Toward prediction of abscopal effect in radioimmunotherapy: Pre-clinical investigation

Abstract

Purpose Immunotherapy (IT) and radiotherapy (RT) can act synergistically, enhancing antitumor response beyond what either treatment can achieve separately. Anecdotal reports suggest that these results are in part due to the induction of an abscopal effect on non-irradiated lesions. Systematic data on incidence of the abscopal effect are scarce, while the existence and the identification of predictive signatures or this phenomenon are lacking. The purpose of this pre-clinical investigational work is to shed more light on the subject by identifying several imaging features and blood counts, which can be utilized to build a predictive binary logistic model. Materials and methods This proof-of-principle study was performed on Lewis Lung Carcinoma in a syngeneic, subcutaneous murine model. Nineteen mice were used: four as control and the rest were subjected to combined RT plus IT regimen. Tumors were implanted on both flanks and after reaching volume of ~200 mm3 the animals were CT and MRI imaged and blood was collected. Quantitative imaging features (radiomics) were extracted for both flanks. Subsequently, the treated animals received radiation (only to the right flank) in three 8 Gy fractions followed by PD-1 inhibitor administrations. Tumor volumes were followed and animals exhibiting identical of better tumor growth delay on the non-irradiated (left) flank as compared to the irradiated flank were identified as experiencing an abscopal effect. Binary logistic regression analysis was performed to create models for CT and MRI radiomics and blood counts, which are predictive of the abscopal effect. Results Four of the treated animals experienced an abscopal effect. Three CT and two MRI radiomics features together with the pre-treatment neutrophil-to-lymphocyte (NLR) ratio correlated with the abscopal effect. Predictive models were created by combining the radiomics with NLR. ROC analyses indicated that the CT model had AUC of 0.846, while the MRI model had AUC of 0.946. Conclusions The combination of CT and MRI radiomics with blood counts resulted in models with AUCs of 1 on the modeling dataset. Application of the models to the validation dataset exhibited AUCs above 0.84, indicating very good predictive power of the combination between quantitative imaging and blood counts.

Imaging approaches and radiomics: toward a new era of ultraprecision radioimmunotherapy?

“…Regarding the prediction of out-of-field ‘abscopal’ response, a preclinical study evaluated CT and MRI radiomics on Lewis Lung Carcinoma in a syngeneic, subcutaneous murine model. 76 Tumors were implanted on both flanks of 19 mice. Fifteen mice received radiotherapy on the right flank (3×8 Gy) followed by immunotherapy (anti PD-1), and four mice presented abscopal response on the left flank.…”

“…This proof-of-concept study, although very promising, must be interpreted with caution due to the low number of mice and events (occurrence of abscopal response). 76 However, it suggests that radiomics may help to identify lesions favorable to the occurrence of an abscopal response. Such biomarkers would be of particular interest to guide potential low-dose immunogenic radiotherapy to improve systemic responses.…”

On target methods to induce abscopal phenomenon for Off‐Target effects: From happenstance to happenings

“…43 Interestingly, Mihaylov et al were able to elicit abscopal response in murine models where abscopal response rate of 26% were noted when treated with 24Gy/3# followed by PD-1 antibody therapy which was validated by CT and MRI radiomics imaging and lower pretreatment neutrophil to lymphocyte ratios. 44 In clinical practice, one phase 2 trial looked at sequencing combinatory or sequential SBRT with optimal delivery of ipilimumab in tumors with liver or lung spread. Out of 106 patients, clinical benefit rate (CBR) in the distant out of field lesions were 26% in both arms while it was higher (28% vs 20%) when ipilimumab was staggered after RT in contrast to simultaneous administration.…”

Oligometastatic Disease in Prostate Cancer. Evolving paradigm: current knowledge, diagnostic techniques and treatment strategies

“…Intensive research is underway to uncover the biological and biochemical (immunology) basis [82], [83] of its mechanisms of action as well as the possibility of exploiting its impact in regular oncology practice.…”