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Timnik, V.R.* ; Zoeschg, A.* ; Diederich, S.* ; Nefzger, S.M.* ; Huang, Z.* ; Schmid, N.A.* ; Giller, M.* ; Steiger, K.* ; Combs, S.E. ; Kroemer, G.* ; Schmid, T.E. ; Fischer, J.C.*

Experimental investigation of hematological toxicity after radiation therapy combined with immune checkpoint inhibitors.

Int. J. Radiat. Oncol. Biol. Phys. 123, 523-535 (2025)

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PURPOSE: Combining immune checkpoint inhibitors (ICIs) with radiation therapy (RT) has led to significant advancements in cancer treatment. However, evidence from clinical and experimental studies suggests that this combination may increase hematopoietic and lymphatic toxicity. This study aims to investigate the effects of the concurrent application of ICIs (anti-PD-1 and anti-CTLA-4) on radiation-induced hematopoietic and lymphatic injuries under standardized and controlled experimental conditions. MATERIALS AND METHODS: We utilized various experimental models in C57BL/6 and BALB/c mice to evaluate the impact of ICIs combined with RT on the hematopoietic system. These models involved different RT doses, regimens, and target sites in both healthy and tumor-bearing mice. RESULTS: Our findings showed that the concurrent use of ICIs did not meaningfully affect post-RT pancytopenia kinetics or the regeneration of specific blood cell lineages over time. Consistently, combining RT with ICIs did not significantly enhance DNA damage in immune cells within the bloodstream. This outcome was comparable across different RT doses, regimens, and target sites and was reproducible in both tumor-bearing and non-tumor-bearing mice. Additionally, there were no significant increases in late side effects, including reductions in bone marrow cell counts or megakaryocyte numbers, after combined radioimmunotherapy. CONCLUSION: These findings suggest that combining ICIs with RT does not exacerbate hematological toxicity. This information is valuable for interpreting adverse events in clinical trials involving radioimmunotherapy and for predicting potential hematological side effects in cancer patients receiving these treatments.

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