Radio-immunotherapy has antitumor activity but also causes toxicity, which limits its clinical application. JS-201 is a dual antibody targeting PD-1 and TGF-β signaling. We investigated the antitumor effect of JS-201 combined with radiotherapy (RT) and the effect on radiation-induced lung injury (RILI). Different tumor models were established to detect the antitumor effects of the combination of JS-201 and RT, and RILI models were established to observe the effects of JS-201. Transcriptome sequencing showed that JS-201 optimized the tumor microenvironment by inhibiting extracellular matrix formation and angiogenesis. Combining JS-201 with RT further increased the inflammatory response and immune infiltration and showed great abscopal effects in Lewis lung cancer luciferase-positive models. Single-cell sequencing demonstrated that JS-201 reduced fibroblast proliferation by inhibiting the TGF-β/Smad pathway and the release of neutrophil extracellular traps mediated by ROS, thereby relieving radiation-induced pulmonary fibrosis. In conclusion, the JS-201 and RT combination enhances antitumor effects while mitigating acute and chronic RILI, and it may have potential for translational investigation as a cancer treatment strategy.

Although the role of circular RNAs (circRNAs) in tumor progression and immune regulation is well-known, the specific circRNA molecules that mediate immune responses after radiotherapy (RT) and the underlying mechanisms have not been identified.

Cytometry with time-of-flight (CyTOF) was used to analyze blood samples from patients with liver cancer exhibiting abscopal effects (AEs) after stereotactic body radiotherapy (SBRT) to quantify the number of dendritic cells (DCs) and CD8+ T cells and interferon-beta (IFN-β) level. circTMEM56 and IFN-β levels were measured in 76 patients with liver cancer using qPCR and ELISA. Immunohistochemistry validated circTMEM56 and CD141 staining in tissues. The interaction between circTMEM56, miR-136-5p, and STING, as well as the impact on anti-tumor immunity, was verified using circTMEM56-specific probes, dual-luciferase activity assays, proteomics analysis, and western blot analysis.

The role of circTMEM56 in enhancing anti-tumor immunity and response to RT in hepatocellular carcinoma (HCC) was determined. Higher circTMEM56 levels were linked to an improved RT response and better clinical outcomes in patients with HCC. circTMEM56 enhanced cGAS-STING signaling, increased the number of tumor-infiltrating CD8+ T cells, and elevated the serum IFN-β levels. Moreover, circTMEM56 administration significantly boosted the response to RT in tumors with low circTMEM56 expression.

High circTMEM56 expression in HCC modulates the distant effects of HCC RT by activating the cGAS-STING pathway to reshape the tumor microenvironment. This study provides a new approach to improve RT efficacy for HCC.

Combining immune checkpoint inhibitors (ICIs) with radiation therapy (RT) has led to significant advancements in cancer treatment. However, evidence from clinical and experimental studies suggests that this combination may increase hematopoietic and lymphatic toxicity. This study aims to investigate the effects of the concurrent application of ICIs (anti-PD-1 and anti-CTLA-4) on radiation-induced hematopoietic and lymphatic injuries under standardized and controlled experimental conditions.

We used various experimental models in C57BL/6 and BALB/c mice to evaluate the impact of ICIs combined with RT on the hematopoietic system. These models involved different RT doses, regimens, and target sites in both healthy and tumor-bearing mice.

Our findings showed that the concurrent use of ICIs did not meaningfully affect post-RT pancytopenia kinetics or the regeneration of specific blood cell lineages over time. Consistently, combining RT with ICIs did not significantly enhance DNA damage in immune cells within the bloodstream. This outcome was comparable across different RT doses, regimens, and target sites and was reproducible in both tumor-bearing and nontumor-bearing mice. Additionally, there were no significant increases in late side effects, including reductions in bone marrow cell counts or megakaryocyte numbers, after combined radioimmunotherapy.

These findings suggest that combining ICIs with RT does not exacerbate hematological toxicity. This information is valuable for interpreting adverse events in clinical trials involving radioimmunotherapy and for predicting potential hematological side effects in cancer patients receiving these treatments.

The therapeutic landscape for recurrent or metastatic cervical cancer remains limited, with few options available. According to National Comprehensive Cancer Network (NCCN) guidelines, pembrolizumab combined with chemotherapy, with or without bevacizumab, is recommended for affected patients. Despite these guidelines, recurrence rates remain elevated, and survival outcomes following standard interventions are unsatisfactory. Furthermore, real-world management of recurrent or metastatic cervical cancer presents inherent complexities, often requiring an integrative, multidimensional treatment approach to enhance long-term survival. The pressing need to refine and adopt multimodal therapeutic strategies is evident in addressing the persistent challenges associated with disease recurrence and progression.

The case involved a 40-year-old female diagnosed with advanced cervical cancer who underwent radical hysterectomy. Postoperative pathology identified high-risk features, including lymph node involvement, necessitating adjuvant chemoradiotherapy. However, disease progression occurred during treatment, manifesting as metastases in the left supraclavicular and axillary lymph nodes. Subsequent local radiotherapy and systemic therapy led to a favorable response. By November 2024, overall survival (OS) had surpassed 72 months, with toripalimab administered for 65 months, during which no immunotherapy-related adverse events occurred.

This case offers clinical insight into the efficacy and safety of integrating chemotherapy, immunotherapy, and radiotherapy in recurrent or metastatic cervical cancer. The multimodal approach contributes to prolonged survival in this patient. Further clinical trials are essential to substantiate the therapeutic benefits of this regimen in broader patient cohorts.

Over the past few decades, breakthroughs in cancer biology at the molecular level have revolutionised cancer treatment. Enhanced precision in radiotherapy has not only reduced patient side-effects, but also enabled the delivery of high-dose stereotactic extracranial irradiation with unprecedented accuracy. Simultaneously, the number of medical therapies available for clinical care continues to grow. Despite the progress made with combined chemoradiotherapy, only a few drug-radiotherapy combinations have received clinical approval, leaving a vast landscape of untapped opportunities for basic, translational, and clinical research, particularly in early-phase drug-radiotherapy trials. New and promising pharmaceutical therapies, paired with advanced radiotherapy technologies, are now being tested in innovative clinical trial designs. Moreover, the integration of biological and imaging markers-both tumour-specific and peripheral-holds the potential to personalise drug-radiotherapy combinations, thereby enhancing the therapeutic index for specific patient populations. In this Review, we highlight the latest developments and future directions for early-phase clinical trials that combine precision drug-radiotherapy strategies in adult patients, with the aims of improving outcomes and expanding treatment options.

Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors, including in soft-tissue sarcoma (STS). However, the ideal combination of treatment modalities remains to be determined, and reliable biomarkers to predict which patients will benefit are lacking. Here, we report the results of the STS cohort of the SABR-PDL1 phase II trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy (SBRT) delivered concurrently with the 2nd cycle to at least one tumor site. Eligible patients received atezolizumab until progression or unmanageable toxicity, with SBRT at 45 Gy in 3 fractions). The primary endpoint was one-year progression-free survival (PFS) rate with success defined as 13 patients achieving 1-year PFS. Sixty-one heavily pretreated patients with STS (median 5 prior lines; 52% men; median age 54 years; 28% leiomyosarcoma) were enrolled across two centers (France, Spain). SBRT was delivered to 55 patients (90%), with the lung being the most commonly irradiated site (50%). After a median follow-up of 45 months, the one-year PFS rate was 8.3% [95% CI: 3.6-18.1]. Median PFS and overall survival were 2.5 and 8.6 months, respectively. Best responses included partial responses (5%) and stable disease (60%). Immune profiling revealed increased immunosuppressive tumor-associated macrophages (e.g., IL4I1, HES1) and monocyte-recruiting chemokines in non-responders. Higher monocyte/lymphocyte ratios (MonoLR) in tumor and blood correlated with progression. PD-L1 status, lymphoid infiltration, and tertiary-lymphoid structures were not predictive. Although the primary endpoint was not met, this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy. EudraCT No. 2015-005464-42; Clinicaltrial.gov number: NCT02992912.

In patients with unresectable, stage III non-small cell lung cancer (NSCLC), durvalumab maintenance after concurrent chemoradiotherapy (cCRT) was shown to improve survival over placebo. As subgroup analyses indicated better outcomes with earlier start of durvalumab, several trials evaluated concomitant checkpoint inhibition (CPI) with cCRT. However, this may introduce an increased risk of treatment-related pulmonary toxicity.

We conducted a systematic review and meta-analysis of clinical trials of combined cCRT plus CPI followed by CPI maintenance in patients with stage III NSCLC. Endpoints included incidence of pneumonitis by any cause, objective response rate (ORR), progression-free (PFS), and overall survival (OS).

A total of 7 trials comprising 653 patients were included. In trials of single-agent CPI with cCRT, pneumonitis occurred in 33 % of patients (95 % confidence interval [CI], 28-39) with 7 % (5-9) having CTCAE grade 3-5. In one trial, double CPI (PD-1 and CTLA4) plus cCRT was associated with excessive pneumonitis-related mortality of 16 % (4-40). Across all trials, ORR was 69 % (63-76). Median PFS and OS were 16.3 (95 % CI, 14.0-20.5) and 39.5 months (35.3-45.9), respectively. Three-year PFS and OS were 36.8 % (95 % CI, 32.7-41.4) and 53.1 % (49.1-57.4). Sensitivity analysis showed that induction chemoimmunotherapy prior cCRT plus CPI was associated with improved PFS of 48.0 % at 3 years (95 % CI, 40.7-56.7) in one trial.

Addition of single-agent CPI to cCRT is manageable in selected patients with stage III NSCLC. Efficacy outcomes appear to be in line with previous data of cCRT followed by CPI maintenance.

Analyze the incidence and risk factors of thyroid dysfunction in patients with advanced nasopharyngeal carcinoma (LA-NPC) after intensity-modulated radiotherapy (IMRT) and PD⁃1 inhibitor treatment and their relationship with treatment efficacy and prognosis.

Eighty-five LA-NPC patients treated with IMRT and PD-1 inhibitors were retrospectively collected from March 1, 2019, to May 30, 2022. The incidence of thyroid dysfunction after combination therapy was analyzed. The Kaplan-Meier method was used to analyze the relationship between thyroid dysfunction and patient prognosis. Logistic regression analysis was used to screen independent risk factors for thyroid dysfunction.

As of data cutoff (May 31, 2024), the median follow-up time was 27.8 months (range: 25.6 to 32.0 months). The median time of onset of thyroid dysfunction was 8.26 months. The incidence of thyroid dysfunction is 47.06% (40/85), with clinical hypothyroidism being the main cause at an incidence rate of 28.24% (24/85) and clinical hyperthyroidism at an incidence rate of 3.53% (3/85). The incidence of grade 1 thyroid immune-related adverse events (irAEs) was 29.41% (25/85), and the incidence of grade 2 thyroid irAEs was 17.65% (15/85). Patients with thyroid dysfunction had longer overall survival, progression-free survival, and distant metastasis-free survival at both one and two years compared to patients with normal thyroid function, but the difference was not statistically significant (p > 0.05). Multivariate logistic regression analysis showed that pretreatment lactate dehydrogenase (LDH) (p = 0.079) is an independent predictor of thyroid dysfunction after radiotherapy in combination with immunotherapy for LA-NPC.

The study found that the addition of immunotherapy increases the risk and shortens the onset time of thyroid dysfunction in LA-NPC patients treated with chemoradiotherapy. Pretreatment LDH may serve as an independent risk factor for thyroid dysfunction for LA-NPC patients.

Small-cell lung cancer (SCLC) is highly malignant. Despite being highly sensitive to initial chemotherapy and radiotherapy, the recurrence rate is high. Atezolizumab is the first immune checkpoint inhibitor (ICI) that has been proven to provide an overall survival (OS) benefit for extensive-stage SCLC (ES-SCLC), making ICIs in combination with chemotherapy the standard first-line treatment for ES-SCLC. However, the real-world treatment of SCLC is more complex, and multimodal therapy may be needed to achieve long-term patient survival. Few reports on later-line chemotherapy combined with immunotherapy have been published thus far. Moreover, there is limited data on the efficacy and safety of thoracic radiotherapy and radiotherapy for metastatic lesions after multiple lines of treatment have failed in ES-SCLC, and the value of small-molecule antiangiogenesis combined with immunotherapy also needs further exploration.

A patient was diagnosed with mediastinal limited-stage SCLC (LS-SCLC) and experienced local progression following standard chemoradiotherapy and prophylactic cranial irradiation. Subsequently, the patient underwent second-line irinotecan chemotherapy, which resulted in severe hematological toxicity. Upon initiation of third-line therapy with anlotinib, the disease remained stable for 9 months. Unfortunately, imaging revealed the presence of a new lesion at the right lung apex. Nevertheless, there was renewed hope for survival when atezolizumab was introduced as part of the treatment regimen. Despite the later development of brain metastases and metastasis adjacent to the aortic arch, long-term survival was achieved through combination therapy involving immunotherapy, antiangiogenic therapy, and radiotherapy targeting the metastatic lesions. By March 2024, the OS had reached 70 months, with a duration of treatment with atezolizumab of 48 months, and only grade II hypothyroidism occurred during treatment, with no other immunotherapy-related adverse events being observed.

This case report suggests the potential efficacy and safety of integrating chemotherapy, immunotherapy, radiotherapy, and antiangiogenic therapy for the treatment of SCLC. Further clinical trials are warranted to validate the value of combining chemotherapy, immunotherapy, radiotherapy, and antiangiogenic therapy.

Radiotherapy showed synergy with immunotherapy, yet the comparative effectiveness of combining immunotherapy (iRT) or chemotherapy (CRT) after platinum therapy failure in advanced non-small cell lung cancer (NSCLC) remains unexplored. We analyzed 163 patients (iRT: n = 120 vs. CRT: n = 43) eligible for combination radiotherapy. Before matching, median overall survival (OS) was significantly longer in iRT group (7.79 vs. 4.57 months, hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.41-0.94, p = 0.024). After 1:2 propensity score matching (PSM) and inverse probability of treatment weighting (IPTW), iRT group showed improved OS, consistent with unmatched analysis (PSM, p = 0.033 and IPTW, p = 0.035). Exploratory analysis suggested that PD1+, central memory PD1+, and effector memory PD-L1+ CD4+ T cells were strong predictive biomarkers for iRT-treated patients (P OS = 0.025, P OS = 0.002, P OS = 0.010, respectively). Proliferative CD4+ T celllow was a prognostic (P OS = 0.008) and predictive biomarker for iRT (P OS < 0.001). Our work revealed iRT was prolonged OS in previously treated advanced NSCLC patients. Additionally, proliferative CD4+ T cell served as prognostic and predictive biomarkers.

Patients with advanced tumors enrolled in phase I trials display strong treatment expectations and few therapeutic alternatives. When oligoacquired resistance (OAR; ≤3 lesions of disease progression) occurs, local ablative stereotactic radiation therapy (SRT) could allow disease control and continuing the experimental systemic treatment.

Data from patients enrolled in phase I trials evaluating systemic treatments, who experienced OAR while on the phase I systemic therapy and subsequently received SRT between January 2014 and April 2023, were retrospectively analyzed. Progression-free survival (PFS)1 (trial entry to OAR), PFS2 (SRT to first subsequent relapse), time to next systemic treatment (TTNT), and overall survival (OS) were assessed. First subsequent patterns of relapse after SRT were distinguished as OAR2, which could be locally rechallenged, or systemic acquired resistance (SAR; >3 lesions of disease progression). When available, correlations between molecular profile and pathway enrichments of OAR and SAR were explored.

Forty-two patients with 52 oligoprogressive lesions were analyzed. The median follow-up was 24 months. SRT allowed a median PFS2 of 7.1 months and a median TTNT of 12.8 months. PFS2 included 49% OAR2 and 51% SAR. Median time to first subsequent relapse (9.6 vs 3.5 months; P = .014) and TTNT (22.4 vs 7.6 months; P < .001) were longer for OAR2 compared with that for SAR. No severe toxicities were reported. A PFS1 of <6 months and de novo oligoprogressive lesions were associated with the presence of SAR. More diverse enriched gene pathways were observed for SAR compared with that for OAR2.

In patients enrolled in phase I trials, OAR managed with SRT may increase time on investigational systemic treatments. Predictive factors reflecting tumor aggressiveness and clonal heterogeneity could help deciphering OAR2 from SAR and maximize SRT output in the oligoprogressive setting.

Lung cancer is the leading cause of cancer-related deaths worldwide, with about 85% of patients being diagnosed as non-small cell lung cancer (NSCLC); and most presenting with stage IV disease initially. With the continuous advancement of treatment strategies of oncology, immunotherapy with/without chemo-immunotherapy has become the first-line treatment for patients with stage IV NSCLC. However, a proportion of patients still develop resistance to the treatment regimen and experience local progression, and primary lung lesion progression is the main progression pattern of stage IV NSCLC. Preclinical and clinical studies have demonstrated the potential of radiotherapy in anti-tumor treatment and suggest that administering local radiotherapy prior to cancer progression can prolong survival. Therefore, we consider whether adding local radiotherapy before the progression of a pulmonary lesion in stage IV NSCLC patients receiving chemo-immunotherapy would be beneficial. The present review aims to explore the efficacy and safety of combining radiotherapy with immunotherapy in the treatment of stage IV NSCLC, delving into the intricacies of their underlying mechanism.

The other side of radiotherapy (RT), in addition to the cytotoxic effect, is the ability to modulate the immune system in terms of activation or suppression, also depending on the dose and fractionation delivered. This immune RT effect can be detected both locally in the irradiated tumor site and in the peripheral blood. The aim of this study was to assess the consequence of pelvic irradiation on peripheral immune cells and cytokine secretions in localized prostate cancer (PC) patients undergoing pelvic irradiation with a simultaneous moderately hypofractionated prostate/prostate bed boost by Volumetric Modulated Arc Therapy (VMAT). Furthermore, we analyzed whether there was a correlation between these peripheral immune parameters and acute and late genitourinary (GU) and gastrointestinal (GI) toxicity.

Thirty-eight PC patients were treated with pelvis irradiation (dose per fraction 1.8 Gy) and simultaneous hypofractionated (median dose per fraction: 2.7 Gy) prostate/prostate bed boost. A longitudinal analysis was performed for 12 months on peripheral blood to assess changes in 9 different lymphocyte subpopulations by flow cytometry and 10 circulating cytokines by Multiplex Luminex assay and ELISA.

Our analysis revealed that basal IFN-γ serum values were significantly lower in the definitive (curative intent for patients with prostate) patient group respect to the post-operative one. All the lymphocyte subsets and IFN-α, IFN-β and Il-2 peripheral concentrations displayed significant variations between the different time points considered. The immune cell population that suffers the greatest RT toxicity in the blood was B lymphocyte. We found an interesting correlation between basal TGF-β1 and late GU toxicity. In particular, TGF-β1 concentrations before RT were significantly higher in patients that experienced grade 2-3 of late GU toxicity, respect to grade 0-1. Exploring possible correlations between some clinical/biological findings and radiation planning parameters, we found no statistical significance.

Our study analyzed, in the context of hypofractionated radiotherapy in prostate cancer, different parameters of the peripheral immune system. We have highlighted longitudinally the peripheral behavior of the different lymphocyte subpopulations and of a group of 10 cytokines during the first year after RT. One of the analyzed cytokines, such as TGF-β1, has proven to be promising predictive factor of severe late GU toxicity.

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5-2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

We conducted a systematic review and meta-analysis to assess the risk of respiratory adverse effects in patients with solid tumors treated with immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 inhibitors) in combination with radiation therapy.

We selected eligible studies through the following databases: PubMed, Embase, Cochrane Library, and Clinicaltrials ( https://clinicaltrials.gov/ ). The data was analyzed by using Rstudio.

Among 3737 studies, 26 clinical trials, including 2670 patients, were qualified for the meta-analysis. We evaluated the incidence rates of adverse respiratory events, including cough, pneumonia, upper respiratory tract infections, and others: grades 1-5 cough, 0.176 (95%CI: 0.113-0.274, I2 = 92.36%); grades 1-5 pneumonitis, 0.118 (95%CI: 0.067-0.198, I2 = 88.64%); grades 1-5 upper respiratory tract infection, 0.064 (95%CI: 0.049-0.080, I2 = 0.98%); grades 3-5 cough, 0.050 (95%CI: 0.012-0.204, I2 = 8.90%); grades 3-5 pneumonitis, 0.052 (95%CI: 0.031-0.078, I2 = 83.86%); grades 3-5 upper respiratory tract infection, 0.040 (95%CI: 0.007-0.249, I2 = 45.31%).

Our meta-analysis demonstrated that ICI combined with radiotherapy for solid tumors can produce respiratory adverse effects. ICIs combination treatment, a tumor located in the chest, is more likely to cause adverse reactions, and SBRT treatment and synchronous treatment will bring less incidence of adverse reactions. This study provide insights for clinicians to balance the risks of radiotherapy in the course of treating oncology patients.

Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier.

This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers.

Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.

The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).

The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage.

Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group.

Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.

Radiation therapy may induce off-target antitumor "abscopal" immunostimulatory and immunosuppressive effects. Several preclinical and early clinical studies revealed promising results when combining radiation therapy with immunostimulatory agents. Most radioimmunotherapy randomized trials showed disappointing results in patients with advanced tumors. In contrast, outcomes were encouraging when immunotherapy was delivered on top of gross disease elimination with curative-intent radiation therapy. In this review, we highlight available results from randomized trials and discuss the potential impact of overall tumor burden on the observed efficacy of radioimmunotherapy.

There is no established treatment for terminal cancer patients who no longer respond to surgery, radiotherapy, or chemotherapy, and palliative care is the standard worldwide. We performed intensity-modulated radiation therapy for pain relief in a 40-year-old male patient with end-stage small intestinal cancer who had been diagnosed with a life expectancy of two months after chemotherapy had been ineffective. Subsequent administration of seven doses of dendritic cell vaccine recognizing Wim's tumor 1 (WT1) and α-galactosylceramide antigens resulted in significant shrinkage of the cancer and marked improvement of the patient's general condition. The combination therapy of radiotherapy and dendritic cell vaccine therapy may suppress cancer progression and prolong survival, even in patients with chemotherapy-refractory terminal cancer. In particular, double dendritic cell vaccine therapy with WT1 and α-galactosylceramide-pulsed dendritic cell may provide an anti-tumor immune effect that is superior to that of the respective monotherapy.

High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to induce complex and clustered DNA lesions. However, the development of radiation resistance poses a significant barrier. The potential molecular mechanisms that could confer resistance development are translesion synthesis (TLS), replication gap suppression (RGS) mechanisms, autophagy, epithelial-mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes. This article will discuss various types of complex clustered DNA damage, their repair mechanisms, mutagenic potential, and the development of radiation resistance strategies. Furthermore, it highlights the importance of careful consideration and patient selection when employing high-LET radiotherapy in clinical settings.

Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.

High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.

Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.

For unique surface plasmon absorption and fluorescence characteristics, gold nanorods have been developed and widely employed in the biomedical field. However, limitations still exist due their low specific surface area, instability and tendency agglomerate in cytoplasm. Mesoporous silica materials have been broadly applied in field of catalysts, adsorbents, nanoreactors, and drug carriers due to its unique mesoporous structure, highly comparative surface area, good stability and biocompatibility. Therefore, coating gold nanorods with a dendritic mesopore channels can effectively prevent particle agglomeration, while increasing the specific surface area and drug loading efficiency. This review discusses the advancements of GNR@MSN in synthetic process, bio-imaging technique and tumor therapy. Additionally, the further application of GNR@MSN in imaging-guided treatment modalities is explored, while its promising superior application prospect is highlighted. Finally, the issues related to in vivo studies are critically examined for facilitating the transition of this promising nanoplatform into clinical trials.

Radiotherapy is a crucial treatment modality for cancer patients, with approximately 60% of individuals undergoing ionizing radiation as part of their disease management. In recent years, there has been a growing trend toward minimizing irradiation fields through the use of image-guided dosimetry and innovative technologies. These advancements allow for selective irradiation, delivering higher local doses while reducing the number of treatment sessions. Consequently, computer-assisted methods have significantly enhanced the effectiveness of radiotherapy in the curative and palliative treatment of various cancers. Although radiation therapy alone can effectively achieve local control in some cancer types, it may not be sufficient for others. As a result, further preclinical research is necessary to explore novel approaches including new schedules of radiotherapy treatments. Unfortunately, there is a concerning lack of correlation between clinical outcomes and experiments conducted on mouse models. We hypothesize that this disparity arises from the differences in irradiation strategies employed in preclinical studies compared to those used in clinical practice, which ultimately affects the translatability of findings to patients. In this study, we present two comprehensive radiotherapy protocols for the treatment of orthotopic melanoma and glioblastoma tumors. These protocols utilize a small animal radiation research platform, which is an ideal radiation device for delivering localized and precise X-ray doses to the tumor mass. By employing these platforms, we aim to limit the side effects associated with irradiating healthy surrounding tissues. Our detailed protocols offer a valuable framework for conducting preclinical studies that closely mimic clinical radiotherapy techniques, bridging the gap between experimental results and patient outcomes.

Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.

Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.

Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses.

This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy.

EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912.

Platinum-etoposide chemotherapy combined with immune checkpoint inhibitors (ICIs) has been recommended as the first-line standard treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, the effect of thoracic radiotherapy (TRT) on these patients is still unknown. This study aimed to evaluate the efficacy and safety of TRT for ES-SCLC patients who responded to first-line ICIs and chemotherapy (CHT).

Patients who received 4 to 6 cycles of ICIs and CHT as first-line therapy at three hospitals between 2018 and 2022 were included in the analysis. All patients were divided into two groups based on whether they received TRT as first-line treatment, and propensity score matching (PSM) was performed to ensure that the characteristics of two groups were well-balanced. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was toxic effects.

A total of 276 patients were included, and the median follow-up time was 22.3 (range, 4.0-53.73) months. After PSM, 197 patients were further analysed, and 99 of whom received TRT. The baseline characteristics were well-balanced between patients in the TRT and non-TRT groups. There were significant differences in PFS between the TRT and non-TRT groups, with the median PFS of 10.76 and 7.63 months, respectively (P = 0.014). Significantly improved OS was observed in the TRT group (21.67 vs. 16.6 months, P = 0.009). In addition, the use of TRT was an independent prognostic factor for PFS and OS of ES-SCLC patients receiving ICIs plus CHT. In terms of safety, no significant increase of any grades adverse event (AE) (P = 0.874) and G3-4 AE (P = 0.909) was observed for patients receiving TRT. Radiation esophagitis, gastrointestinal and hematologic toxicities were the most common AEs in TRT group, which were tolerable. And high-dose radiotherapy was associated with higher incidence of pneumonitis.

Addition of TRT showed significant survival benefits and well tolerability in ES-SCLC patients receiving platinum-etoposide CHT and ICIs, which could be a feasible first-line treatment strategy for ES-SCLC patients.

We report a 10-year experience in cancer therapy with concomitant treatment of percutaneous thermal ablation (PTA) and immune checkpoint blockers (ICBs).

This retrospective cohort study included all patients at a single tertiary cancer center who had received ICBs at most 90 days before, or 30 days after, PTA. Feasibility and safety were assessed as the primary outcomes. The procedure-related complications and immune-related adverse events (irAEs) were categorized according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Efficacy was evaluated based on overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) according to the indication, ablation modality, neoplasm histology, and ICB type.

Between 2010 and 2021, 78 patients (57% male; median age: 61 years) were included. The PTA modality was predominantly cryoablation (CA) (61%), followed by radiofrequency ablation (RFA) (31%). PTA indications were the treatment of oligo-persistence (29%), oligo-progression (14%), and palliation of symptomatic lesions or prevention of skeletal-related events (SREs) (56%). Most patients received anti-PD1 ICB monotherapy with pembrolizumab (n = 35) or nivolumab (n = 24). The feasibility was excellent, with all combined treatment performed and completed as planned. Ten patients (13%) experienced procedure-related complications (90% grade 1-2), and 34 patients (44%) experienced an irAE (86% grade 1-2). The only factor statistically associated with better OS and PFS was the ablation indication, favoring oligo-persistence (p = 0.02). Tumor response was suggestive of an abscopal effect in four patients (5%).

The concomitant treatment of PTA and ICBs within 2-4 weeks is feasible and safe for both palliative and local control indications. Overall, PTA outcomes were found to be similar to standards for patients not on ICB therapy. While a consistently reproducible abscopal effect remains elusive, the safety profile of concomitant therapy provides the framework for continued assessment as ICB therapies evolve.

Unlike drug selection, radiation parameters (field, dose) are not based on driver gene mutations in patients with metastatic non-small cell lung cancer (NSCLC). This study aimed to compare radiosensitivity in NSCLC with and without EGFR driver gene mutations using clinical and in vitro data. The clinical study included 42 patients who underwent whole-brain radiotherapy for brain metastases from NSCLC; of these, 13 patients had EGFR mutation-positive tumors. The Kaplan-Meier method was used to calculate the cranial control rate without intracranial recurrence. In the in vitro study, colony formation and double-strand DNA breaks were examined in two EGFR mutation-negative and three EGFR mutation-positive NSCLC-derived cell lines. Colony formation was assessed 14 days after irradiation with 0 (control), 2, 4, or 8 Gy. DNA double-strand breaks were evaluated 0.5 and 24 h after irradiation. EGFR mutation-positive patients had a significantly better cranial control rates than EGFR mutation-negative patients (p = 0.021). EGFR mutation-positive cells formed significantly fewer colonies after irradiation with 2 or 4 Gy than EGFR mutation-negative cells (p = 0.002, respectively) and had significantly more DNA double-strand breaks at 24 h after irradiation (p < 0.001). Both clinical and in vitro data suggest that EGFR mutation-positive NSCLC is radiosensitive.

The incidence of brain metastasis is high and still increasing. Among local therapies, stereotactic radiosurgery (SRS) is an effective treatment option, optimally sparing normal brain, even for multiple brain metastases. Immune checkpoint inhibitors (ICIs) become the new standard of care in an increasing number of cancers, and the combination SRS and ICI is often proposed to patients, but few data have been published on the efficacy and the toxicity of this association.

Explaining this lack of consensus: retrospective studies with different primary cancers, various treatment lines and unknown levels of steroid exposure. Concerning the toxicity, the independent association of radionecrosis with brain-PTV volume was confirmed, and a decreased dose of SRS is now tested in a randomized study. Finally, a 'concurrent' delivery of SRS and ICI (within a 4 weeks' interval) seems the optimal schedule; fractionated radiosurgery for large brain metastasis should be favored. Radio-sensitizing nanoparticles and devices aiming to increase the permeability of the blood brain barrier should be considered in future combinations.

The efficacy/toxicity balance of SRS-ICI combination should be regularly re-evaluated, anticipating continued progress in ICI and SRS delivery, with more long-survivors potentially exposed to long-term toxicities. Patients should be included in clinical trials and clearly informed to participate more closely in the final choice.

Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.

Immunotherapy has revolutionized the treatment of cancer. However, microsatellite stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to PD-1 inhibitors. Antiangiogenic therapy can enhance anti-PD-1 efficacy, but it still cannot meet clinical needs. Increasing evidence supported a close relationship between gut microbiome and anti-PD-1 efficacy. This study aimed to explore the efficacy and safety of the combination of fecal microbiota transplantation (FMT) and tislelizumab and fruquintinib in refractory MSS mCRC.

In the phase II trial, MSS mCRC patients were administered FMT plus tislelizumab and fruquintinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), clinical benefit rate (CBR), safety and quality of life. Feces and peripheral blood were collected for exploratory biomarker analysis. This study is registered with Chictr.org.cn, identifier ChiCTR2100046768.

From May 10, 2021 to January 17, 2022, 20 patients were enrolled. Median follow-up was 13.7 months. Median PFS was 9.6 months (95% CI 4.1-15.1). Median OS was 13.7 months (95% CI 9.3-17.7). Median DoR was 8.1 months (95% CI 1.7-10.6). ORR was 20% (95% CI 5.7-43.7). DCR was 95% (95% CI 75.1-99.9). CBR was 60% (95% CI 36.1-80.9). Nineteen patients (95%) experienced at least one treatment-related adverse event (TRAE). Six patients (30%) had grade 3-4 TRAEs, with the most common being albuminuria (10%), urine occult blood (10%), fecal occult blood (10%), hypertension (5%), hyperglycemia (5%), liver dysfunction (5%), hand-foot skin reaction (5%), and hypothyroidism (5%). No treatment-related deaths occurred. Responders had a high-abundance of Proteobacteria and Lachnospiraceae family and a low-abundance of Actinobacteriota and Bifidobacterium. The treatment did not change the structure of peripheral blood TCR repertoire. However, the expanded TCRs exhibited the characteristics of antigen-driven responses in responders.

FMT plus tislelizumab and fruquintinib as third-line or above treatment showed improved survival and manageable safety in refractory MSS mCRC, suggesting a valuable new treatment option for this patient population.

This study was supported by the National Natural Science Foundation of China (82102954 to Wensi Zhao) and the Special Project of Central Government for Local Science and Technology Development of Hubei Province (ZYYD2020000169 to Yongshun Chen).

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and poses a major burden on the human health worldwide. At the moment, treatment of CRC consists of surgery in combination with (neo)adjuvant chemotherapy and/or radiotherapy. More recently, immune checkpoint blockers (ICBs) have also been approved for CRC treatment. In addition, recent studies have shown that radiotherapy and ICBs act synergistically, with radiotherapy stimulating the immune system that is activated by ICBs. However, both treatments are also associated with severe toxicity and efficacy issues, which can lead to temporary or permanent discontinuation of these treatment programs. There's growing evidence pointing to the gut microbiome playing a role in these issues. Some microorganisms seem to contribute to radiotherapy-associated toxicity and hinder ICB efficacy, while others seem to reduce radiotherapy-associated toxicity or enhance ICB efficacy. Consequently, fecal microbiota transplantation (FMT) has been applied to reduce radio- and immunotherapy-related toxicity and enhance their efficacies. Here, we have reviewed the currently available preclinical and clinical data in CRC treatment, with a focus on how the gut microbiome influences radio- and immunotherapy toxicity and efficacy and if these treatments could benefit from FMT.

Progresses of systemic treatments in advanced non-small cell lung cancer (NSCLC), such as immune checkpoint blockers (ICB) and targeted therapies, led to the increased incidence of oligoprogressive disease (OPD). The OPD is a subtype of oligometastatic disease (OMD) defined as a progression of a limited number of lesions during systemic treatment exposure. The hypothesis was formulated that local radical treatments (LRT) could eradicate progressive lesions resulting from resistant clones, ultimately leading to systemic treatment sensitivity restoration. Recently published international consensuses and guidelines aim to obtain a uniform definition of OMD NSCLC, to standardize the inclusion of these patients in future clinical trials, as well as their management in daily practice. Although there is no specific definition of OPD, LRT strategies in OPD are supported after reporting promising results. Both retrospective and preliminary prospective randomized data of LRT for patients with OPD NSCLC are encouraging. More clinical and translational data are needed for selecting best scenarios where LRT should be delivered. In this review, we analyze the current available literature on LRT for patients with OPD in advanced NSCLC and discuss about future trial design and challenges.

The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE).

A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers.

The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity.

Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.