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Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. CMC patients treated weekly with acPD-1 (n = 3) or CPMV/acPD-1 (n = 3) for four weeks or with CPMV/acPD-1 (n = 3 patients not candidates for surgery) for up to 11 weeks did not experience immune-related adverse events. We found that acPD-1 and CPMV/acPD-1 injections resulted in tumor control and a reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of treated dogs. In two metastatic CMC patients, CPMV/acPD-1 treatments resulted in the control and reduction of established lung metastases. CPMV/acPD-1 treatments were associated with altered gene expression related to TLR1-4 signaling and complement pathways. These novel therapies could be effective for CMC patients. Owing to the extensive similarities between CMC and human BC, IT CPMV combined with approved anti-PD-1 therapies could be a novel and effective immunotherapy to treat local BC and suppress metastatic BC.

Objective To investigate the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) on the abscopal effect of radiotherapy in mice with lung cancer via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and the underlying mechanism. Methods Lung cancer LLC1 cells in the logarithmic growth phase were randomly divided into the control group and irradiation group. Cells in the control group were cultured normally without intervention, while cells in the irradiation group were irradiated with 4 Gy (2 Gy/min for 2 min). Twenty-four hours later, the mRNA levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IRF7, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT related genes in the cells were determined by real-time PCR (rtPCR). In addition, 100 µL of LLC1 cell suspension in the logarithmic growth phase was injected subcutaneously into the groin of mice to prepare bilateral subcutaneous tumor-bearing models. The tumor-bearing mice were randomly divided into the control group, 8 Gy group, EGFRTKI group, and 8 Gy + EGFR-TKI group, with 3 mice in each group. The tumor-bearing mice in the control group were not intervened. The tumor-bearing mice in the 8 Gy group were radiated at 8 Gy for 3 times, the tumor-bearing mice in the EGFR-TKI group were intragastrically administered 1 mg/g EGFR-TKI for 3 times, and the tumor-bearing mice in the 8 Gy + EGFR-TKI group received both radiation and EGFR-TKI as above. The tumor on the right side of the mice was taken out after 17 days of intervention. The levels of cGAS, STING, p-STING, and type I interferon (IFN-1) proteins in the tumor tissues were determined by Western blotting. Tumor cell proliferation antigen (ki67) and tumor microenvironment-related proteins CD4, CD8, epidermal growth factor receptor (EGFR), forkhead transcription factor p3 (Foxp3), calreticulin (CRT), and major histocompatibility complex (MHC) were detected by immunohistochemistry. Results Compared with the control group, LLC1 cells in the radiation group showed significantly higher mRNA expression levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT (all P<0. 05), and lower IRF7 mRNA expression (P<0. 05). After 17 days of intervention, compared with the control group, tumor volume, tumor weight and relative expression of ki67 protein decreased in all three intervention groups (all P<0. 05), with the largest decrease in the 8 Gy + EGFR-TKI group. Compared with the control group, the EGFR-TKI group showed no significant difference in expression levels of cGAS, STING, p-STING or IFN-1 (all P>0. 05); the 8 Gy group showed no significant difference in expression levels of STING or IFN-1 proteins (both P>0. 05), but significantly elevated cGAS and p-STING protein expression (both P<0. 05); the 8 Gy + EGFR-TKI group showed significantly elevated expression of all cGAS, STING, p-STING and IFN-1 proteins (all P<0. 05). Compared with the 8 Gy + EGFR-TKI group, the expression levels of cGAS, IFN-1, and STING proteins were significantly lower in both the 8 Gy group and EGRF-TKI group (all P<0. 05). The expression levels of CD4, CD8, and MHC proteins in all three intervention groups significantly increased (all P<0. 05), and the expression levels of EGFR, Foxp3, and CRT proteins significantly decreased in comparison with those of the control group (all P< 0. 05). Compared with the radiation group, the 8 Gy+EGFR-TKI group had higher CD4, CD8, and MHC proteins, and lower EGFR and CRT protein levels (all P<0. 05). Similarly, CD4, CD8, and MHC were significantly higher, and EGFR, Foxp3, and CRT were significantly lower in the 8 Gy+ EGFR-TKI group than in the EGFR-TKI group (all P<0. 05). Conclusion EGFR-TKI improves the immune function of the tumor microenvironment by activating the cGAS-STING pathway, thereby enhancing the abscopal effect of radiotherapy in mice with lung cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Seventy years ago, Robin Mole introduced the concept of the abscopal effect to describe a rare phenomenon. This occurs when local radiation triggers an immune-mediated reduction in tumors outside the treated area but within the same organism. Observing this effect has been linked to improved overall and progression-free survival in patients who experience it. While the abscopal effect was once considered rare, it is now being observed more frequently due to the combination of radiation with immunotherapy. As a result, more researchers are exploring this study area, which shows promise for excellent results. This review focuses explicitly on the immunological implications of activating the abscopal effect through ionizing radiation in the central nervous system and explores the potentially involved immunological pathways.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response—the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in pancreatic tumors to understand the pathophysiological mechanisms of RFA and its effect on the TME, which could prevent recurrence and resistance. We reviewed clinical, preclinical, and in vitro studies on RFA mechanisms in pancreatic adenocarcinoma, discussing the unique immunomodulatory effects of EUS-RFA. Recent findings suggest that combining RFA with immune adjuvants enhances responses in pancreatic adenocarcinoma. EUS-RFA offers a dual benefit against PDAC by directly reducing tumor viability and indirectly enhancing anti-tumor immunity. Observations of neutrophil-mediated immunomodulation and programmed cell death ligand 1 (PD-L1) modulation support integrating EUS-RFA with targeted immunotherapies for managing pancreatic adenocarcinoma. Integrating EUS-RFA in PDAC treatment promises direct cytoreduction and synergistic effects with molecular targeted therapies. Prospective clinical trials are crucial to assess the efficacy of this combined approach in improving outcomes and survival rates in advanced PDAC cases.

Abstract 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.

Abstract 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.

Objective To explore the sensitizing effect of manganese for radiotherapy against tumors and its possible mechanisms. Methods A total of 300 male C57BL/6 mice (6~8 weeks old, weighing 20~23 g) with subcutaneous tumor were randomly divided into 4 groups: control group, radiotherapy group, manganese treatment group, and combined radiotherapy and manganese treatment group. Nasal drip with 10 μg manganese adjuvant was applied to the mice from the latter 2 groups on day 9 of tumor bearing, then single dose of 20 Gy radiation was locally administered on day 10. Tumor growth and mouse survival were monitored regularly. The sensitizing effect of manganese on radiotherapy was determined by monitoring and comparing the tumor growth among different unilateral mouse models. Bilateral tumor-bearing model was used to examine the effect of manganese on abscopal effects induced by radiotherapy. Flow cytometry was used to illustrate the changes in tumor-infiltrating immune cells in unilateral tumor bearing model. Immunohistochemical staining was employed to evaluate the spleen function in unilateral tumor bearing mice. Results Based on repeated validation of 3 different unilateral tumor-bearing models, radiotherapy combined with manganese therapy significantly inhibited tumor growth and prolonged survival of mice (P < 0.05). The results of bilateral tumor-bearing model showed that manganese therapy enhanced abscopal effects of radiotherapy, and significant regression was observed in both side of tumor under radiotherapy or not (P < 0.05). Flow cytometry revealed that manganese further increased radiation-induced CD8+T infiltration (P < 0.05) and decreased radiation-induced infiltration of Treg cells and myeloid-derived suppressor cells (MDSCs) (P < 0.05). Furthermore, manganese increased lymphocyte reserve pool of the spleen and improved its function. Conclusion Manganese adjuvant could act as a sensitizing agent for radiotherapy, by improving the function of spleen and reprogramming the tumor microenvironment synergistically.

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.

Simple Summary: Radiobiology has evolved from a mechanistic model based on DNA damage, and other response factors, into a more complex model including 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 anti-tumor immunity through pro-inflammatory cytokines and endothelial damage, the recruitment of immune cells, and radiation-induced immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and tumor antigens. Irradiation activates both the innate and adaptive arms of the immune system. Irradiation also produces immunosuppression via the recruitment and activation of immune cells, with immunosuppressive effects. In this work, we discuss the mechanism involved in radiation-induced immune effects on which the combination of radiotherapy and immunotherapy for gynecological cancers is based. 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. [ABSTRACT FROM AUTHOR]

Objectives Patients and Methods Results Conclusions 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).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.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.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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) has a low five-year survival rate because of its high rate of recurrence and metastasis. After surgical resection or radiation, the main treatments for HNSCC, patients sometimes experience functional or aesthetic disorders. Therefore, there is a great demand for the development of non-surgical treatment strategies to improve clinical outcomes and patients' quality of life. One such non-surgical treatment is mild hyperthermia (mHT). Many studies have investigated combination treatments with mHT and immune checkpoint inhibitors in preclinical settings. However, there have been no detailed reports on the effects of mHT on immune checkpoint molecules. Here, we investigated the effects of mHT on the tumor microenvironment (TME), particularly on programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1), in SCCVII cells and a squamous cell carcinoma mouse model. First, we found that PD-L1 mRNA levels and surface PD-L1 expression significantly increased after mHT. Second, a single tumor model was used to determine the effect of HT on the TME. mHT enhanced the accumulation of CD4+ and CD8+ T cells, elevated PD-L1 expression in the TME, and decreased the PD-1 positive rate of CD4+ T cells. Finally, using a bilateral tumor model, we found that anti-PD-L1 monotherapy and combination therapy resulted in longer survival than the isotype control or mHT monotherapy. Moreover, the combination therapy resulted in a significantly higher survival rate than anti-PD-L1 monotherapy. In conclusion, our findings elucidate changes in PD-L1 expression in the TME and strengthen the rationale for mHT and PD-L1 blockade combination therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 PDL1 expression. [ABSTRACT FROM AUTHOR]

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) Article highlights Background In situ vaccination refers to a method to reverse suppressive tumor microenvironment, stimulate tumor immunogenicity and tumor-specific T cells by radiotherapy or intratumoral injection. Radiotherapy can induce immunogenic cell death, while intratumoral injection promote the release of large number of antigens, enhancing the capacity of antigen-presenting cells to enhance antitumor immunity. Patients & methods This exploratory clinical study is designed as an open-label, single-center trial aimed at treating patients with advanced solid tumors who are unresponsive or intolerant to standard treatment by combining radiotherapy, intratumoral injection and PD-1 blockade. The objective efficacy and safety of the combined regimen will be evaluated. Discussion Radiotherapy alone does not induce a robust in situ vaccine effect in most cases. Studies have shown that radiotherapy can cause upregulation of programmed death-ligand 1 expression. As a result, the combination of radiation with PD-1 mAb may be a feasible strategy to enhance antitumor immunity. In this study, the combination of radiotherapy, intratumoral immune injection and intravenous PD-1 inhibitor will be utilized to treat patients with advanced solid tumors to augment antitumor immunity. Conclusion Safety and efficacy of the combined regimen will be further confirmed. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors help treat malignant melanoma, but show limited use in treating malignant vaginal melanoma, an aggressive, rare gynecological malignancy. We identified two patients treated with ipilimumab and nivolumab for vaginal melanoma; both were immunonegative for programmed cell death-ligand 1 and wild-type BRAF. Case 1, a 56-year-old female who underwent radical surgery for stage 1 malignant vaginal melanoma, experienced recurrence 15 months postoperatively. She briefly responded to ipilimumab and nivolumab combination therapy before showing disease progression. Tumor shrinkage occurred with nivolumab and local radiotherapy and, 45 months postoperatively, she survives with the melanoma. Case 2, a 50-year-old female, presented with a 4-cm blackish polypoid vaginal tumor with metastatic pelvic lymph nodes. She received ipilimumab and nivolumab combination therapy for stage III unresectable malignant vaginal melanoma. The vaginal tumor shrank after the third course of treatment, and the lymphadenopathy disappeared. The patient underwent radical surgery and is currently disease-free, using nivolumab for maintenance therapy. Both patients had immune-related adverse events coinciding with periods of high therapeutic efficacy of immune checkpoint inhibitors. Neoadjuvant therapy with immune checkpoint inhibitors and radiotherapy for immune checkpoint inhibitor resensitization may effectively treat advanced or recurrent vaginal melanoma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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The abscopal effect refers to an anti-tumor response that occurs in areas where radiotherapy (RT) has not been directly administered but is triggered by the immune system. We presented a case of an undifferentiated pleomorphic sarcoma with three relapses that showed a complete response after distant metastatic disease. The tumor was initially detected in the left pectoral muscle. Fifteen months after adjuvant RT and chemotherapy, a nearby recurrent lesion was surgically removed. Another 15 months later, a second recurrence appeared on the left lateral chest wall. The patient underwent a third surgery and received adjuvant radiation, but distant metastases were discovered 6 months later. Shortly after a biopsy confirmed distant metastasis, all metastatic foci went into spontaneous remission. This phenomenon is identified as the abscopal effect. The patient experienced no metastasis or local recurrences during follow-up and showed a complete response to the abscopal effect for 36 months. The abscopal effect in malignant mesenchymal tumors is extremely rare.

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.

Background: Patients with metastatic colorectal cancer (mCRC) carrying a deficit in the mismatch repair system/microsatellite instability (dMMR/MSI) show great responses to immune checkpoint inhibitors. However, 30% of patients with dMMR/MSI are primarily immunoresistant, and another 30% develop secondary resistance. Thus several combinations such as anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) are being pursued. The combination of radiotherapy and immunotherapy is another avenue of research that can increase the release of neoantigens resulting in the abscopal effect. This phenomenon has demonstrated promising potential activity in colon cancer preclinical studies; nevertheless, clinical results are limited to just a few case series. Patients and methods: We conducted a prospective interventional single-institution study to assess the feasibility, safety, and disease control rate of the combination of pembrolizumab and stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive patients with dMMR/MSI mCRC. Results: Among the 14 patients enrolled, 11 received SABR in combination with pembrolizumab as the first to the fourth line. The disease control rate was 50% in the intention-to-treat population, with six patients still maintaining the response after >15 months. Any-grade treatment-related adverse events occurred in 50% of patients, with grade 3 (G3) events in three patients; no treatment-related death occurred. Conclusions: Our findings convey no signal of enhanced systemic efficacy compared with historical data on pembrolizumab alone even if the local control rate is high. To our knowledge, this represents the largest study conducted in this population; further studies could extend the knowledge on the toxicity profile of this combination.

We present the case of a 64-year-old patient with metastatic renal cell carcinoma, who experienced disease progression despite undergoing multiple lines of systemic therapy, including immune checkpoint inhibitors (ICI). Two months after stereotactic radiosurgery to his brain lesions and while the patient was not on any systemic therapy, restaging scans demonstrated a dramatic near complete regression of the primary renal lesion and metastatic sites, which was attributed to the abscopal effect, mediated by the exposure to ICI and radiotherapy. While its mechanisms are not fully understood, it is believed to stem from the tumor immunosuppression and immunogenicity induced by radiation.

Abstract 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.

The abscopal effect in oncology has been known for 70 years, but until recently its clinical significance was rather low. The development of immune response checkpoint inhibitors has led to an active study of this phenomenon. There is now evidence of improved survival among patients, in whom the abscopal effect has been documented, opening new perspectives for the treatment of cancers at different stages. This review presents data on the mechanisms of the abscopal effect, experimental and clinical data, current limitations and possible perspectives. The aim of the study was to investigate the current concept of the abscopal effect occurrence and to evaluate the prospects of using the abscopal effect in therapy of metastatic cancer. Material and Methods. We searched publications in Pubmed system from 2010 to 2023. Of 286 publications, 72 were used for writing the review. Results. In the era of widespread use of immune checkpoint inhibitors (ICIs) for cancer therapy, the abscopal effect appears to be an effective therapeutic approach with broad prospects of application in the treatment of patients with metastatic cancer. Conclusion. The incidence of the abscopal effect has increased with the advent of immune therapy, and the use of ICIs with radiation therapy (RT) has shown improved survival even in patients with advanced disease. More research is needed to establish standardized treatment protocols, including the optimal dose and timing of RT, as well as the efficacy and safety of combination therapy with different classes of ICIs. Further search for clinical and laboratory abscopal effect predictors, which could allow personalized treatment approaches, is required.

Abstract Particle therapy and radiopharmaceuticals are emerging fields in the treatment of genitourinary cancers. With these novel techniques and the ever‐growing immunotherapy options, the combinations of these therapies have the potential to improve current cancer cure rates. However, the most effective sequence and combination of these therapies is unknown and is a question that is actively being explored in multiple ongoing clinical trials. Here, we review the immunological effects of particle therapy and the available radiopharmaceuticals and discuss how best to combine these therapies.

Introduction: While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. Methods: We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. Results: Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. Discussion: Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapyimmunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy. [ABSTRACT FROM AUTHOR]

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. Synopsis: The abscopal effect, e.g., when local treatment affects both treated and untreated tumors, is rarely observed in HCC following radiotherapy. Subcutaneous administration of poly(I:C) during radiotherapy promoted the abscopal effects in irradiated HCC mice. Poly(I:C) enhanced radiotherapy efficacy in HCC by promoting tumor ferroptosis in both irradiated and non-irradiated tumors. Poly(I:C) improved tumor ferroptosis by promoting tumor antigen presentation by dendritic cells and activating TLR3 signaling in tissue-infiltrating CD8+ T cells. Poly(I:C) combined with radiotherapy was shown to be a safe and effective strategy for enhancing the abscopal effect in HCC patients. Administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) strengthened the abscopal effect during radiotherapy (RT) through ferroptosis, and combination of poly(I:C) and RT improved the clinical benefits of advanced HCC patients. [ABSTRACT FROM AUTHOR]

Purpose: The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor response; however, the abscopal effect is always precluded by the tumor microenvironment, which may limit sufficient T-cell infiltration of distant nonirradiated tumors for certain kinds of inhibitory factors, such as regulatory T-cells (Tregs). Additionally, low-dose cyclophosphamide (LD-CYC) can specifically kill regulatory Tregs and strongly synergize antigen-specific immune responses, which could promote an abscopal effect. Materials and Methods: We explored whether a triple regimen consisting of HFRT, ICI, and LD-CYC could achieve a better systemic antitumor response in bilateral mouse tumor models. Result: Our data demonstrate that LD-CYC combined with HFRT and antiprogrammed cell death ligand 1 (PDL-1) therapy could enhance the abscopal effect than only HFRT/antiPDL-1 or HFRT alone. Surprisingly, repeat CYC doses cannot further restrain tumor proliferation but can prolong murine overall survival, as revealed by the major pathologic responses. These results are associated with increased CD8 + effector T-cell infiltration, although LD-CYC did not upregulate PDL-1 expression in the tumor. Conclusions: Compared with traditional strategies, for the first time, we demonstrated that a triple treatment strategy remarkably increased the number of radiation-induced tumor-infiltrating CD8 + T-cells, effectively decreasing infiltrating Tregs, and promoting an abscopal effect. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is an important and effective modality in treating cancer patients. Radiation-induced cardiovascular injury is one of the consequences of radiotherapy due to undesired exposure of the heart. The non-targeted effects of radiation add to the risk of cardiovascular injury following radiotherapy. Accordingly, we investigated the abscopal effect of radiation in the myocardium of partially irradiated rats and compared the abscopal effect with the effect induced in the myocardium following either direct or sham irradiation. Materials and Methods: Twenty male rats divided into four groups; sham, 2Gy whole-body, 2Gy cranially- and 2Gy lower-limb irradiated, were used. Myocardium samples were collected and examined for MDA, p53, caspase 3, and glutathione reduced expression. Additionally, TGF-β and NF-κB expression levels were investigated. Results: Our data revealed elevated levels of lipid peroxidation in abscopal myocardium following cranial-/lowerlimb irradiation with 2 Gy γ-radiation, as compared with the sham or whole-body irradiated groups. Similar behavior was noticed with p53 and caspase3 expression, suggesting apoptosis induction in the abscopal cardiomyocytes. The rise in lipid peroxidation and apoptosis markers in the abscopal myocardium was associated with an increase in glutathione reduced. The data propose oxidative stress induction in the myocardium following distant irradiation, which was further confirmed by the elevation in TGF-β and nuclear NF-κB expression. Conclusion: Abscopal effect was induced in the myocardium of partially-irradiated rats, suggesting increased risk of myocardial injury following localized radiotherapy. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we aimed to examine parameters of cryoablation, tumor characteristics, and their correlations with distant tumor response and survival of liver metastatic melanoma patients receiving cryoablation and PD-1 blockade (cryo-PD-1) combination treatment. Materials and methods: A retrospective study was conducted among 45 melanoma patients who received combined PD-1 blockade therapy and cryoablation for liver metastasis from 2018 to 2022. Cox regression was utilized to determine the associations between factors and overall survival (OS). Changes in cytokines and immune cell compositions in peripheral blood samples following the combined treatment were investigated, along with their correlations with treatment response. Results: The mean cycle of cryo-PD-1 combination treatment was 2.2 (range, 1–6), and the 3-month overall response rate (RECIST 1.1 criteria) was 26.7%. Of the 21 patients who failed previous PD-1 blockade therapy after diagnosis of liver metastasis, 4 (19.0%) achieved response within 3 months since combination treatment. The diameter of ablated lesion ≤ 30 mm, metastatic organs ≤ 2, and pre-treatment LDH level ≤ 300 U/L were independent prognostic factors for favorable OS. Further analysis showed patients with intrahepatic tumor size of 15–45 mm, and ablated lesion size of ≤ 30 mm had significantly higher 3-month response rate (42.9% vs 12.5%; P = 0.022) and survival time (30.5 vs 14.2 months; P = 0.045) than their counterparts. The average increase in NLR among patients with ablated tumor size of ≤ 3 cm and > 3 cm were 3.59 ± 5.01 and 7.21 ± 12.57, respectively. The average increase in serum IL-6 levels among patients with ablated tumor size of ≤ 3 cm and > 3 cm were 8.62 ± 7.95 pg/ml and 15.40 ± 11.43 pg/ml, respectively. Conclusion: Size selection of intrahepatic lesions for cryoablation is important in order to achieve abscopal effect and long-term survival among patients with liver metastatic melanoma receiving PD-1 blockade therapy. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor‐bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single‐cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor‐derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I‐IFN) secretion and M1 polarization via the miR‐872‐3p/IRF7 axis. Secreted I‐IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN‐γ and GZMB secretion. Together, the study shows that tumor‐derived exosomes promote I‐IFN secretion via the circPIK3R3/miR‐872‐3p/IRF7 axis in macrophages and enhance the anti‐tumor immune response of CD8+ T cells. [ABSTRACT FROM AUTHOR]

Purpose: Given the uncertainty surrounding the abscopal effect (AE), it is imperative to identify promising treatment targets. In this study, we aimed to explore the incidence of AE when administering radiotherapy to patients with oligoprogressive solid tumours while they are undergoing treatment with immune checkpoint inhibitors (ICIs). Materials and methods: In this multicentre prospective observational study, oligoprogressive disease was defined as a < 20% increase in lesions compared to > 2 months before enrolment. We enrolled patients who requested radiotherapy during the ICI rest period between 2020 and 2023. AE was considered present if ≥ 1 non-irradiated lesion decreased by ≥ 30% before the next line of systemic therapy started. Results: Twelve patients were included in this study; the common primary lesions were in the lungs (four patients) and kidneys (three patients). AEs were observed in six (50%) patients, with a median time to onset of 4 (range 2–9) months after radiotherapy. No significant predictors of AEs were identified. Patients in the AE group had a significantly better 1-year progression-free survival (PFS) rate than those in the non-AE group (p = 0.008). Two patients from the AE group were untreated and progression-free at the last follow-up. Four (33%) patients experienced grade 2 toxicity, with two cases attributed to radiotherapy and the other two to ICI treatment. No grade 3 or higher toxicities were observed in any category. Conclusion: Patients with oligoprogressive disease may be promising targets with potential for AEs. AEs can lead to improved PFS and, in rare cases, to a certain progression-free period without treatment. Irradiating solid tumours in patients with oligoprogressive disease during immune checkpoint inhibitor therapy may be a promising target with the potential for abscopal effects (AEs). AEs can lead to improved progression-free survival and, in rare cases, to a certain progression-free period without treatment. [ABSTRACT FROM AUTHOR]

Every year, over 600,000 new cases of esophageal cancer are registered worldwide. Treatment depends on the stage of the disease. In the early stages, surgical treatment is the basis (T1–T2 lesion < 3 cm, N0M0), while in more advanced stages, surgical treatment is preceded by radiochemotherapy or only radiochemotherapy is used. In the case of generalized disease, the main treatments used are systemic treatments of chemotherapy, immunotherapy and palliative teleradiotherapy or brachytherapy. Brachytherapy can be used at virtually any stage of disease, both as a radical treatment and as a palliative treatment. This paper presents the possibilities of using brachytherapy at various stages of esophageal cancer treatment. Particular attention was paid to the role of combining brachytherapy and immunotherapy and the possibility of an abscopal effect. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) not only can directly kill tumor cells by causing DNA double-strand break, but also exerts anti-tumor effects through modulating local and systemic immune responses. The immunomodulatory effects of RT are generally considered as a double-edged sword. On the one hand, RT effectively enhances the immunogenicity of tumor cells, triggers type I interferon response, induces immunogenic cell death to activate immune cell function, increases the release of proinflammatory factors, and reshapes the tumor immune microenvironment, thereby positively promoting anti-tumor immune responses. On the other hand, RT stimulates tumor cells to express immunosuppressive cytokines, upregulates the function of inhibitory immune cells, leads to lymphocytopenia and depletion of immune effector cells, and thus negatively suppresses immune responses. Nonetheless, it is notable that RT has promising abscopal effects and may achieve potent synergistic effects, especially when combined with immunotherapy in the daily clinical practice. This systematic review will provide a comprehensive profile of the latest research progress with respect to the immunomodulatory effects of RT, as well as the abscopal effect of radioimmunotherapy combinations, from the perspective of biological basis and clinical practice. [ABSTRACT FROM AUTHOR]

Radiofrequency ablation (RFA) of cancer induces an anti-tumor immunity, which is insufficient to prevent recurrences. In mice, RFA–intratumoral immunotherapy by granulocyte–macrophage colony-stimulating factor (GM-CSF) and Bacillus Calmette-Guerin resulted in complete metastases regression. Infectious risk in human needs replacement of live vaccines. Intratumoral purified protein derivatives (PPD) have never been tested in digestive cancers, and the safety of intratumoral immunotherapy after RFA has not yet been validated in human models. We investigated the therapeutic efficacy of combined radiofrequency ablation (RFA) and intratumoral immunotherapy (ITI) using an immune-muco-adherent thermogel (IMT) in a mouse model of metastatic colorectal cancer (CRC) and the safety of this approach in a pig model. Intratumoral stability of the immunogel was assessed using magnetic resonance imaging (MRI) and bioluminescent imaging. Seventy-four CT26 tumor-bearing female BALB/c mice were treated with RFA either alone or in combination with intratumoral IMT. Regression of distant metastasis and survival were monitored for 60 days. Six pigs that received liver radiofrequency and intralesional IMT injections were followed for 15 days. Experimental gel embolisms were treated using an intravascular approach. Pertinent rheology of IMT was confirmed in tumors, by the signal stability during 3 days in MRI and 7 days in bioluminescence imaging. In mice, the abscopal effect of RFA–intratumoral immunotherapy resulted in regression of distant lesions completed at day 16 vs. a volume of 350 ± 99.3 mm3 in the RFA group at day 25 and a 10-fold survival rate at 60 days. In pigs, injection of immunogel in the liver RFA area was safe after volume adjustment without clinical, hematological, and liver biology disorder. Flow cytometry showed an early increase in CD3 TCRγδ+T cells at D7 (p < 0.05) and a late decrease in CD29+-CD8 T cells at D15 (p < 0.05), reflecting the inflammation status changes. Systemic GM-CSF release was not detectable. Experimental caval and pulmonary thermogel embolisms were treated by percutaneous catheterism and cold serum infusion. RFA–intratumoral immunotherapy as efficient and safe mini-invasive interventional oncology is able to improve ablative treatment of colorectal liver metastases. [ABSTRACT FROM AUTHOR]

Background: The low response rate of immune checkpoint inhibitors (ICIs) prompts the exploration of novel combination therapies for patients with hepatocellular carcinoma (HCC). Here, we aimed to examine the efficiency and potential mechanism of cryo‐thermal ablation (Cryo‐A) combined with anti‐programmed death protein 1 (αPD1) and/or cytotoxic T‐lymphocyte antigen 4 (αCTLA4) inhibitors in a murine hepatoma model. Method: Immunocompetent C57BL/6 mice inoculated with unilateral or bilateral H22 hepatic tumour cells were treated with Cryo‐A and/or ICIs (αPD1 and/or αCTLA4). Flow cytometry, immunohistochemistry, ELISpot assay, time‐of‐flight cytometry, tumour rechallenging, and T‐cell depletion assay were used to assess the dynamic changes of immune cell subsets following therapy. Results: We found Cryo‐A resulted in immunogenic cell death of tumour cells, activation of dendritic cells, and enhancement of antitumor immunity. Cryo‐A alone was insufficient to extend survival, combining Cryo‐A with αPD1 and αCTLA4 further modulated the tumour microenvironment, inducing a durable antitumor immune response by tumour‐reactive CD8+ T cells and significantly prolonged survival. Time‐of‐flight cytometry (CyTOF) data revealed that combination therapies reshaped the tumour microenvironment by the increase of intratumoral CD8+ T cells expressed higher levels of cytotoxic markers and immune checkpoint molecules, and by downregulation of intratumoral granulocytes. The combination also resulted in the eradication of remote unablated tumours (abscopal effect). Conclusions: These findings suggested that Cryo‐A turned HCC from "cold" tumours to "hot" tumours and the combination of Cryo‐A with αPD1 and αCTLA4 may be a promising approach to improve the prognosis of HCC. [ABSTRACT FROM AUTHOR]

Systemic drug delivery is the current clinically preferred route for cancer therapy. However, challenges associated with tumor localization and off-tumor toxic effects limit the clinical effectiveness of this route. Locoregional drug delivery is an emerging viable alternative to systemic therapies. With the improvement in real-time imaging technologies and tools for direct access to tumor lesions, the clinical applicability of locoregional drug delivery is becoming more prominent. Theoretically, locoregional treatments can bypass challenges faced by systemic drug delivery. Preclinically, locoregional delivery of drugs has demonstrated enhanced therapeutic efficacy with limited off-target effects while still yielding an abscopal effect. Clinically, an array of locoregional strategies is under investigation for the delivery of drugs ranging in target and size. Locoregional tumor treatment strategies can be classified into two main categories: 1) direct drug infusion via injection or implanted port and 2) extended drug elution via injected or implanted depot. The number of studies investigating locoregional drug delivery strategies for cancer treatment is rising exponentially, in both preclinical and clinical settings, with some approaches approved for clinical use. Here, we highlight key preclinical advances and the clinical relevance of such locoregional delivery strategies in the treatment of cancer. Furthermore, we critically analyze 949 clinical trials involving locoregional drug delivery and discuss emerging trends. [Display omitted] • Locoregional delivery is an effective alternative to systemic delivery for oncotherapy. • Locoregional delivery can be achieved via direct infusion or depot-based strategies. • Preclinical studies indicate strong abscopal potential of locoregional delivery. • Clinical trials investigating locoregional delivery are increasing exponentially. • Procedure standardization and combination strategy may be fruitful in near future. [ABSTRACT FROM AUTHOR]

The abscopal effect, a rare phenomenon in cancer treatment, involves tumor regression in a distant location from the targeted therapy. This case focuses on a 74-year-old woman with metastatic papillary thyroid cancer. Despite prior treatments, she experienced pulmonary nodule progression and hemoptysis. Bland particle embolization was performed on the right bronchial artery branches supplying lung metastases, leading to significant reductions in size, number, and metabolic activity of the right-sided nodules and decreased metabolic activity of the untreated left-sided nodules, without additional cancer-related treatments. The abscopal effect has been observed with various interventional oncologic procedures, indicating a potential role in stimulating the immune response and altering the tumor microenvironment. Further investigation is needed to understand bland embolization's immunomodulatory effects and implications for triggering the abscopal effect. [ABSTRACT FROM AUTHOR]

Previously, radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break. Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses. However, the immunomodulatory effect of radiotherapy is double-sided. On the one hand, it can activate anti-tumor immune-promoting effect, on the other hand, it may also produce immunosuppressive effect. The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include: induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes; activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to induce type Ⅰ interferon response; changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility; stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment; upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response. In addition, the mechanisms of negative immune suppression by radiotherapy mainly include: induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors; enhancing the function and effect of various immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells; leading to the decreased number of lymphocytes and the depletion of immunologic effector cells. Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy, significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy, such as the abscopal effect in the context of immunotherapy era, that is, the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy, as well as the increased efficacy benefit when stereotactic body radiation therapy or low-dose radiotherapy combined with immune checkpoint inhibitors. However, at present, the synergistic mechanism of radiotherapy plus immunotherapy and its influencing factors are unclear. In the future, more in-depth investigations on optimal radiotherapy dose, segmentation regimens, irradiation sites and target volume design, immunotherapy agent selection and the sequence of combining radiotherapy with immunotherapy are necessary, in order to further improve efficacy and promote the translational application of immunomodulatory biological effects of radiotherapy. This article systematically reviewed the latest advancements of basic and clinical research on the immunomodulatory effect of radiotherapy and the synergy of combing radiotherapy with immunotherapy, aiming to provide guidance on the development of theoretical basis and clinical practice regarding the combination of radiotherapy and immunotherapy.

Aggregation-Induced Emission luminogen (AIEgen) possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety. Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and penetration to tumor. Herein, we construct a delivery platform that Salmonella VNP20009 act as an activated bacteria vector loaded the as-prepared novel AIEgen (TBTP-Au, VNP@TBTP-Au), which showed excellent radio-immunotherapy. VNP@TBTP-Au could target and retain AIEgen at the tumor site and deliver it into tumor cells specially, upon X-ray irradiation, much ROS was generated to induce immunogenic cell death via cGAS-STING signaling pathway to evoke immune response, thus achieving efficient radioimmunotherapy of the primary tumor with good biosafety. More importantly, the radioimmunotherapy with VNP@TBTP-Au formatted good abscopal effect that was able to suppress the growth of distant tumor. Our strategy pioneer a novel and simple strategy for the organic combination of bacteria and imaging-guided radiotherapy, and also pave the foundation for the combination with immunotherapy for better therapeutic effects.

Brain metastases stemming from lung cancer represent a common and challenging complication that significantly impacts patients' overall health. The migration of these cancerous cells from lung lesions to the central nervous system is facilitated by diverse molecular changes and a specific environment that supports their affinity for neural tissues. The advent of immunotherapy and its varied combinations in non-small cell lung cancer has notably improved patient survival rates, even in cases involving brain metastases. These therapies exhibit enhanced penetration into the central nervous system compared to traditional chemotherapy. This review outlines the molecular mechanisms underlying the development of brain metastases in lung cancer and explores the efficacy of novel immunotherapy approaches and their combinations. [ABSTRACT FROM AUTHOR]

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms. [ABSTRACT FROM AUTHOR]

Rare but consistent reports of abscopal remission in patients challenge the notion that radiotherapy (RT) is a local treatment; radiation‐induced cancer cell death can trigger activation and recruitment of dendritic cells to the primary tumor site, which subsequently initiates systemic immune responses against metastatic lesions. Although this abscopal effect was initially considered an anomaly, combining RT with immune checkpoint inhibitor therapies has been shown to greatly improve the incidence of abscopal responses via modulation of the immunosuppressive tumor microenvironment. Preclinical studies have demonstrated that nanomaterials can further improve the reliability and potency of the abscopal effect for various different types of cancer by (1) altering the cell death process to be more immunogenic, (2) facilitating the capture and transfer of tumor antigens from the site of cancer cell death to antigen‐presenting cells, and (3) co‐delivering immune checkpoint inhibitors along with radio‐enhancing agents. Several unanswered questions remain concerning the exact mechanisms of action for nanomaterial‐enhanced RT and for its combination with immune checkpoint inhibition and other immunostimulatory treatments in clinically relevant settings. The purpose of this article is to summarize key recent developments in this field and also highlight knowledge gaps that exist in this field. An improved mechanistic understanding will be critical for clinical translation of nanomaterials for advanced radio‐immunotherapy. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease [ABSTRACT FROM AUTHOR]

Metastatic upper tract urothelial carcinoma (mUTUC) has a poor prognosis. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in patients with metastatic urothelial carcinoma. However, data supporting the use of ICIs in patients with mUTUC are limited. A promising synergy between ICI and concomitant radiotherapy (RT) has been reported in patients with mUTUC. Our research involved a case-based investigation and emphasized the successful integration of different specialists' skills. Observed after partial urethrectomy procedures for muscle-invasive upper tract urothelial carcinoma (UTUC), the radiological detection of lung metastases prompted us to implement cisplatin-based first-line chemotherapy and molecular characterization in the treatment process. We uncovered alterations in the ERBB2 and FGFR3 genes and mismatch repair deficiency at a molecular level. First-line chemotherapy treatment led to a stable disease, and the patient was started on maintenance immunotherapy with Avelumab. Subsequently, an increase in the size of the lung nodules was described, and the patient received radiotherapy for three lung lesions in combination with immunotherapy. After 3 months, a restaging CT scan reported a complete response, which is still ongoing. We discuss the mechanisms driving RT/ICI synergy and the molecular profile of mUTUC as factors that should be considered in therapeutic strategy planning. Molecular insight enhances the originality of our study, providing a nuanced understanding of the genetic landscape of mUTUC and paving the way for targeted therapeutic strategies. The therapeutic armamentarium expansion encourages the design of a multimodal and personalized approach for each mUTUC patient, taking into account tumor heterogeneity and molecular profiling. [ABSTRACT FROM AUTHOR]

Previously, radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break. Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses. However, the immunomodulatory effect of radiotherapy is double-sided. On the one hand, it can activate anti-tumor immune-promoting effect, on the other hand, it may also produce immunosuppressive effect. The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include: induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes; activation of the cyclic GMP-AMP synthasestimulator of interferon genes pathway to induce type Ⅰ interferon response; changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility; stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment; upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response. In addition, the mechanisms of negative immune suppression by radiotherapy mainly include: induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors; enhancing the function and effect of various immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells; leading to the decreased number of lymphocytes and the depletion of immunologic effector cells. Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy, significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy, such as the abscopal effect in the context of immunotherapy era, that is, the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy, as well as the increased efficacy benefit when stereotactic body radiation therapy or low-dose radiotherapy combined with immune checkpoint inhibitors. However, at present, the synergistic mechanism of radiotherapy plus immunotherapy and its influencing factors are unclear. In the future, more in-depth investigations on optimal radiotherapy dose, segmentation regimens, irradiation sites and target volume design, immunotherapy agent selection and the sequence of combining radiotherapy with immunotherapy are necessary, in order to further improve efficacy and promote the translational application of immunomodulatory biological effects of radiotherapy. This article systematically reviewed the latest advancements of basic and clinical research on the immunomodulatory effect of radiotherapy and the synergy of combing radiotherapy with immunotherapy, aiming to provide guidance on the development of theoretical basis and clinical practice regarding the combination of radiotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

High-precision Radiation Therapy (RT) has effectively achieved local tumor control. However, for patients with metastatic cancer, it has been reported that local control alone does not lead to extended survival. Recently, out of-field tumor rejection occurred by RT, which is called the “abscopal effect”, has been investigated. Although this phenomenon remains extremely rare in clinical situations, the combination of RT with an immune checkpoint inhibitor (ICI) can increase the chance of inducing an abscopal effect. In this review, we described the impact of the ICI-administer timing, total RT dose, and the number of RT fractions on the occurring abscopal effect. Furthermore, we described the availability and utility of carbon ion irradiation, which has better physical and biological features than photons. [ABSTRACT FROM AUTHOR]