Glioblastomas are extremely malignant tumors of the brain; despite different therapeutic
approaches, the median survival is only about 1 ½ years. This makes the need for action
to investigate the mechanisms of action of new drug approaches all the more urgent. In
the therapy of malignant intracerebral neoplasms, immunological processes between tumor
and endogenous immune response represent a key phenomenon for understanding response.
In the CheckMate-143 trial, an anti-programmed cell death-1 monoclonal antibody
disappointed by ineffectiveness in the vast majority of Glioblastoma patients (although a
minority benefited significantly). This will be largely explained by the immunological
milieu of the tumor. One-third of the cells in Glioblastoma constitute the microglia or
monocyte cell population. These immunocompetent cells also serve as a protective shield
for the Glioblastoma against a possible therapy-induced endogenous immune response.
Corresponding research is being conducted preclinically on cell cultures, brain tissue
samples (immunohistochemistry, autoradiography) and in animal models. A major role is
played by microglial cells, which perform the immunocompetent function in the brain.
Microglia and monocytes have an activation state as well as an opposite of a suppressive
one in their immunological function. This M1 or M2 concept is similar to the old
postulated Th1 or Th2 principle in lymphocytes. Different purinergic receptors -P2Y12R
and Purine receptor 2XR - are active here, respectively. Recently, antibody-based
positron-emitter-labeled tracers have been developed for this purpose and thus, in
principle, positron emission tomography (PET) imaging in vivo is possible.
The subsequent clinical relevance of a better understanding of these processes would
consist in a combined therapeutic concept, in which additionally an immunomodulation in
the desired direction of the regional activity of the immunocompetent cells could take
place.
Methods for in vivo imaging of activated microglia in positron emission computed
tomography scanners (PET) have already been developed - e.g. translocator protein
positron emission tomography (TSPO-PET) by detecting mitochondrial activation of
microglial cells. Here, however, it is not possible to distinguish between pro- and
anti-inflammatory function of the immunocompetent cells. However, it is possible to do so
by specific receptor recognition. For example, the purinergic receptor P2X7 is only
expressed during proinflammatory activity. For this purpose, the positron emission
tomography scanners (PET) tracer [18-Fluorine] Johnson & Johnson (JNJ)-64413739 has been
developed in the academic research field. Patient cohort studies are still pending in
this regard. Our intention is to investigate in patients with untreated Glioblastoma
whether effective imaging of immunological disease activity is possible in this way.
