Maarten van der Doelen

Chapter 8

In conclusion, next to parameters related to the extent of disease, the PSMA uptake on baseline 68 Ga-PSMA PET is predictive for the response to 177 Lu-PSMA RLT and prognostic for OS. Future studies on biomarkers for early response monitoring are essential when implementing PSMA-targeting RLT as new therapeutic option for patients with mCRPC. Effect evaluation of radium-223 therapy Standard of care during radium-223 therapy currently includes monthly biochemical tests (complete blood count plus tumor markers) and conventional imaging with bone scintigraphy and CT of thorax, abdomen and pelvis before and after radium-223 therapy. (25) Next to these more traditional outcome measures, newer response outcomes, including immunological biomarkers, may provide information about treatment response. Immunomonitoring during radium-223 therapy It is mechanistically still largely unclear how radium-223 translates to survival benefit. Preclinical studies have shown that radium-223 localizes at the bone surface adjacent to the tumor and has a dual targeting mode-of-action there; radium-223 induces tumor cell death and suppresses tumor-induced pathologic bone formation in the tumor microenvironment of bone metastases. (26, 27) This suggests an indirect mechanism of action. It is known that ionizing radiation triggers an immune response via the release of danger-associated molecular patterns which induce neo-antigen presentation and stimulate antigen-presenting cells to activate cytotoxic T lymphocytes, thereby inducing immunogenic cell death. (28) Radium-223 is an alpha emitter and has the ability to induce double-strand DNA breaks in prostate cancer cells, which could lead to immunogenic cell death. The latter event could ignite an systemic immune response. (29) In chapter 3 of this thesis, we showed that a substantial decrease in absolute lymphocyte counts occurs during radium-223 therapy. This decrease in absolute lymphocyte counts was accompanied by a decrease in hemoglobin and platelet levels, and might be a consequence of the direct cytotoxic effects of radium-223 on the bone marrow in patients with already impaired bone marrow reserves due to extensive bone metastases and prior hematotoxic chemotherapy in the majority of patients. Next to the decreasing level of lymphocytes, we observed an increase in the proportion of T cells that expressed costimulatory or inhibitory checkpoint molecules. Checkpoint molecules play an essential role in the regulation of immune cell activity. We found both an increase in a costimulatory checkpoint molecule (ICOS) as well as in inhibitory checkpoint molecules (PD-L1, PD-1, and TIM-3). Thus, together with the relative increase in regulatory T cells

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