A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger?

Abstract

BackgroundPreclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR). In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects.MethodsWe reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED). To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells.ResultsOur results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated.ConclusionOur study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice.

Using immunotherapy to boost the abscopal effect

“…On the basis of the preclinical studies (TABLE 1), the optimal dosing and fractionation strategy for each cancer type has not been determined yet, as both single and fractionated radiotherapy doses have been reported to boost abscopal responses when combined with different immunotherapies 23,34,41 . For example, a preclinical study combining radiotherapy with anti-CTLA4 for breast and colon cancer models concluded that 3 fractions of 8 Gy and 5 fractions of 6 Gy are superior to a single ablative dose of 20 Gy (REF.…”

Synergistic effects of anti-PDL-1 with ablative radiation comparing to other regimens with same biological effect dose based on different immunogenic response

“…A recent meta-analysis study shows when the BED increases, the occurrence rate of abscopal effects also increases due to immunological responses in preclinical models [17]. However, studies have not yet determined whether different regimens with the same BED (when the biological effects of the regimens are equal) have different immunogenic effects, whether they affect tumor recurrence associated with immunological responses, In addition, can these regimens respond differently to combination therapy?…”

Hypofractionated Irradiation Suppressed the Off-Target Mouse Hepatocarcinoma Growth by Inhibiting Myeloid-Derived Suppressor Cell-Mediated Immune Suppression

“…It has been reported that IR with different dose per fraction schemes could change the tumor immune microenvironment (32,33) and create "in situ vaccine" to induce an effective abscopal effect on remote tumors (off target) (34,35). This study, using two HCC mouse models, demonstrated that hypofractionated IR was more effective to create the abscopal effect with a high dose per fraction in the same 40-Gy total dose, that is, ≥4 Gy/fraction.…”