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.

Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients.

Background: The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. Materials and methods: Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. Results: A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast, a decrease of tumor-specific Th1 response was documented in 7 out of 10 evaluated patients. We found high frequency of pre-existing tumor-specific Th1 response among patients with objective response after CRT compared to non-responders. Conclusion: Cisplatin-based CRT promotes expansion of Treg and decrease of circulating anti-tumor Th1 response in peripheral blood. The balance towards a sustained specific anti-tumor T-cell response appears to be associated with response to CRT.

Background: The role of inflammation in the development and prognosis of bladder cancer (BC) is now established. We evaluated the significance of neutrophil-to-lymphocyte ratio (NLR) and neutrophil count (PNN) in patients with localized BC treated with chemoradiation. Methods: Clinical characteristics and baseline biological data were retrospectively collected. We tested the association between NLR, PNN, and overall survival (OS) and progression-free survival (PFS). Results: One hundred and ninety-four patients were included. Median PNN was 4000.0/mm³ [1500.0–16,858.0] and median NLR was 2.6 [0.6–19.2]. In patients with NLR > 2.6, median OS and PFS were lower (OS: 25.5 vs. 58.4 months, p = 0.02; PFS: 14.1 vs. 26.7 months, p = 0.07). Patients with PNN > 4000/mm³ had significantly lower OS (21.8 vs. 70.1 months, p < 0.001) and PFS (13.7 vs. 38.8 months, p < 0.001). Contrary to NLR, PNN > 4000/mm³ was associated with shorter OS and PFS in multivariate analysis. Conclusions: Elevated PNN at baseline was associated with worse OS and PFS. NLR was not an independent prognostic factor.

In locally advanced rectal cancer (LARC), neoadjuvant radiation therapy (RT) consists of either a long-course scheme (i.e., five fractions of 1.8–2 Gy per week for 5 weeks) combined with chemothera...

For non-operable, localized esophageal cancer, definitive concurrent chemoradiotherapy is the standard treatment. Currently, the radiation dose recommended is 50 to 50,4Gy. However, the optimal radiation dose remains controversial. Many studies have demonstrated that locoregional failure remains a common failure pattern, most likely to occur within the original gross tumor volume. Several retrospective studies have indicated that higher radiation dose may improve local control and survival while others failed to demonstrate improved oucomes. In three randomized trials (INT0123, ARTDECO, and CONCORDE), dose escalation did not improve locoregional control nor survival, establishing 50Gy as the standard chemoradiation dose for patients who will not undergo surgery. Here, we reviewed the results of dose escalation in the literature in the neoadjuvant and definitive settings.