Immune Response Evaluation in Oligorecurrent and Oligoprogressive Prostate Cancer Patients Treated With SBRT

Prostate cancer (PC) represents the second most common cancer in men worldwide, managed with surgery or radiotherapy (RT) in case of localized disease.

Advanced PC can metastasize and often presents as an oligometastatic state, defined as an intermediate state between localized and widespread diffused disease. Oligometastatic PC is characterized by the presence of a limited number of metastases, commonly 1 to 5 lesions. Recently, the ESTRO-EORTC collaboration characterized the oligometastatic disease and provided a classification into oligorecurrence, and oligoprogression, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy.

Most common sites of metastases from PC are bones and lymph nodes. Different studies have been already published for oligometastatic PC patients. Singh et al. reported that a number of metastases limited to 5, developed during follow-up after curative treatment of primary tumor, is significantly associated to a better 5-year survival rate (73% vs 43% of patients with more than 5 metastases).

In case of limited number of metastases, stereotactic body radiation therapy (SBRT) seems to be effective but its role in the management of metastatic PC is still debated, due to the paucity of prospective and randomized trials.

We reported the outcome of 92 oligometastatic PC patients treated with SBRT, reaching 1 and 3 years control of treated lesions in 90.9% (95%CI 81.8 - 95.6) and 85.5% (95%CI 74.4 - 92.0), and a median overall survival of 91.6 months.

Ost et al. conducted a randomized trial comparing surveillance versus metastases directed therapy in a sample of 62 hormone naïve metastatic PC patients. With a median follow-up time of 3 years, the median ADT-free survival was 13 months for surveillance group versus 21 for the treatment group. In terms of PFS, the median time until progression was 6 months for the surveillance group, as compared with 10 months for the MDT group (p = 0.03).

Main benefits from SBRT in oligometastatic setting are potentially the increasing time of freedom from systemic therapy in naïve patients the delay of the intensification of systemic therapy in patients already under treatment. Moreover another relevant advantage from SBRT is the ability to modulate the tumor immune microenvironment as showed by preliminary studies. In particular, SBRT has been shown to induce immune responses in treated patients with potentially improved tumor control.

RT is able to elicit a potent anti-tumour immune response, driven by the activation of T cells infiltrating the tumor and the increase of antigen-presenting cell cross-presentation, and on the other hand, also seems to enhance immunosuppression in cancer, mainly mediated by the recruitment and activation of anti-inflammatory and pro-tumorigenic myeloid cell subsets. The immune landscape of patients may interfere with the efficacy of radiation therapy and, on the other side, SBRT may modulate the immune response by driving immuno-tolerance.

The impact of RT may vary depending on tumor type and time of delivery. In addition the immune modulation determined by RT may depend on the dose per fraction. On this regard ablative dose of fractionated radiations were shown to elicit an anti-tumorigenic response mediated by T cell activation in a model of breast cancer, that was not observed at conventional doses. So far, no relevant studies have been published regarding the role of SBRT in the immune modulation of metastatic PC patients. Neither the combination of SBRT and androgen deprivation has been explored prospectively in terms of immune response. This however is an area of interest, considering that preclinical studies showed that hormonal therapy seems to increase the numbers of circulating naive T cells shortly after beginning of ADT, and decrease numbers of circulating CD4+ Treg. At the same time infiltrating myeloid subsets have been reported to facilitate resistance to ADT in mouse models of PC.

At the moment there is a lack of data in the setting of oligometastatic PC in particular regarding the interaction between ablative SBRT, ADT and patient's immune system response.

The hypothesis underlying this project consists in the idea that the patient's immunological context, RT and ADT may interact in the context of metastatic PC. Indeed the immune landscape of patients may interfere with the efficacy of SBRT and on the other side RT may modulate the immune response by driving immunotolerance.

Scope of the study will be to investigate the immune modulation after SBRT in:

• patients with diagnosis of oligorecurrence during a treatment-free interval
• patients with oligoprogression or oligopersistance during hormonal therapy