Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination.

PURPOSE/OBJECTIVE: Radiotherapy (RT) induces an immunogenic antitumor response, but also some immunosuppressive barriers. It remains unclear how different fractionation protocols can modulate the immune microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors (ICI) in association with RT. However, only few trials aim to optimize the RT fractionation to improve efficacy of these associations. Here we sought to characterize the effect of different fractionation protocols on immune response with a view to associating them with ICI. MATERIALS/METHODS: Mice bearing subcutaneous CT26 colon tumors were irradiated using a SARRP device according to different radiation schemes with a same biologically effective dose. Mice were monitored for tumor growth. The radiation immune response (lymphoid, myeloid cells, lymphoid cytokines and immune checkpoint targets) was monitored by flow cytometry at different timepoints after treatment and by RNA sequencing analysis (RNAseq). The same radiation protocols were performed with and without inhibitors of immune checkpoints modulated by RT. RESULTS: In the absence of ICI, we showed that 18x2Gy and 3x8Gy induced the longest tumor growth delay compared to 1×16.4Gy. While 3x8Gy and 1×16.4Gy induced a lymphoid response (CD8+ T-cells, Regulators T-cells), 18x2Gy induced a myeloid response (myeloid-derived suppressor cells, tumor-associated macrophages 2). The secretion of granzyme B by CD8+ T cells was increased to a greater extent with 3x8Gy. The expression of PD-L1 by tumor cells was moderately increased by RT, but most durably with 18x2Gy. T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression by CD8+ T-cells was increased with 3x8Gy, but decreased with 18x2Gy. These results were also observed with RNAseq. RT was dramatically more effective with 3x8Gy compared to all the other treatments schemes when associated with anti-TIGIT and anti-PD-L1 (9/10 mice in complete response). The association of anti-PD-L1 and RT was also effective in the 18x2Gy group (8/12 mice in complete response). CONCLUSION: Each fractionation scheme induced different lymphoid and myeloid responses as well as various modulations of PD-L1 and TIGIT expression. Furthermore, 3x8Gy was the most effective protocol when associated with anti-PD-L1 and anti-TIGIT. This is the first study combining RT and anti-TIGIT with promising results; further studies are warranted.

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response.

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology.

Combination of breast imaging parameters obtained from 18F-FDG PET and CT scan can improve the prediction of breast-conserving surgery after neoadjuvant chemotherapy in luminal/HER2-negative breast cancer.

INTRODUCTION: The luminal/Human Epidermal growth factor Receptor 2 (HER2) negative subtype of breast cancer has low chemo-sensitivity. When neoadjuvant chemotherapy (NAC) is indicated in this subtype, before a possible breast-conserving surgery (BCS), it is more reasonable to target tumor shrinkage than complete pathological tumor response. We aimed to identify breast and tumor 18Fluoro-deoxy-glucose (18F-FDG) PET-CT scan imaging features for the early prediction of BCS after NAC in luminal/HER2 negative subtypes of breast cancer. MATERIAL AND METHODS: Seventy-seven consecutive women with luminal/HER2-negative breast cancer for whom BCS was initially not feasible and NAC was prescribed, to decrease tumor size before surgery, were included retrospectively. An 18F-FDG PET-CT scan exam was performed before and after the first course of NAC. RESULTS: After NAC, 36% (28/77) of women had a mastectomy and 64% (49/77) underwent BCS. Patients with a mastectomy had lower total breast volume (BVtotal) (p = 0.002), lower decrease in Δmetabolic tumor volume (ΔMTV) (p = 0.03) and lower SUVmax2 (p = 0.05). Using ROC Curve analyses to define the optimal predictive threshold of BVtotal (496 cm3) and ΔMTV (-17.1%), 3 subgroups of women with different odds of BCS after treatment were identified (p = 0.001): low, medium and high probability groups (respectively 29%, 62% and 82%). CONCLUSIONS: For patients with Luminal/HER2 negative breast cancer, the combination of the imaging features of the tumor and the mammary gland, obtained with 18F-FDG PET-CT at baseline and after the first cycle of NAC, may allow the physician to evaluate the probability of BCS.

Patterns of Bone Failure in Localized Prostate Cancer Previously Irradiated: The Preventive Role of External Radiotherapy on Pelvic Bone Metastases.

Introduction: External beam radiation therapy (EBRT) can cure localized prostate cancer (PCa) by sterilizing cancer cells in the prostate gland and surrounding tissues at risk of microscopic dissemination. We hypothesized that pelvic EBRT for localized PCa might have an unexpected prophylactic impact on the occurrence of pelvic bone metastases. Material and Methods: We reviewed the data of 332 metastatic PCa patients. We examined associations between the number (≤5 vs. >5) and the location of bone metastases (in-field vs. out-of-field), which occurred at first relapse, and a previous history of EBRT for PCa (EBRT vs. No-EBRT). Results: One hundred and ten patients M0 at baseline were eligible. Fifty-six patients (51%) were in the No-EBRT group, and 54 patients (49%) in the EBRT group. The proportion of patients who developed >5 bone metastases in the bony pelvis was higher in the No-EBRT group vs. the EBRT group: 10 patients (18%) vs. 2 patients (4%), respectively (p = 0.02). By multivariate analysis EBRT was associated with a lesser occurrence of patients who had >5 bone metastases in the bony pelvis (OR = 0.17 [95%CI, 0.04-0.87], p = 0.03). Time to occurrence of bone metastases ≥5 years (OR = 0.10 [95%CI, 0.05-0.19], p < 0.01), prior curative prostate treatment (OR = 0.58 [95%CI, 0.36-0.91], p = 0.02), >5 bone metastases in bony pelvis (OR = 2.61 [95%CI, 1.28-5.31], p < 0.01), >5 bone metastases out of bony pelvis (OR = 1.73 [95%CI, 1.09-2.76], p = 0.02) were all predictive of overall survival. Conclusion: Previous pelvic EBRT for PCa is associated with a lower number of pelvic bone metastases, which is associated with better overall survival.