Phase II Prospective, Open-Label Randomized Controlled Trial Comparing Standard of Care Chemotherapy With and Without Sequential Cytoreductive Interventions for Patients with Oligometastatic Foregut Adenocarcinoma and Undetectable Circulating Tumor Deoxyribose Nucleic Acid (ctDNA) Levels.

BACKGROUND: Metastatic adenocarcinomas of foregut origin are aggressive and have limited treatment options, poor quality of life, and a dismal prognosis. A subset of such patients with limited metastatic disease might have favorable outcomes with locoregional metastasis-directed therapies. This study investigates the role of sequential cytoreductive interventions in addition to the standard of care chemotherapy in patients with oligometastatic foregut adenocarcinoma. METHODS: This is a single-center, phase II, open-label randomized clinical trial. Eligible patients include adults with synchronous or metachronous oligometastatic (metastasis limited to two sites and amenable for curative/ablative treatment) adenocarcinoma of the foregut without progression after induction chemotherapy and having undetectable ctDNA. These patients will undergo induction chemotherapy and will then be randomized (1:1) to either sequential curative intervention followed by maintenance chemotherapy versus routine continued chemotherapy. The primary endpoint is progression-free survival (PFS), and a total of 48 patients will be enrolled to detect an improvement in the median PFS in the intervention arm with a hazard ratio (HR) of 0.5 with 80% power and a one-sided alpha of 0.1. Secondary endpoints include disease-free survival (DFS) in the intervention arm, overall survival (OS), ctDNA conversion rate pre/post-induction chemotherapy, ctDNA PFS, PFS2, adverse events, quality of life, and financial toxicity. DISCUSSION: This is the first randomized study that aims to prospectively evaluate the efficacy and safety of surgical/ablative interventions in patients with ctDNA-negative oligometastatic adenocarcinoma of foregut origin post-induction chemotherapy. The results from this study will likely develop pertinent, timely, and relevant knowledge in oncology.

A prospective clinical and transcriptomic feasibility study of oral-only hormonal therapy with radiation for unfavorable prostate cancer in men 70 years of age and older or with comorbidity.

BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression. METHODS: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment. RESULTS: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling. CONCLUSIONS: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression.

Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold.

Radiotherapy and immunotherapy are most effective as cancer therapies in the setting of low-volume disease. Although initial studies of radio-immunotherapy in patients with metastatic cancer have not confirmed the efficacy of this approach, the role of radio-immunotherapy in patients with limited metastatic burden is unclear. We propose that further investigation of radio-immunotherapy in metastatic patients should focus upon patients with oligometastatic disease.

Integration of radiotherapy and immunotherapy for treatment of oligometastases.

Metastasis is the leading cause of cancer-related mortality and remains one of the prevailing challenges in cancer treatment. Most patients with metastatic disease are treated with systemic agents, which prolong survival and improve symptoms but are typically not curative. The oligometastatic hypothesis challenges the perspective that metastasis is an invariably disseminated process, and proposes a biological spectrum of metastatic virulence. Mounting evidence supports the idea that patients with numerically and spatially restricted sites of metastases, termed oligometastases, can achieve prolonged survival following metastasis-directed therapies, such as surgery or radiotherapy. Improvements in clinical and molecular staging of metastatic disease, as well as integration of effective systemic therapies with localised interventions, might achieve better outcomes for patients with diverse metastatic states. In this Series paper, we propose a rationale for the integration of immune checkpoint inhibitors with radiotherapy to advance the potential for effective treatment along the spectrum of disease, with emphasis on how immunotherapy can potentiate radiotherapy treatment in the oligometastatic setting.

Oligometastatic prostate cancer: Reality or figment of imagination?

The term "oligometastatic prostate cancer" refers to a heterogeneous group of disease states currently defined solely on the basis of clinical features. Oligorecurrent disease, de novo oligometastases, and oligoprogressive disease likely have unique biologic underpinnings and natural histories. Evidence suggesting the existence of a subset of patients who harbor prostate cancer with limited metastatic potential currently includes disparate and overwhelmingly retrospective reports. Nevertheless, emerging prospective data have corroborated the "better-than-expected," retrospectively observed outcomes, particularly in the setting of oligorecurrent prostate cancer. Improved functional imaging with prostate-specific membrane antigen-targeted strategies may enhance the identification of patients with oligometastatic prostate cancer in the short term. In the long term, refinement of the oligometastatic case definition likely will require biologic risk-stratification schemes. To determine optimal treatment strategies and identify patients most likely to benefit from metastasis-directed therapy, future efforts should focus on conducting high-quality, prospective trials with much-needed molecular correlative studies.

RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNß. Specifically (i) suppression of LGP2 leads to enhanced IFNß, (ii) cytotoxic effects following IR correlated with expression of IFNß inasmuch as inhibition of IFNß by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNß and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNß.

Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT).

BACKGROUND: The selection of patients for oligometastasis-directed ablative therapy remains a challenge. The authors report on clinical and molecular predictors of survival from a stereotactic body radiotherapy (SBRT) dose-escalation trial for oligometastases. METHODS: Patients who had from 1 to 5 metastases, a life expectancy of >3 months, and a Karnofsky performance status of >60 received escalating SBRT doses to all known cancer sites. Time to progression, progression-free survival, and overall survival (OS) were calculated at the completion of SBRT, and clinical predictors of OS were modeled. Primary tumor microRNA expression was analyzed to identify molecular predictors of OS. RESULTS: Sixty-one evaluable patients were enrolled from 2004 to 2009. The median follow-up was 2.3 years for all patients (range, 0.2-9.3 years) and 6.8 years for survivors (range, 2.0-9.3 years). The median, 2-year, and 5-year estimated OS were 2.4 years, 57%, and 32%, respectively. The rate of progression after SBRT was associated with an increased risk of death (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.24-1.82). The time from initial cancer diagnosis to metastasis (HR, 0.98; 95% CI, 0.98-0.99), the time from metastasis to SBRT (HR, 0.98; 95% CI, 0.98-0.99), and breast cancer histology (HR, 0.12; 95% CI, 0.07-0.37) were significant predictors of OS. In an exploratory analysis, a candidate classifier using expression levels of 3 microRNAs (miR-23b, miR-449a, and miR-449b) predicted survival among 17 patients who had primary tumor microRNA expression data available. CONCLUSIONS: A subset of oligometastatic patients achieves long-term survival after metastasis-directed SBRT. Clinical features and primary tumor microRNA expression profiling, if validated in an independent dataset, may help select oligometastatic patients most likely to benefit from metastasis-directed therapy. Cancer 2016;122:2242-50. © 2016 American Cancer Society.

Hormonal Therapy and Radiation Therapy in Prostate Cancer: 5-Year Outcomes From a Trial Evaluating Combined Androgen Blockade With 5-Alpha Reductase Inhibitors as an Alternative to Gonadotropin Releasing Hormone Agonists.

BACKGROUND: We previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control. METHODS: In this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels. RESULTS: Between 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P>.1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05). CONCLUSIONS: In this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.

Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials.

PURPOSE: Stereotactic body radiation therapy (SBRT) safely and effectively controls liver metastases (LMs), but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of 3 phase 1 trials of combination SBRT and ICI evaluates whether LM-SBRT increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. METHODS AND MATERIALS: Data were analyzed from 3 phase 1 trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700 cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure, autoimmune hepatitis, or elevation of aspartate transaminase, alanine transaminase, bilirubin, or alkaline phosphatase using Common Terminology Criteria for Adverse Events version 4.0. Cumulative incidence of HAEs and local failure were modeled with death as a competing risk. Competing risk regression was performed using Fine-Gray modeling. Survival was estimated via the Kaplan-Meier method. RESULTS: Two hundred patients were analyzed, including 81 patients with LM, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively non-significant (NS). Radiographic evidence for liver disease and dual-agent ICI was significantly associated with HAEs on univariable and multivariable analysis, but liver dose metrics were not. Patients with LM had significantly worse progression-free and overall survival compared with those without, and local failure of treated LM was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, P < .001). CONCLUSIONS: Combination LM-SBRT and ICI did not significantly increase the risk for HAEs compared with ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver radiation therapy, such as choice of ICI. LM is associated with worse overall survival and local control outcomes.

Radiotherapy and immunology.

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

Bladder-Preserving Trimodality Therapy With Capecitabine.

INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites.

PURPOSE: Radiotherapy (RT) is a widely employed anticancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. The purpose of this study is to investigate immune suppressive factors of radiotherapy. EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated. RESULTS: Through analysis of PD-L1 expression and myeloid-derived suppressor cells (MDSC) frequencies using patient peripheral blood mononuclear cells and murine two-tumor and metastasis models, we report that local irradiation can induce a systemic increase in MDSC, as well as PD-L1 expression on dendritic cells and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, nonirradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSC can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT. CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during irradiation can enhance abscopal tumor control and reduce metastasis.

Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization.

Numerous clinical studies are investigating the integration of radiotherapy and immune checkpoint inhibitors (ICI) in the management of advanced or metastatic solid cancers based on preclinical evidence demonstrating a synergistic interaction between these treatments. However, it remains unclear how to optimally integrate these therapeutic modalities in the treatment of cancer patients. Beyond disease-specific factors there exists numerous unanswered questions regarding optimal sequencing of radiation and ICI, as well as, radiation dosing and target selection. Here, we examine the available clinical evidence for combination radiation and ICI approaches and propose strategies to expand investigations of the potential synergy in cancer patients.

Oligometastases: Characterizing the Role of Epigenetic Regulation of Epithelial-Mesenchymal Transition.

The "oligometastasis" hypothesis proposes that metastases exist as a spectrum and are not always disseminated. According to this theory, a subset of patients with metastatic disease could benefit from aggressive local therapies. However, the identification of patients most likely to exhibit an oligometastatic phenotype remains challenging. Recent literature focusing on basic and translational studies has identified novel epigenetic regulators of epithelial-mesenchymal transition (EMT) and the emergence of a spectrum of metastatic behavior. Herein, we review these scientific advances and suggest that the spectrum of metastatic virulence produced by these epigenetic mechanisms broadly contributes to the emergence of clinically evident "oligometastases." Epigenetic regulation of EMT programs can result in a spectrum of cell trajectories (e.g., quasi-mesenchymal and highly mesenchymal states) with differential propensity to develop metastases. We propose that quasi-mesenchymal cell states may be associated with a polymetastatic phenotype, whereas highly mesenchymal cell states may be associated with a more oligometastatic phenotype. The mechanisms governing epigenetic regulation of EMT and its array of intermediate states are multifaceted and may contribute to the development of the metastatic spectrum observed clinically. Within this context, translational studies that support the role of EMT and its epigenetic regulation are discussed. Continued translation of these mechanistic discoveries into novel biomarkers may help optimally select patients most likely to exhibit an oligometastatic phenotype and benefit from aggressive local therapies, such as surgery, radiotherapy, and other ablative procedures.

RNA m6A methylation and MDSCs: Roles and therapeutic implications for radiotherapy.

Emerging evidence suggests that local tumor radiotherapy reshapes the repertoire of circulating myeloid-derived suppressor cells (MDSCs) and leads to their infiltration into the tumor microenvironment, which poses a major obstacle for radiotherapy efficacy. Recent findings have identified RNA m6A modification at the nexus of both anti-tumor immunity and radiation response. Here, we examine the mechanisms by which this RNA modification modulates the immune milieu of the radiation-remodeled tumor microenvironment. We discuss potential therapeutic interventions targeting m6A machinery to improve radiotherapy response.

Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial.

Importance: Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal. Objective: To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial. Design, Setting, and Participants: This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021. Interventions: Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort. Main Outcomes and Measures: A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS). Results: A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively. Conclusions and Relevance: In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases. Trial Registration: isrctn.org Identifier: ISRCTN22944367.

Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma.

PURPOSE: Immunotherapy has emerged as a promising therapeutic option for advanced or unresectable hepatocellular carcinoma (HCC). However, survival remains poor with only a subset of patients deriving benefit. This trial investigated the safety and efficacy of stereotactic body radiation therapy (SBRT) with immunotherapy in HCC. METHODS AND MATERIALS: In this multicenter phase 1 randomized trial, patients with advanced or unresectable HCC received liver SBRT (40 Gy in 5 fractions) followed by either nivolumab alone or nivolumab plus ipilimumab. The primary endpoint was dose-limiting toxicity occurring within 6 months of SBRT. Secondary endpoints included overall response rate, progression-free survival, overall survival (OS), distant disease control, and local control of the irradiated tumor. Disease status and response endpoints were assessed radiographically every 8 weeks until progression or initiation of nonprotocol therapy. Response was determined using both RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST. RESULTS: Fourteen patients were enrolled across 3 centers. Thirteen patients were evaluated for study endpoints. The study was closed early because of slow accrual. The median follow-up time was 42.7 months. Dose-limiting toxicities within 6 months occurred in 2 (15.4%) of 13 patients: 1 of 6 patients in the nivolumab arm (16.7%; 90% confidence interval [CI], 0.9%-58.2%) and 1 of 7 patients in the nivolumab plus ipilimumab arm (14.3%; 90% CI, 0.7%-52.1%). Grade 3 adverse events occurred in 8 (61.6%), 5 (71.4%), and 3 (50.0%) patients in the overall nivolumab plus ipilimumab and nivolumab cohorts. Grade 3 hepatotoxicity occurred in 4 (30.8%), 3 (42.9%), and 1 (16.7%) patients in the respective cohorts. Clinical outcomes favored the nivolumab plus ipilimumab arm compared with nivolumab alone, including an overall response rate of 57% (4 of 7 patients; 90% CI, 23%-87%) versus 0% (0 of 6 patients; 90% CI, 0%-39%), median progression-free survival of 11.6 months (90% CI, 4.5 months to not reached) versus 2.7 months (90% CI, 1.3-4.7 months), and median OS of 41.6 months (90% CI, 4.5 months to not reached) versus 4.7 months (90% CI, 2.0-16.2 months) (all P < .05). With combination immunotherapy, 3-year OS was 57% (90% CI, 23%-81%), with 2 patients alive after 42.7 months without progression and negative PET. CONCLUSIONS: In this first prospective trial investigating the combination of SBRT and immunotherapy for HCC, multimodal therapy demonstrated acceptable safety. SBRT with nivolumab plus ipilimumab compared favorably to outcomes of immunotherapy alone and warrants further investigation.

YTHDF2 inhibition potentiates radiotherapy antitumor efficacy.

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.