Herter-Sprie, Grit | Herter, Jan | Ullrich, Roland - B 02

Despite the recent success of immune checkpoint inhibitor (ICI)-based treatments in cancer patients, improved strategies are urgently needed to benefit more patients. Here, we aim to investigate the clinical phenomenon of the abscopal effect potentially providing substantial benefit to patients receiving localized cancer therapies.

This research focuses on gaining mechanistical insights of the abscopal effect and how it could be triggered clinically to improve tumor control distant to the treated region.

Cancer remains to be a leading cause of death worldwide, accounting for almost 10 million deaths in 2018 – which represents 1 in 6 deaths overall. The recent rediscovery of immunotherapeutics in cancer therapy has also led to a reinvigorated interest in the “abscopal effect”: Originally described in 1953 by R.H. Mole, this effect describes the phenomenon that following local tumor treatment, most commonly with radiation therapy (RT), tumor lesions outside the area of treatment exhibit a treatment response.

The abscopal effect, if it was to be reliably induced, could provide tremendous clinical benefit as the foremost problem of localized therapies is recurrence at distant sites – most likely from tumor cells not yet detectable by imaging modalities, but resistant to chemotherapy due to a state of cell senescence.

While it appears plausible that the abscopal effect is mediated by an immune reaction, the actual underlying mechanism of the abscopal effect remains unknown. It is the context of a wider spread use of immune checkpoint inhibitors (ICIs) that this effect has been rediscovered; however, even though its incidence has been reported in conjunction of RT and immunotherapy, the current state of knowledge goes little beyond anecdotal reports. Here, we propose to test the hypothesis of ICI-facilitated off-target effects following RT in both a setting of a known antigen and in a translational polyclonal environment using different radiation strategies and treatment concepts.

1.  Which fractionation strategy is clinically most beneficial?
2.  Does activation of T cells correlate with the treatment response?
3.  Which role plays macrophage repolarization in the abscopal effect?
4.  Can the occurrence of the abscopal effect be facilitated?

In our previous work (Herter-Sprie et al. Nature Communications 2014), we were able to introduce a novel model of Kras-driven murine lung cancer to perform highly translational research. Particularly, like in the human setting, lung cancer originates from a limited number of cells and grows in a single nodule fashion upon activation of human cancer-mimicking oncogenes.

This model has been used to study the effects of adjuvant PD-1 inhibition following RT (Herter-Sprie et al. JCI Insight 2016) – as it has now been implemented into the clinical standard of care. Interestingly, we observed treatment responses of contralateral lung tumors, although only one tumor lesion had been irradiated directly: Without RT to any lung tumor, no change in tumor volume or growth was detected. This is particularly noteworthy, as the PD-1 blocking therapy did not yield in treatment efficiency in our model of Kras-driven lung cancer – a lung cancer entity so far without any viable treatment options.

We thus hypothesize that the observed abscopal effect was mediated by an induced immune reaction following RT applied to the contralateral tumor and sustained with adjuvant PD-1 blocking therapy.