Immune response dynamics in Gleason 9-10 patients undergoing radiotherapy: A proof of principle study
Lucas C. Mendez MD, Odette Cancer Centre, Sunnybrook Health Sciences Centre
Stanley Liu MD, PhD, Odette Cancer Centre, Sunnybrook Health Sciences Centre
Lead Investigator Bio:
Dr. Mendez, MD, is an early-career radiation oncology clinical fellow at Sunnybrook-Odette Cancer Centre engaged in developing creative and new treatment solutions in prostate cancers. He has been awarded with a prostate research grant by Ride for Dad in 2017, and is currently a co-principal investigator on a clinical trial (DELIGHT trial) investigating the role of a novel prostate brachytherapy technique. He also has an appointment as a Master of Science Graduate student in the Institute of Medical Science at the University of Toronto.
Dr. Liu is a clinician-scientist who treats prostate cancer patients at Sunnybrook Odette Cancer Centre, and runs a translational research lab (stanleyliulab.com) which has five lab members including graduate students, clinical fellows and residents, research associate and technician. He performed his PhD, MD and residency studies in Radiation Oncology at University of Toronto, followed by a translational research fellowship at University of Oxford. He has worked at Sunnybrook since 2011, and his overall research interests are in determining how small genetic material (microRNA) may make certain types of prostate cancer more likely to recur after radiation treatment. Additionally, his team is investigating patient biofluids as ‘liquid biopsies’ to help personalize management and treatment decisions for prostate cancer patients.
Treatment of prostate cancer patients who have aggressive cancer (Gleason 9-10) with external beam radiotherapy and hormones or surgery, results in poor outcomes. Therapies using prostate brachytherapy with external radiotherapy and hormones have shown more promising outcomes. In a recent study, this combined treatment was compared to surgery or external beam radiotherapy with hormones and the results demonstrated a reduced number of metastasis and prostate cancer death in the group using brachytherapy. Currently, it is not clear how a local treatment, such as prostate brachytherapy, results in less metastasis. One possible explanation for this clinical finding is that an extremely high dose of radiation could result in significant tumour death, and aid the immune system in recognizing tumour cells. This proof of principle research project aims to study and compare the underlying immune response between patients treated with external radiotherapy and hormones or brachytherapy plus external radiotherapy and hormones.
High Gleason (9-10) prostate cancer behaves aggressively with high incidence of metastatic spread. Retrospective studies demonstrate that brachytherapy boost (BT) and EBRT is superior to EBRT or surgery in this setting. This was seen despite the fact that patients treated EBRT alone received a longer duration of ADT. The metastasis-specific survival curves diverged early suggesting that reduction in metastasis may not entirely result from better local control. We hypothesize that BT functions as an “in situ prostate cancer vaccination” in Gleason 9-10 prostate cancers and primes the immune system against micrometastatic spread of disease. We will investigate potential differences in immune system response between Gleason 9-10 prostate cancer patients treated with BT+EBRT+ADT versus EBRT+ADT. Ten patients (EBRT+ADT (n=5) and BT+EBRT+ADT (n=5)) will have blood drawn before, during and after treatment. Flow cytometry for T lymphocyte and subsets will assess immune response and activation. Patients treated with BT boost will have a transperineal prostate biopsy immediately prior to BT to correlate with immune changes in the blood. This research may help clarify the current unexplored immunological events associated with BT, and provide an avenue for immune response as a new biomarker for early treatment response.
Impact on prostate cancer patients:
In many different oncological settings such as melanoma, lung and renal cell cancers, immunotherapies have successfully increased survival. These drugs were able to trigger the immune system against malignant cells, often resulting in an impressive systemic response. In the prostate cancer setting, no similar benefit has yet been shown by immunotherapy, except for the small increment in survival appreciated with Sipuluecel-T in the metastatic scenario. Recent results presented by Kishan and collaborators may challenge this current paradigm, as an important reduction in metastatic events was seen in the group receiving prostate brachytherapy when compared to the other groups. Importantly, this benefit was sustained even though the patients in the EBRT+ADT group had used ADT twice as long as patients in the BT arm. Therefore, it is possible that the mechanism through which brachytherapy results in higher metastasis-free survival is through specific immune system activation due to significant tumor cell death and subsequent tumor-antigen presentation. This study aims to investigate immune response and lymphocyte activation kinetics after EBRT+ADT or BT+EBRT+ADT and it is possible that this proof of principle evaluation may help clarify the current unexplored immunological events associated with HDR-BT.