Targeting two radiation-induced immunosuppressive pathways to improve the efficacy of normofractionated radiation therapy in a preclinical colorectal cancer model.

PURPOSE: We have previously demonstrated in a murine colorectal cancer model that normofractionated RT (normoRT: 18 × 2 Gy) induced MDSC infiltration and PD-L1 expression, while hypofractionated RT (hypoRT: 3 × 8 Gy) induced Treg. Here, we wanted to assess whether the association of normoRT with treatments that target two radiation-induced immunosuppressive pathways (MDSC and PD-L1) could improve tumor control. MATERIALS AND METHODS: Subcutaneous tumors were induced using colon tumor cells (CT26) in immunocompetent mice (BALB/c) and were treated with RT alone (18 × 2 Gy or 3 × 8 Gy), or concomitantly with 5-Fluorouracil (5FU) (10 mg/kg) to deplete MDSC, and/or anti-PD-L1 (10 mg/kg). We assessed the impact of these combinations on tumor growth and immune cells infiltration by flow cytometry. In addition, we performed tumor rechallenge experiments and IFN-γ ELISpots to study the long-term memory response. RESULTS: Even though tumor growth was significantly delayed in the RT + 5FU compared to 5FU and untreated groups (p < .05), there was no significant difference between RT + 5FU (CRT) and RT alone. The rate of MDSC increased significantly 1 week after the end of normoRT (8.09% ± 1.03%, p < .05) and decreased with the addition of 5FU (3.39% ± 0.69%, p < .05). PD-L1 expressing tumor cells were increased after treatment. Adding anti-PD-L1 significantly delayed tumor growth, achieved the highest complete response rate, and induced a long-lasting protective specific anti-tumor immunity. CONCLUSIONS: These results tend to demonstrate the interest of inhibiting two radiation-induced immunosuppressive mechanisms. In patients, the combination of normoRT with 5FU is already the standard of care in locally advanced rectal cancer. Adding an anti-PD-L1 to this treatment could show promising results.

Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

BACKGROUND: Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. METHODS: We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. RESULTS: Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. CONCLUSION: Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

Novel platform for subcutaneous tumor irradiation in mice.

Preclinical development of cancer treatments including radiotherapy (RT) is now crucial to optimize all the treatment aspects for a better efficacy and to help clinicians to build new clinical trials based on robust results. More and more teams use preclinical irradiators to deliver radiotherapy in a comparable way to clinical treatments (image-based RT, arc therapy, stereotactic body RT…). In daily conditions, users usually need to develop easy to use techniques (for applicator technicians for example), allowing to treat many mice per day with a high level of reproducibility. Besides, the best compromise between a satisfying dose coverage to the tumor and nearby organs at risk sparing has to be ensured. We describe here new a home-made immobilization device to irradiate grafted tumors, as well as the different steps to develop the treatment planning and generate an easy procedure to routinely irradiate subcutaneous tumor model.

Tolerance and Oncological Outcomes of In-Field Reirradiation for Locally Recurrent Breast Cancer: A Long-Term Single-Center Experience.

BACKGROUND: The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue. The aim of this work was to report our experience with breast reirradiation for locoregionally recurrent breast cancer. METHODS: All patients who underwent breast or chest wall in-field reirradiation at the Institut Curie, Paris, France, between 2003 and 2019, were identified. Efficacy outcomes and physician-reported toxicities were retrospectively assessed. RESULTS: A total of 21,372 patients underwent breast irradiation in our institution. Of these, 28 received a second course of radiotherapy to the homolateral breast/chest wall. A total of 18 (64%) patients were treated with a curative intent, and 10 (36%) were treated for palliative purposes. Only one acute and one late grade 3 adverse events were reported. One patient with major cardiovascular risk factors died of myocardial infarction 13 months after left breast reirradiation. The 2-year LRFS, OS, DSS, PFS and MFS were 59%, 79%, 82%, 46% and 75%, respectively, in the whole cohort. The 2-year LRFS (72% vs. 31%, p = 0.02), OS (94% vs. 50%, p < 0.01), DSS (94% vs. 56%, p < 0.01) and PFS (61% vs. 20%, p = 0.02) differed significantly between patients treated with curative or palliative intent but not the MFS (78% vs. 69%, p = 0.77). Among the patients, eight (29%) remained relapse-free 5 years after reirradiation. CONCLUSION: Breast/chest wall reirradiation appears to be feasible with good disease control, especially in patients treated with a curative intent, and presents acceptable toxicity rates.

Combining radiotherapy and NK cell-based therapies: The time has come.

Natural killer (NK) cells are innate lymphoid cells that play an essential role in the anti-tumor response through immunosurveillance, multiple mechanisms of cytotoxicity and the synthesis of cytokines modulating the immune tumor microenvironment (TME). After the dramatic advances in immunotherapy targeting T cells including the success of checkpoint inhibitors or autologous chimeric antigen receptor (CAR) expressing T cells in clinical practice, NK cells have gained growing interest for the development of new therapies. Although NK cells have shown promising responses in leukemia patients, the effects of NK-targeted therapies are currently limited in the treatment of solid tumors. Thus, radiotherapy could provide a valuable solution to improve treatments targeting NK cells. Indeed, ionizing radiations represent a powerful immuno-modulator that can either induce a pro-inflammatory and anti-tumor TME, or conversely lead to immunosuppression of effector immune cells in favor of tumor growth and therapeutic escape, depending on how it is delivered and tumor models. However, the effects of ionizing radiation on NK cells are only partially understood. Therefore, we review the effects of radiotherapy on the NK cell-mediated anti-tumor response, and propose potential strategies to reinvigorate NK cells by combining radiotherapy with NK cell-targeted therapies.

Deep learning application for abdominal organs segmentation on 0.35 T MR-Linac images.

Introduction: Linear accelerator (linac) incorporating a magnetic resonance (MR) imaging device providing enhanced soft tissue contrast is particularly suited for abdominal radiation therapy. In particular, accurate segmentation for abdominal tumors and organs at risk (OARs) required for the treatment planning is becoming possible. Currently, this segmentation is performed manually by radiation oncologists. This process is very time consuming and subject to inter and intra operator variabilities. In this work, deep learning based automatic segmentation solutions were investigated for abdominal OARs on 0.35 T MR-images. Methods: One hundred and twenty one sets of abdominal MR images and their corresponding ground truth segmentations were collected and used for this work. The OARs of interest included the liver, the kidneys, the spinal cord, the stomach and the duodenum. Several UNet based models have been trained in 2D (the Classical UNet, the ResAttention UNet, the EfficientNet UNet, and the nnUNet). The best model was then trained with a 3D strategy in order to investigate possible improvements. Geometrical metrics such as Dice Similarity Coefficient (DSC), Intersection over Union (IoU), Hausdorff Distance (HD) and analysis of the calculated volumes (thanks to Bland-Altman plot) were performed to evaluate the results. Results: The nnUNet trained in 3D mode achieved the best performance, with DSC scores for the liver, the kidneys, the spinal cord, the stomach, and the duodenum of 0.96 ± 0.01, 0.91 ± 0.02, 0.91 ± 0.01, 0.83 ± 0.10, and 0.69 ± 0.15, respectively. The matching IoU scores were 0.92 ± 0.01, 0.84 ± 0.04, 0.84 ± 0.02, 0.54 ± 0.16 and 0.72 ± 0.13. The corresponding HD scores were 13.0 ± 6.0 mm, 16.0 ± 6.6 mm, 3.3 ± 0.7 mm, 35.0 ± 33.0 mm, and 42.0 ± 24.0 mm. The analysis of the calculated volumes followed the same behavior. Discussion: Although the segmentation results for the duodenum were not optimal, these findings imply a potential clinical application of the 3D nnUNet model for the segmentation of abdominal OARs for images from 0.35 T MR-Linac.

Combining androgen deprivation and radiation therapy in the treatment of localised prostate cancer: Summary of level 1 evidence and current gaps in knowledge.

•Localized prostate cancer.•Androgen deprivation therapy.•Radiation therapy.

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies.

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.