Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.

Indwelling pleural catheters (IPC) are increasingly becoming a first-line treatment in the management of malignant pleural effusions. Ambulatory management using IPC are increasingly used in this patient group whilst they are receiving concurrent chemotherapy. There are currently no prospective trials examining IPC safety in chemotherapy. This study’s objective is to determine if IPC insertion is safe in patients undergoing chemotherapy. We conducted a retrospective analysis of all patients who underwent IPC insertion for malignant pleural effusion at our trust from September 2010 to December 2014. Data was collected on IPC insertion and removal, tumour type, systemic chemotherapy, pleural infection and other complications. One hundred four patients were identified, 43 in chemotherapy group and 61 in non-chemotherapy group. The incidence of pleural infection in chemotherapy group vs non-chemotherapy group, 4 (9.3 %) vs 3 (4.9 %) respectively, was not statistically different (Fisher’s exact p = 0.311). There was no significant difference in six-month infection-free duration from the date of IPC insertion (log rank p = 0.394). Overall six-month mortality in chemotherapy group was significantly lower than in non-chemotherapy group (log rank p = 0.007). This is the second largest retrospective case–control series that concludes systemic chemotherapy is safe in patients with IPC undergoing chemotherapy.

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A⁺PD-1⁺ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8⁺ and CD4⁺ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.

Etoposide (E) at 100 mg/m2 combined with Cisplatin (P) at 20 mg/m2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17–71). Half the cases were GCT (n = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN (n = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis (n = 100, 96%), within 24 h (n = 93, 89%) and out-of-hours (n = 74, 70%). Indications for Em-EP included symptomatic disease (n = 66, 63%), high-burden disease, (n = 51, 49%) and organ failure requiring Intensive Care Unit support (n = 9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation.