Are charged particles a good match for combination with immunotherapy? Current knowledge and perspectives

Treatment of cancer nowadays commonly applies combinations of local as well as systemic therapies. Among these, the combination of photon radiotherapy (RT) and immunotherapy (IT) has partly generated promising results. The synergy is based on the immune-mediated abscopal effect, which arises from irradiation (Abuodeh et al., 2016; Formenti and Demaria, 2009) and, occurring seldom as a spontaneous response, can be enhanced by adding IT (Gonzales Carazas et al., 2021). However, despite having evoked hope for the treatment of metastatic cancer disease mainly due to results of pre-clinical studies, this synergy does not always translate in a response in clinical studies, which, along with the study design, can be attributed to RT being Janus-faced featuring both immunostimulating and immunosuppressive effects (Monjazeb et al., 2020). For the general role of RT in combination with IT and the underlying cellular and molecular mechanisms, involving, e.g., the cancer-immunity cycle, we refer to further reviews (Chen and Mellman, 2013; Rodríguez-Ruiz et al., 2018). As revealed in current clinical studies, this combination is highly encouraging especially for the treatment of metastatic cancer disease (for a recent overview see (Zhang et al., 2022)). In the context of combination with RT, the IT part mainly uses immune checkpoint inhibitors (IPI).

There is accumulating data from recent clinical trials, e.g., in non-small-cell lung cancer (NSCLC) (Antonia et al., 2017; Faivre-Finn et al., 2021), prostate (Fizazi et al., 2020) and pancreas cancer (Zhu et al., 2022) showing improved overall survival or progression-free survival in patients treated with a combination of RT and IT, compared to patients receiving single RT alone. One of the first studies, conducted by Formenti and colleagues, reported that patients with NSCLC, not responding to IT did respond when they additionally received RT (Formenti et al., 2018).

Nonetheless, the mortality of patients remains high, and many do not respond, or their response is transient. Current research and clinical trials are hence focused on the components of combined therapy, e.g., dose and fractionation regimen, and also on the number of metastatic sites to be irradiated or the timing of IPI administration relative to irradiation (Brooks and Chang, 2019; Helm et al., 2022; Zhang et al., 2022). To date not fully explored, the radiation quality, namely charged particle therapy (CPT) represents such components with advantages in combination therapy. In the following, we will summarize the current knowledge of its application in combination with IT. For a comprehensive review on the combination of RT and IT, we refer to Marcus and colleagues (Marcus et al., 2021), while we will focus on external beam radiotherapy of CPT. As for targeted radionuclide therapy or targeted alpha-particle therapy in the context of combination therapy we refer to Keisari and Kelson (Keisari and Kelson, 2021) as well as Constanzo and colleagues (Constanzo et al., 2022).

To appreciate the rationale of a combination of CPT with IT, it is pivotal to understand the basic differences in radiobiology between RT and CPT, which we therefore briefly introduce in the following. Physical characteristics of charged particles, i.e., accelerated protons and heavy ions, and the biological effects in irradiated tissue are advantageous for their use in radiotherapy. The most important features of CPT are the sparing of the healthy, normal surrounding tissue and, for charged particles heavier than protons, the enhanced biological effectiveness in the target volume (i.e., the tumor). The peculiar detailed physical characteristics are beyond the scope of this work but are reviewed comprehensively elsewhere (Durante et al., 2021; Schardt et al., 2010; Weber and Kraft, 2009). We will only briefly address them in the following and provide an overview of the resulting characteristic biological effects rendering radiobiology of RT and CPT different.

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