BETHESDA, MD USA (UroToday.com) - Dr. David Lubaroff initially gave an overall summary of immunotherapy. Immunotherapy is the use of immune responses, generated by tumor-specific antigens, to treat cancer. The classic view of anti-tumor immunity is that tumors release associated antigens which enter draining lymph nodes where antigen-present cells are present and which process these antigens to immunogenic peptides and present them to CD4 and CD9 effector cells. This interaction transforms these cells into anti-tumor immune cells, which then enter circulation and hone back to the tumor cells. Multiple tumor antigens for prostate cancer have been identified, including PSA and PAP. In their research, Dr. Lubaroff’s group focused on PSA as an antigen and used it to develop Adenovirus/PSA vaccine.
He subsequently presented their data on pre-clinical, phase I and phase II trials with a goal to demonstrate “proof of principal” that a PSA-transformed adenovirus could induce anti-PSA immune responses and that these responses could mediate the destruction of PSA-secreting tumor cells. Pre-clinical trial in Adenovirus/PSA-vaccinated mice showed strong anti-PSA immune cells with 70% surviving mice rejecting cancer. In phase I clinical trials in men with measurable metastatic CRPC, 34% produced anti-PSA antibody responses and 68% produced anti-PSA T-cell responses. 46% demonstrated an increase in PSADT, and 55% survived longer than predicted using Halabi nomogram. To patients’ benefit, there were no major vaccine-related adverse events, even at high doses. Phase II trials were performed in two groups of patients—one group with first evidence of biochemical recurrence and another group with low burden of metastatic CRPC, and 89% of all patients studied, to date, produced anti-PSA T-cell responses. Additionally, both groups of patients has an increase in PSADT.
Subsequent to discussing favorable results on PSA/Adenovirus vaccination trials, Dr. Lubaroff argued that “all is not simple as it looks; there are negative regulatory elements or checkpoints that act to prevent or dampen anti-tumor-antigen immune responses.”
Up to now, most work has focused on the stimulatory aspect of immunotherapy against cancer cells, i.e., vaccinations against antigens. However, excitingly, several negative elements of immune response have been identified, and inhibitors of these negative elements have identified with the goal to boost anti-tumor immune response. These negative elements of immune response are focused on Treg immune cells, which have CTLA4 and PDL1 checkpoint receptors that dampen immune responses.
CTLA-4 acts to dampen immune responses after the induction of antigen-specific responses. PD-1 receptor is responsible for T cell exhaustion and occurs late in immune response, in the effector phase. Inhibitors of either of these receptors have been identified (iplimumab for CTLA-4 receptor, Nivolumab among many for PD-1 receptor).
Studies on these immune-checkpoint receptors are ongoing. A recent study (Kwon et al,, The Lancet Oncology 2014) on the use of iplimumab versus placebo after radiotherapy in patients with metastatic castrate-resistant prostate cancer showed median survival was 11.2 months with iplimumab and 10.0 months with placebo. However, unlike vaccination-based immunotherapies, the checkpoint receptor inhibitors have significant immune-related side effects with up to 26% Grade III/IV adverse events, including dermatitis and colitis.
Overall, Dr. Lubaroff gave a nice overview on the potential of immunotherapy in prostate cancer. He also showed exciting immune targets that are currently being investigated for therapeutics and which may show promise.
Presented by:
David M. Lubroff, PhD
University of Iowa
Reported by:
Mohammed Haseebuddin, MD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA