprivation. In both groups, the androgen deprivation therapy (ADT) lasted for a total of 12 months and was then stopped."
Dr. Antonarakis, et al. presented the immune results from that trial..."We don't yet have any clinical information from these patients, such as PSA recurrence or metastases free-survival; that data will come later. We're presenting the immunological results. First, we did find that one of the two sequences was probably better than the other in terms of immune phenomena: the immune response seemed to be better when you gave the hormone-suppression therapy first followed by the (Provenge®) vaccine second. We looked at a number of immune studies to make that determination, the first of which was cytokines. Cytokines represent a number of different signaling proteins that are released into the blood and have immunological properties. As we looked at a range of cytokines, almost every cytokine we looked at was increased more so in the blood of patients that got the hormone therapy first and then the vaccine, rather than the vaccine first and then the hormone therapy. Therefore, a number of cytokines were augmented preferentially in the group of patients that received the hormone therapy first, followed by the vaccine second.
"We then subdivided that into what's known as TH1 cytokines and TH2 cytokines. The TH1 cytokines are related to activation of CD8 T-cells, which are the killer T-cells that theoretically attack and kill the cancer. The most important TH1 cytokine is interferon-gamma (IFN-γ) which increased more in the patients that received the hormone therapy first followed by the vaccine, than the other way around. The second class of cytokines is called the TH2 cytokines, and those are more related with B-cell stimulation and antibody production. In that family as well, 3 or 4 cytokines within that family were also increased more so in the patients who received hormone therapy first followed by the vaccine.
"The second type of immunological analysis that we did was to look at something that is called interferon-gamma (IFN-γ) ELISPOT (it is a test that reflects activated antigen-specific CD8 T-cells); it’s a surrogate measure of the T-cells which are specifically targeting cancer cells that express the target antigen, which in this case is PA2024 (a fusion of PAP and GM-CSF, which is the immunogenic antigen of sipuleucel-T). Although the results of this particular analysis were not statistically significant, there was a numeric increase in the IFN-γ ELISPOT responses for those patients who received the hormone therapy first and the vaccine therapy afterwards, rather than the other way around. Those findings, although they're not yet significant, demonstrate a trend towards increased CD8 T-cell densities in those patients, and that would go in line with the increase in the TH1 cytokines that we also saw in the blood.
"And the third thing we looked at was antibodies against the immunizing antigen PA2024. In both groups of patients, the antibodies against PA2024 were increased across time, but there were no differences in the amount of antibodies against PA2024 between the 2 groups. So, in both groups, the sipuleucel-T vaccine did what it was supposed to do; it increased antibody responses against PA2024. However, within that particular outcome, there were no statistical differences between the two groups.
"In summary, at this point in time, I think we have strong preliminary evidence, at least immunological evidence, suggesting that if you had to choose between the optimal sequence of vaccine first followed by hormone therapy or hormone therapy followed by vaccine, in patients with biochemically-recurrent prostate cancer, it does appear at the current time that the superior sequence in terms of immune activation is to give the hormone therapy first followed afterwards by the vaccine therapy. This finding actually recapitulates some preclinical findings in the laboratory using mouse models of prostate cancer, where people like Dr. Charles Drake and others have shown in the lab that vaccines given after castration therapy (or hormone deprivation therapy) are more effective in that order, suggesting hormone deprivation may act as a immunological “prime,” and sipuleucel-T (or other vaccines) given after the hormone therapy can act as an immunological “boost.”
"Now, we are eagerly awaiting the clinical data from this particular trial. We are specifically looking at PSA recurrence as one of our clinical endpoints, as well as metastases-free survival as a second important clinical endpoint. Our hypothesis is the patients who have received hormone therapy first followed by sipuleucel-T (because they have what appears to be augmented immune responses) may also have improved clinical outcomes -- although that still remains to be seen.”
Presented by Emmanuel S. Antonarakis, Adam Kibel, Robert Claude Tyler, Candice McCoy, Yang Wang, Nadeem A. Sheikh, Charles G. Drake at the 2013 Genitourinary Cancers Symposium - February 14 - 16, 2013 - Rosen Shingle Creek - Orlando, Florida USA
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Brigham and Women’s Hospital, Boston, MA; Dendreon Corporation, Seattle, WA
Reported by Karen Roberts, medical editor for UroToday.com