Combining Heavy-Ion Therapy with Immunotherapy: An Update on Recent Developments

Abstract

Clinical trials and case reports of cancer therapies combining radiation therapy with immunotherapy have at times demonstrated total reduction or elimination of metastatic disease. While virtually all trials focus on the use of immunotherapy combined with conventional photon irradiation, the dose-distributive benefits of particles, in particular the distinct biological effects of heavy ions, have unknown potential vis-a-vis systemic disease response. Here, we review recent developments and evidence with a focus on the potential for heavy-ion combination therapy.

Keywords: abscopal effect; combination immunotherapy-radiotherapy; heavy-ion radiotherapy; radiation-induced immunogenic cell death.

Figure.

Overview of mechanisms involved in the immunogenicity of (particle) radiation exposure. Immunogenicity of radiation and the related immunogenic cell death generally depend on antigenicity and adjuvanticity, both important for an effective immune response. Antigenicity of radiation comprises increased expression of various tumor-associated antigens (TAAs) and major histocompatibility complex-I (MHC-I), thus enhancing presentation of neo-antigens. Adjuvanticity in this context describes a variety of molecular processes, predominantly the release of damage-associated molecular patterns (DAMPs), including high-mobility group protein 1 (HMGB1) and adenosine triphosphate (ATP) as well as the translocation of calreticulin (CRT) from the endoplasmatic reticulum (ER) to the cell membrane. The release of ATP seems to be related with radiation-induced autophagy, which may be triggered via unfolded protein response (UPR) stimulation. Particle radiation has further been associated with a decreased expression of programmed death-ligand 1 (PD-L1), possibly indicating a chance for greater T-cell activity. The dosing seems to play a major role in the activation of an effective immunogenic response upon radiation exposure and a dualism of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) on the one hand and three prime repair exonuclease 1 (Trex1) on the other hand has been reported to guide such activation. The underlying common factor of this dualism seem to be cytosolic double-stranded DNA (dsDNA) fragments, whose rising concentration results in the activation of STING via dsDNA sensing by cGAS and a subsequent increased expression and secretion of type I interferon (type I IFN). Nonetheless, a certain threshold concentration of cytosolic dsDNA is assumed, after which Trex1 activation leads to the degradation of dsDNA, hence resulting in a lower type I IFN expression. This suggests a minimum dose as well as an upper threshold dose that guides effective immune responses and remains to be investigated for particle radiation. Ways for dsDNA to reach the cytoplasm upon radiation stress have recently been discussed and may involve nuclear envelope rupture of the cell nucleus or the involvement of micronuclei (MN) formation and the subsequent rupture of their envelopes. Particle radiation, which features an increased formation of MN in many cell lines may hence be considered particularly effective in the induction of an immune response.