Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy.

BACKGROUND: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models. METHODS: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. RESULTS: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations. CONCLUSION: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

Abscopal effect: from a rare phenomenon to a new frontier in cancer therapy.

Radiotherapy (RT) controls local lesions, meantime it has the capability to induce systemic response to inhibit distant, metastatic, non-radiated tumors, which is referred to as the "abscopal effect". It is widely recognized that radiotherapy can stimulate systemic immune response. This provides a compelling theoretical basis for the combination of immune therapy combined with radiotherapy(iRT). Indeed, this phenomenon has also been observed in clinical treatment, bringing significant clinical benefits to patients, and a series of basic studies are underway to amplify this effect. However, the molecular mechanisms of immune response induced by RT, determination of the optimal treatment regimen for iRT, and how to amplify the abscopal effect. In order to amplify and utilize this effect in clinical management, these key issues require to be well addressed; In this review, we comprehensively summarize the growing consensus and emphasize the emerging limitations of enhancing the abscopal effect with radiotherapy or immunotherapy. Finally, we discuss the prospects and barriers to the current clinical translational applications.

Integrative Approaches in Non-Small Cell Lung Cancer Management: The Role of Radiotherapy.

Treatment guidelines for non-small cell lung cancer (NSCLC) vary by several factors including pathological stage, patient candidacy, and goal of treatment. With many therapeutics and even more combinations available in the NSCLC clinician's toolkit, a multitude of questions remain unanswered vis-a-vis treatment optimization. While some studies have begun exploring the interplay among the many pillars of NSCLC treatment-surgical resection, radiotherapy, chemotherapy, and immunotherapy-the vast number of combinations and permutations of different therapy modalities in addition to the modulation of each constituent therapy leaves much to be desired in a field that is otherwise rapidly evolving. Given NSCLC's high incidence and lethality, the experimentation of synergistic benefits that combinatorial treatment may confer presents a ripe target for advancement and increased understanding without the cost and burden of novel drug development. This review introduces, synthesizes, and compares prominent NSCLC therapies, placing emphasis on the interplay among types of therapies and the synergistic benefits some combinatorial therapies have demonstrated over the past several years.

Abscopal effect in a patient with advanced hepatocellular carcinoma upon resuming bevacizumab in combination with atezolizumab after radiotherapy.

Combining bevacizumab with atezolizumab enhances the antitumor effects of the treatment by activating an immune response. This combination is approved for the treatment of unresectable hepatocellular carcinoma (HCC). An abscopal effect is associated with an immune response triggered by radiation-induced immunogenic cell death, based on experimental models. Thus, combining radiotherapy and immunotherapy is expected to induce an abscopal effect. However, the clinical significance of immunotherapy in the abscopal effect remains unknown due to the rarity of clinical cases. Herein, we report a case of advanced HCC with lung and adrenal metastases. The antitumor efficacy of atezolizumab and bevacizumab (atezo/bev) was enhanced following stereotactic body radiotherapy (SBRT), although atezo/bev did not yield a sufficient therapeutic response pre-SBRT. Furthermore, an abscopal effect following SBRT was not observed during atezolizumab alone but was evoked after resuming bevacizumab in combination with atezolizumab, culminating in the patient achieving a complete response status. These findings suggest that immune activation following radiotherapy may be related to the induction of an abscopal effect in clinical practice as well as in experimental settings, and combining immunotherapy with bevacizumab post-radiotherapy could evoke an abscopal effect in a case of HCC, even though immune checkpoint inhibitor use alone may be insufficient.

p53-armed oncolytic virotherapy induces abscopal effect in osteosarcoma by promoting immunogenic cell death.

Osteosarcoma (OS), the most frequent primary malignant tumor of bone in children and adolescents, is refractory to immune checkpoint inhibitors due to its poor antitumor immune response. Chemotherapy and virotherapy induce immunogenic cell death (ICD) and antitumor immune responses, leading to the abscopal effect in untreated tumors. We previously demonstrated the antitumor activity of the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 in human OS cells. Here, we show the therapeutic potential of chemotherapeutic drugs (doxorubicin, cisplatin) and telomerase-specific oncolytic adenoviruses (OBP-301, p53-armed OBP-702) to induce ICD in human OS cells (U2OS, MNNG/HOS, SaOS-2) and murine OS cells (NHOS). OBP-702 induced more profound ICD via the secretion of adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1) compared with chemotherapy and OBP-301 in human OS cells. Murine NHOS cells were also more sensitive to OBP-702 than OBP-301. Subcutaneous NHOS tumor models demonstrated that intratumoral injection of OBP-702 significantly increased the tumor infiltration of cytotoxic CD8+ T cells and induced the abscopal effect against non-treated tumors compared with OBP-301. Our results suggest that OBP-702 is a promising antitumor reagent to induce ICD with secretion of ATP and HMGB1 and the abscopal effect against OS.

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT).

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.

Combination of radiotherapy and PD-L1 blockade induces abscopal responses in EGFR-mutated lung cancer through activating CD8+ T cells.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+T cells was lower in EGFR-mutated NSCLC. In addition, CD8+T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.

The Effects of Gynecological Tumor Irradiation on the Immune System.

Radiobiology has evolved from a mechanistic model based on DNA damage and response factors into a more complex model that includes effects on the immune system and the tumor microenvironment (TME). Irradiation has an immunomodulatory effect that can manifest as increased anti-tumor immunity or immunosuppression. Irradiation promotes an inflammatory microenvironment through the release of pro-inflammatory cytokines and endothelial damage, which recruit immune system cells to the irradiated area. Radiation-induced immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and tumor antigens, triggers an anti-tumor immune response of both innate and adaptive immunity. Anti-tumor immunity can manifest at a distance from the irradiated area, a phenomenon known as the abscopal effect (AE), which involves dendritic cells and CD8+ T cells. Irradiation also produces an immunosuppressive effect mediated by tumor-associated macrophages (TAMs) and regulatory T lymphocytes (Tregs), which counterbalances the immunostimulatory effect. In this work, we review the mechanisms involved in the radiation-induced immune response, which support the combined treatment of RT and immunotherapy, focusing, where possible, on gynecologic cancer.

Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study.

OBJECTIVES: To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts. RESULTS: Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP. CONCLUSIONS: Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

A good response to anti-PD-1 monoclonal antibody plus SBRT in a patient with PD-L1-negative recurrent advanced esophageal cancer: a long-term follow-up case report of a possible abscopal effect.

There are limited treatment options for recurrent advanced esophageal squamous cell carcinoma. A good response with a possible abscopal effect was observed in a patient with programmed death-ligand 1 (PD-L1)-negative recurrent advanced esophageal squamous cell carcinoma treated with an anti-PD-1 monoclonal antibody plus stereotactic body radiotherapy (SBRT). A 66-year-old male patient was diagnosed with recurrent advanced esophageal squamous cell carcinoma with multiple lung metastases (13 metastatic nodules in total) four months after completing radical radiotherapy plus concurrent and consolidated chemotherapy, and PD-L1 expression in the primary esophageal tumor was negative. This patient received 25 cycles of camrelizumab (an anti-PD-1 monoclonal antibody) in total plus upfront SBRT for two metastatic nodules, which was administered after the first cycle of camrelizumab. After this combined treatment, for most nontarget nodules, an obvious volume decrease and fuzzy change were observed, including two nodules that completely vanished. At the end of follow-up, the progression-free survival and duration of response of this patient were 34 months and 32 months, respectively. This case report indicated that an anti-PD-1 monoclonal antibody combined with SBRT was a promising therapeutic strategy for recurrent esophageal squamous cell carcinoma even in patients with negative PD-L1 expression.

Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy.

BACKGROUND: The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. METHODS: Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. RESULTS: The abscopal effect was further amplified in the "cold" tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. CONCLUSIONS: Bi was used as an artificially implanted anaerobic target to cause a transient "infection" at the tumor, causing the tumor to become locally inflamed and "hot", and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Immune modulation in untreated, contralateral hepatic metastases after Y90-radioembolization of microsatellite stable (MSS) colorectal cancer.

PURPOSE: To assess immunogenic effects in unembolized contralateral tumor after single lobar Y90-radioembolization (SIRT) of colorectal liver metastases(CRLM). MATERIAL AND METHODS: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective BLINDED trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial SIRT treatment of one liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 (4-49) days immediately prior to second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMC) were collected before treatments for immune cell analysis. Patients were stratified into "responders" and "non-responders" based on tumor control or progression during follow up. RESULTS: At baseline, responders (n=4) displayed lower concentrations of FoxP3+ cells and co-location of CD4+FoxP3+ cells than non-responders (both p=0.02) in tumor tissues. At second biopsy, non-responders showed a higher CD68+ macrophage density (p=0.0014) than responders. Responders displayed fewer CD4+FoxP3+ T cells than CD8+ T cells at all timepoints (p=0.02 and p=0.0428). Non-responders demonstrated a trending increase of CD68+ macrophages (p=0.062), as well as a higher CD8+PD1+/CD8+ ratio (p=0.062). PBMC of non-responders displayed lower CD8+PD1+ T cells and CD8+PD1+/CD8+ ratio at both timepoints. CONCLUSION: SIRT induces local immunogenic effects in non-exposed MCC CRLM, as well as systemic exhaustion of immune cells in non-responders. Clinical implications such as a prognostic role or synergism of SIRT and checkpoint inhibition in MSS CRLM warrant further investigation.

An investigator-initiated clinical study in patients with refractory or recurrent solid tumors: 'R-ISV-FOLactis' trial.

Aim: In situ vaccination, a kind of therapeutic cancer vaccine, can be realized by radiotherapy and intratumoral immune injection. This study combines intratumoral injection, radiotherapy and PD-1 blockade for synergistic antitumor effect.Materials & methods: Patients with advanced solid tumors who are unresponsive or intolerant to standard treatment will be treated with hypofractionated radiotherapy, intratumoral injection of FOLactis, PD-1 blockade. The primary end point is to observe the efficacy and safety, with the secondary end point to evaluate abscopal effects and the correlation between the immunological rationale and efficacy.Discussion: The combined regimen will be utilized to trigger antitumor immunity and is expected to be feasible and effective and provide a novel option for the comprehensive treatment of cancer.Clinical Trial Registration: ChiCTR2200060660 (ChiCTR.gov.cn).

[Box: see text].

Novel time-synchronized immune-guided partial tumor irradiation: Proof of principle trial.

BACKGROUND AND PURPOSE: Radiotherapy for bulky tumors often results in palliation with suboptimal outcomes. The prognosis is worsened by immunosuppression caused by radio-chemotherapy, negatively impacting on survival. Novel Partial Tumor Irradiation (PTI) was designed to spare the Peritumoral Immune Microenvironment (PIM) and to be delivered synchronously with immune activity peaks, thus enhancing both local and distant tumor control through immunostimulation. MATERIALS AND METHODS: Present proof-of-principle trial enrolled 26 patients with bulky tumors, comparing outcomes between treatments administered at immune activity peaks versus troughs. The primary endpoint was local-bystander and distal-abscopal response-rate. Secondary endpoints included overall-, progression-free-, cancer-specific survival, neoadjuvant and immunomodulatory potential. RESULTS: All measured outcomes were significantly influenced by treatment-timing. The bystander and abscopal response rates were 77% and 41%, respectively. PTI significantly upregulated pro-inflammatory and cell-death-inducing pathways improving the efficacy of radiotherapy by highly complex tumors. CONCLUSIONS: This study highlights the profound impact PTI can have on a highly palliative patient cohort previously deemed beyond therapeutic hope. With 41 % of these patients still alive after a median follow-up of 50 months, PTI offers a potential lifeline for those facing advanced, treatment-resistant cancers. This approach generated also distant immunogenic anti-tumor responses, offering a promising new avenue for the treatment of advanced cancers.

In situ sustained release hydrogel system delivering GLUT1 inhibitor and chemo-drug for cancer post-surgical treatment.

Systematic administration of small molecular drugs often suffered from the low efficacy and systemic toxicity in cancer therapy. In addition, application of single mode drug usually leads to unsatisfactory therapeutic outcomes. Currently, developing multimodal-drug combination strategy that acts on different pathways without increasing side effects remains great challenge. Here, we developed a hydrogel system that co-delivered glycolysis inhibitor apigenin and chemo-drug gemcitabine to realize combination strategy for combating cancer with minimal systemic toxicity. We demonstrated that this system can not only eliminate tumor cells in situ, but also induce abscopal effect on various tumor models. These results showed that our study provided a safe and effective strategy for clinical cancer treatment.

The Immunomodulatory Potential of Concurrent High-Dose Radiotherapy and Immune Checkpoint Inhibitor Cemiplimab in Advanced Cutaneous Squamous Cell Carcinoma: Initial Results.

In this retrospective case series, we investigate the synergistic effect and the immunomodulatory potential of combination radiotherapy and immunotherapy on 11 patients affected by locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), treated at our institution between 2020 and 2023. The primary endpoints of this study are objective tumor response, assessed by Immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST), and time to treatment failure (disease progression). In all patients, surgery was deemed not amenable, due to its potential functional and aesthetic impact. Therefore, upon multidisciplinary agreement, radiotherapy and immunotherapy with cemiplimab were alternatively administered. After 6 months, an early objective tumor response was observed in 9/11 patients, with 17/20 cutaneous lesions (85%) presenting either a complete or partial response. Only 2/11 patients, with a total of 3/20 cutaneous lesions (15%), had stable disease. These benefits persisted at a longer follow-up (21.4 ± 9.7 months), with no patients presenting disease progression. Despite the retrospective nature of this study and small sample size, our experience highlights the ability of concomitant radiotherapy and cemiplimab to promote an early objective response in patients with advanced CSCC. Moreover, in our population, the clinical benefits were also related to a longer progression-free survival, without any safety alert reported.

Spontaneous remission of a pulmonary sclerosing epithelioid fibrosarcoma: a case report of a possible abscopal effect.

Background: Spontaneous remission (SR) is defined as the complete or partial disappearance of a diagnosed malignant disease in the absence of known active medical treatment. The role of the immune system is thought to be important, but has not yet been elucidated. On this matter, there are studies that suggest that the abscopal effect (AE), which is defined as the remission of untreated lesions beyond the irradiated area, may be explained by the activation of a systemic immune response against the tumor. Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of soft tissue sarcoma that is characterized by a slow evolution, with local recurrences and late metastases. The treatment is based on surgery, leaving a minimal role to chemotherapy (ChT) and radiotherapy (RT) for metastatic unresectable disease, and no cases of SR have been reported in the literature so far. Case Description: We present the case of a patient with a lung metastatic recurrence of SEF, diagnosed and treated with surgery 8 years before. After progression to pazopanib and other ChT drugs, because of the chest pain associated with a pleural mass invading the second costal arch, the patient received antalgic local RT treatment. Months later, and without any further treatment, a partial remission of all the tumoral lesions was presented, and she is alive 25 years after the first diagnosis. Conclusions: As far as reported in the literature, this is the first case of SR in SEF. Among the possible causes of this SR, we think that the most plausible is that palliative treatment with RT of the pleural mass induced an AE, leading to a reduction of all tumoral lesions, even those outside the irradiated region.

The dynamic duo: A narrative review on the synergy between stereotactic body radiotherapy and immunotherapy in lung cancer treatment (Review).

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is undoubtedly one of the major breakthroughs in lung cancer research. Patient survival and prognosis have all been improved as a result, although numerous patients do not respond to immunotherapy due to various immune escape mechanisms of the tumor cells. Recent preclinical and clinical evidence has shown that stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, has a prominent immune priming effect that could elicit antitumor immunity against specific tumor antigens and destroy distant tumor cells, thereby achieving the elusive abscopal effect, with the resulting immuno­active tumor environment also being more conducive to ICIs. Some landmark trials have already demonstrated the survival benefit of the dynamic duo of SBRT plus immunotherapy in metastatic non­small­cell lung cancer, while others such as PEMBRO­RT further suggest that the addition of SBRT to immunotherapy could expand the current indication to those who have historically responded poorly to ICIs. In the present review, the biological mechanisms that drive the synergistic effect of SBRT and immunotherapy were first briefly outlined; then, the current understanding from clinical trials was summarized and new insight into the evolving role of immunotherapy and SBRT synergy in lung cancer treatment was provided. Finally, novel avenues for discovery were highlighted. The innovation of the present review lies in the inclusion of non­ICI immunotherapy in the discussion, which provides a more comprehensive view on the current development and future trend of SBRT + immunotherapy synergy.

Beyond success: unveiling the hidden potential of radiotherapy and immunotherapy in solid tumors.

Immunotherapy, particularly with immune checkpoint inhibitors, has significantly transformed cancer treatment. Despite its success, many patients struggle to respond adequately or sustain long-lasting clinical improvement. A growing consensus has emerged that radiotherapy (RT) enhances the response rate and overall efficacy of immunotherapy. Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results, establishing itself as a dynamic and thriving area of research, clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results, suggesting the need for a more nuanced understanding. This review provides a balanced and updated analysis of the combination of immunotherapy and RT. We summarized the preclinical mechanisms through which RT boosts antitumor immune responses and mainly focused on the outcomes of recently updated clinical trials, including those that may not have met expectations. We investigated the optimization of the therapeutic potential of this combined strategy, including key challenges, such as fractionation and scheduling, lymph node irradiation, and toxicity. Finally, we offered insights into the prospects and challenges associated with the clinical translation of this combination therapy, providing a realistic perspective on the current state of research and potential future directions.

Strategies for overcoming tumour resistance to immunotherapy: harnessing the power of radiation therapy.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; yet their efficacy remains variable across patients. This review delves into the intricate interplay of tumour characteristics contributing to resistance against ICI therapy and suggests that combining with radiotherapy holds promise. Radiation, known for its ability to trigger immunogenic cell death and foster an in situ vaccination effect, may counteract these resistance mechanisms, enhancing ICI response and patient outcomes. However, particularly when delivered at high-dose, it may trigger immunosuppressive mechanism and consequent side-effects. Notably, low-dose radiotherapy (LDRT), with its capacity for tumour reprogramming and reduced side effects, offers the potential for widespread application. Preclinical and clinical studies have shown encouraging results in this regard.