Prostate cancer Immune profiling before, during and after HDR-brachytherapy in local relapsed prostate cancer.

Immunotherapy (IO) is currently revolutionizing the field in oncology. However,
prostate cancer until now fails to respond to classical IO, like PD-1 and
CTLA-4 inhibitors.
Several reasons are mentioned:
Firstly, the tumor micro-environment consist of a whole series of normal immune
cells, together with endothelia, and eventually cancer cells. This is a dynamic
immunosuppressive network: a lack of this network could be form a major
obstacle to immunotherapeutic interventions in prostate cancer.
Secondly, the expression of the programmed death 1 (PD-1) receptor and its
ligand, PD-(L)-1, are detected at extremely low levels ( > 1%), suggesting low
anti-tumor T-cell activity in combination with low mutational indices as the
most probable explanation for failed therapy.
Thirdly, a possible resistance mechanism is upregulation of different immune
regulation mechanisms involved in carcinogenesis (like CXCL12 also known as
stromal-cell derived factor-1*, SDF-1*)
Fourthly, other processes are identified like IL-23, CXCL12 produced by the
myeloid derived suppressor cells acting as a driver of metastatic potency which
is proven in animal models.

Radiotherapy (RT) delivered to the primary tumor impacts both tumor cells and
surrounding stromal cells. RT-induced cancer cell damage exposes tumor-specific
antigens that make them visible to the immune system and leads to improved
priming and activation of cytotoxic T cells. RT-induced modulation of the tumor
microenvironment may also facilitate the recruitment and infiltration of immune
cells.

The main-hypothesis: is that low-dose HDR-brachytherapy of prostate cancer will
make from an immunologically *cold* (no T-cell infiltrations) prostate cancer
an immunologically *hot* (CD4 and CD8-cell infiltrations) tumor.

It is obvious that more research is needed to clarify all these underlying
mechanisms. Consequently methods of enriching the pool of prostate cancer
recognizing T-cells infiltrating the tumor will likely enhance the efficacy of
checkpoint inhibitors. RT can alter the tumor microenvironment by 1/ attracting
T-cells through the release of chemokines and 2/ broadening up the immune
repertoire.

The aim of this small pilot study is to explore the immunostimulary effects of
RT in the context patients having a solitary local tumor relapse within the
prostate after previous RT. Moreover to look at PD-(L)-1, CXCL12, IL-23
receptor and T-cell infiltration in biopsies of local relapses of prostate
cancer patients.

To investigate that low-dose HDR-brachytherapy of prostate cancer will make
from an immunologically *cold* (no T-cell infiltrations) prostate cancer an
immunologically *hot* (CD4 and CD8-cell infiltrations) tumor.

This will be a prospective analysis of repeated biopsies from 10 patients.

Very low risk: it is an unique opportunity to take biopsies in this setting.
The therapeutic context of 3 consecutive treatment sessions allows us to
repeatedly (before and multiple points following RT) sample tumor histology
from these patients without causing any additional burden. This extremely
increase the feasibility of the project. Furthermore a blood sample taking
during the anesthesia is of no additional burden.

It is an unique opportunity to study molecular interactions of radiation and
the immune system within human cancer histology.