Harnessing radiation to improve immunotherapy: better with particles?

Abstract

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.

Figure 1.

Coronal and transverse images of 3D-CRT plan (left), IMRT plan (middle), and proton plan (right) for esophageal cancer. The plans clearly show the large tissue sparing using protons. Treatment plans produced at Loma Linda University Medical Center (CA) details in ref., reproduced with permissions.

Figure 2.

Damage in peripheral blood lymphocytes of a patient during the course of radiotherapy. The karyotype by mFISH shows a translocation involving chromosomes 4 and 8.

Figure 3.

Median values of lymphocyte count in esophageal cancer patients during the course of radiotherapy. Data for protons (1.8 Gy RBE/fraction) and IMRT (1.8 Gy/fraction) are from ref., data for 3DCRT (1.6–2.0 Gy/fraction) and C-ions (2.7–3.6 Gy RBE/fraction) from ref.

Figure 4.

An illustration of immune-mediated effects of ionizing radiation. The green arrow points to the release of HGMB1, that interacts with the toll-like receptor TLR4 activating the dendritic cell maturation. Cartoon from ref., reproduced with permission.

Figure 5.

Concentration of HGMB1 in the medium following irradiation of HeLa cells with sham (0 Gy) radiation (black), 4 Gy C-ions in the plateau region of the Bragg curve, 13 keV/μm (red) and 2 Gy C-ions in the spread-out-Bragg-peak, 70 keV/μm (green). The two doses were chosen to achieve the same 10% survival in irradiated HeLa cells. Data from ref.