Search Results (63)

The combination of immunotherapy and radiotherapy has demonstrated synergistic potential, especially when a combination of immune checkpoint inhibitors (ICIs) is administered. Cytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors or Programmed Cell Death Protein 1 (PD-1) inhibitors have been assessed in both clinical and preclinical studies; the addition of radiotherapy activates immunomodulatory mechanisms materialized by an effect similar to “in situ” vaccination or the “abscopal” distant response of lesions outside the irradiation field. The new therapeutic targets (T cell immune-receptor with Ig and ITIM domains (TIGIT), Lymphocyte activating gene 3 (LAG-3), and T cell Ig- and mucin-domain-containing molecule-3 (TIM-3)) associated with traditional ICIs and radiotherapy open new perspectives to the concept of immuno-radiotherapy. The dynamic evaluation of T lymphocyte expression involved in the antitumor immune response, both in the tumor microenvironment (TME) and in the tumor itself, could have biomarker value in assessing the response to combination therapy with traditional and new ICIs in association with irradiation. Preclinical data justify the initiation of clinical trials in various tumor pathologies to explore this concept. Full article

Background: In situ cancer vaccination is a therapeutic approach that involves stimulating the immune system in order to generate a polyclonal, anti-tumor response against an array of tumor neoantigens. Traditionally, in situ vaccination approaches have utilized adenoviral vectors to deliver immune-stimulating genes directly to the tumor microenvironment. Lipid nanoparticle (LNP)-mediated delivery methods offer several advantages over adenoviral delivery approaches, including increased safety, repeated administration potential, and enhanced tumor microenvironment activation. Methods: To explore in situ vaccination using LNPs, we evaluated LNP-mediated delivery of a reporter gene, mCherry, and an immune-stimulating gene, IFNβ, in several in vitro and in vivo models of lung cancer. Results: In vitro experiments demonstrated successful transfection of murine cancer cell lines with LNPs carrying both mCherry and IFN-β mRNA, resulting in high expression levels and IFNβ production. In vivo studies using LLC.ova flank tumors showed that intratumoral injection of IFNβ-mRNA LNPs led to significant IFNβ production within the tumor microenvironment, with minimal systemic exposure. Therapeutic efficacy was evaluated by injecting established LLC.ova flank tumors with IFNβ-mRNA LNPs bi-weekly for two weeks. Treated tumors showed significant growth inhibition compared to controls. Flow cytometric analysis of tumor-infiltrating leukocytes revealed that tumors injected with IFNβ-mRNA LNPs were associated with an increased CD8:CD4 T-cell ratio among lymphocytes, more CD69-expressing CD8 T-cells, and an increased presence of M1 macrophages. Efficacy and an abscopal effect were confirmed in a squamous cell carcinoma model, MOC1. No toxicity was observed. Conclusions: These findings show that intratumoral LNP delivery of immune-stimulating mRNA transcripts, such as IFNβ, can effectively stimulate local anti-tumor immune responses and warrants further investigation as a potential immunotherapeutic approach for cancer. Full article

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([¹⁷⁷Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and to assess its immunomodulatory potential. Methods: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy—clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. Results: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [¹⁷⁷Lu]Lu-PSMA PRLT. Patients were subgrouped according to clinical variables versus MR. A total of 17 patients had ≥12 months MR (17/36, 47%). The longest duration of MR was 99 months and a mean of 17.44 months (95% CI 10.05–24.84). Previous lines of treatment were evaluated for MR, p = 0.172. Pattern of disease (bone, lymph node, liver, and peritoneal) was evaluated for MR, p = 0.721. The Gleason score was evaluated for MR, p = 0.871. Patients with known BRCA sequencing status (n = 12) were analyzed with mean MR: BRCA1/2 wild-type, 6/12 (50%), 6.67 months; BRCA 1/2 negative, 1/12 (8.33%), 7 months; BRCA germline negative and somatic positive, 1/12 (8.33%), 36 months; BRCA germline negative, somatic negative, 2/12 (16.67%), 27 months; and BRCA 2 positive, 2/12 (16.67%), 43 months. Conclusions: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses. Full article

Background/Objectives: There is increasing evidence to indicate that histotripsy treatment can enhance the host anti-tumor immune responses both locally at the targeting tumor site as well as systemically from abscopal effects. Histotripsy is a non-invasive ultrasound ablation technology that mechanically disrupts target tissue via cavitation. A key factor contributing to histotripsy-induced abscopal effects is believed to be the release of tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) that induce a systemic immune response. In this study, we studied the effect of histotripsy treatment on the release of HER2, a well-defined TAA target for cancer immunotherapy. Methods: A range of doses of histotripsy administered to HER2-postive mammary tumor cells in an in vitro cell culture system and an ex vivo tumor were applied. In addition, a single dose of histotripsy was used for an in vivo murine tumor model. The released proteins, and specifically HER2, in both tumor cell-free supernatants and tumor cell pellets were analyzed by a BCA protein assay, an ultra-performance liquid chromatography (UPLC) assay, and Western blot. Results: Our results showed that histotripsy could significantly trigger the release of HER2 proteins in the current study. The level of HER2 proteins was actually higher in tumor cell-free supernatants than in tumor cell pellets, suggesting that HER2 was released from the intracellular domain into the extracellular compartment. Furthermore, proportionally more HER2 protein was released at higher histotripsy doses, indicating free HER2 was histotripsy-dose-dependent. Conclusions: In conclusion, we have qualitatively and quantitatively demonstrated that histotripsy treatment triggers the release of HER2 from the tumor cells into the extracellular compartment. The histotripsy-mediated release of HER2 antigens provides important insights into the mechanism underlying its immunostimulation and suggests the potential of TSA/TAA-based immunotherapies in numerous cancer types. Full article

Spatially fractionated radiation therapy (SFRT) has a long history of treating bulky and hypoxic tumors. Recent evidence suggests that, compared to conventional uniform dose radiation therapy, SFRT may utilize different mechanisms of tumor cell killing, potentially including bystander and immune-activating effects. The abscopal effect in radiation therapy refers to the control or even elimination of distant untreated tumors following the treatment of a primary tumor with radiation, a process believed to be immune-mediated. Such effects have been shown to be enhanced by immunotherapy, particularly immune checkpoint inhibition. In this manuscript, we explore the potential synergy of spatially fractionated radiation therapy, in the form of kV x-ray minibeam, combined with PD-L1 checkpoint inhibition in a murine mammary carcinoma model at conventional dose-rate. We found that minibeam of peak/valley doses of 50 Gy/3.7 Gy performed statistically equivalent but trending better than that of 100 Gy/7.4 Gy in its abscopal effect and so 50 Gy/3.7 Gy was selected for further studies. Our findings indicate that the abscopal effect is significantly greater in the minibeam plus anti-PD-L1 treated animals compared to those receiving uniform dose radiation therapy plus anti-PD-L1 (p = 0.04948). Immune cell profiling in the minibeam plus anti-PD-L1 group compared to uniform dose reveals a consistent trend towards greater immune cell infiltration in the primary tumor, as well as a higher percentage of CD8+ T cells, both systemically and at the abscopal tumor site. Full article

Introduction: The abscopal effect is a systemic immune response characterized by metastases regression at sites distant from the irradiated lesion. This systematic review aims to explore the immunological mechanisms of action underlying the abscopal effect and to investigate how hyperthermia (HT) can increase the chances of radiotherapy (RT) triggering systemic anti-tumor immune responses. Methods: This review is created in accordance with the PRISMA guidelines. Results and Conclusion: HT and RT have both complementary and synergistic immunological effects. Both methods trigger danger signal release, promoting cytokine and chemokine secretion, which increases T-cell infiltration and facilitates cell death. Both treatments upregulate extracellular tumor HSP70, which could amplify DAMP recognition by macrophages and DCs, leading to stronger tumor antigen presentation and CTL-mediated immune responses. Additionally, the combined increase in cell adhesion molecules (VCAM-1, ICAM-1, E-selectin, L-selectin) could enhance leukocyte adhesion to tumors, improving lymphocyte trafficking and boosting systemic anti-tumor effects. Lastly, HT causes vasodilation and improves blood flow, which might exacerbate those distant effects. We suggest the combination of local radiotherapy with fever-range whole-body hyperthermia to optimally enhance the chances of triggering the abscopal effect mediated by the immune system. Full article

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

Melanoma, the most aggressive form of skin cancer, presents a major clinical challenge due to its tendency to metastasize and recalcitrance to traditional therapies. Despite advances in surgery, chemotherapy, and radiotherapy, the outlook for advanced melanoma remains bleak, reinforcing the urgent need for more effective treatments. Photodynamic therapy (PDT) has emerged as a promising alternative, leading to targeted tumor destruction with minimal harm to surrounding tissues. In this study, the direct and abscopal antitumor effects of PDT in a bilateral murine melanoma model were evaluated. Although only one of the two tumors was treated, effects were observed in both. Our findings revealed significant changes in systemic inflammation and alterations in CD4⁺ and CD8⁺ T cell populations in treated groups, as evidenced by blood analyses and flow cytometry. High-throughput RNA sequencing (RNA-Seq) further unveiled shifts in gene expression profiles in both treated and untreated tumors. This research sheds light on the novel antitumor and abscopal effects of nanoemulsion of aluminum chloride phthalocyanine (AlPcNE)-mediated PDT in melanoma, highlighting the potential of different PDT protocols to modulate immune responses and to achieve more effective and targeted cancer treatments. Full article

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. Full article

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. Full article

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. Full article

Purpose: We report a 10-year experience in cancer therapy with concomitant treatment of percutaneous thermal ablation (PTA) and immune checkpoint blockers (ICBs). Material and methods: This retrospective cohort study included all patients at a single tertiary cancer center who had received ICBs at most 90 days before, or 30 days after, PTA. Feasibility and safety were assessed as the primary outcomes. The procedure-related complications and immune-related adverse events (irAEs) were categorized according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Efficacy was evaluated based on overall survival (OS), progression-free survival (PFS), and local progression-free survival (_LPFS) according to the indication, ablation modality, neoplasm histology, and ICB type. Results: Between 2010 and 2021, 78 patients (57% male; median age: 61 years) were included. The PTA modality was predominantly cryoablation (CA) (61%), followed by radiofrequency ablation (RFA) (31%). PTA indications were the treatment of oligo-persistence (29%), oligo-progression (14%), and palliation of symptomatic lesions or prevention of skeletal-related events (SREs) (56%). Most patients received anti-PD1 ICB monotherapy with pembrolizumab (n = 35) or nivolumab (n = 24). The feasibility was excellent, with all combined treatment performed and completed as planned. Ten patients (13%) experienced procedure-related complications (90% grade 1–2), and 34 patients (44%) experienced an irAE (86% grade 1–2). The only factor statistically associated with better OS and PFS was the ablation indication, favoring oligo-persistence (p = 0.02). Tumor response was suggestive of an abscopal effect in four patients (5%). Conclusions: The concomitant treatment of PTA and ICBs within 2–4 weeks is feasible and safe for both palliative and local control indications. Overall, PTA outcomes were found to be similar to standards for patients not on ICB therapy. While a consistently reproducible abscopal effect remains elusive, the safety profile of concomitant therapy provides the framework for continued assessment as ICB therapies evolve. Full article

We present the case of a patient who was diagnosed in 2018 with nodular Malignant Melanoma (MM) without BRAF V 600 mutations stage 3 C (pT4b pN1a M0), and who underwent adjuvant citokines treatment with Interferon alpha 2b-48 weeks. Immunotherapy was initiated in January 2021 for lung and lymph node metastases. In June 2021, there was a partial response of the lung and lymph node metastases, but there was also progression to brain metastases. Immunotherapy was continued and Whole Brain Radiotherapy (WBRT) was performed. In September 2023, the imaging investigations revealed a favorable response, with no lesions suggestive of secondary determinations. The combination of Radiotherapy (RT) and Immunotherapy (IT) with Immune Checkpoint Inhibitors (ICI) has an abscopal effect. There is a coordinated action in the combination of RT and IT in order to obtain a common result, with the antitumor effect being greater than if RT or IT acted separately. Full article

Microwave ablation (MWA) is an effective treatment for liver cancer (LC), but its impact on distant tumors remains to be fully elucidated. This study investigated the abscopal effects triggered by MWA treatment of LC, at different power levels and with or without combined immune checkpoint inhibition (ICI). We established a mouse model with bilateral subcutaneous LC and applied MWA of varied power levels to ablate the right-sided tumor, with or without immunotherapy. Left-sided tumor growth was monitored to assess the abscopal effect. Immune cell infiltration and distant tumor neovascularization were quantified via immunohistochemistry, revealing insights into the tumor microenvironment and neovascularization status. Th1- and Th2-type cytokine concentrations in peripheral blood were measured using ELISA to evaluate systemic immunological changes. It was found that MWA alone, especially at lower power, promoted distant tumor growth. On the contrary, combining high-power MWA with anti-programmed death (PD)-1 therapy promoted CD8⁺ T-cell infiltration, reduced regulatory T-cell infiltration, upregulated a Th1-type cytokine (TNF-α) in peripheral blood, and inhibited distant tumor growth. In summary, combining high-power MWA with ICI significantly enhances systemic antitumor immune responses and activates the abscopal effect, offering a facile and robust strategy for improving treatment outcomes. Full article

Bromodomain-containing protein 4 (BRD4) is an intracellular protein that regulates expression of various cellular functions. This study investigated whether BRD4 inhibition can alter the immunomodulatory and antitumor effects of radiation therapy (RT). A murine breast cancer cell line was implanted into BALB/c mice. The dual-tumor model was used to evaluate the abscopal effects of RT. A total of 24 Gy was delivered and BRD4 inhibitor was injected intravenously. Tumor size was measured, and in vivo imaging was performed to evaluate tumor growth. Flow cytometry and immunohistochemistry were performed to examine immunologic changes upon treatment. The combination of BRD4 inhibitor and RT significantly suppressed tumor growth compared to RT alone. BRD4 inhibitor reduced the size of the unirradiated tumor, indicating that it may induce systemic immune responses. The expression of HIF-1α and PD-L1 in the tumor was significantly downregulated by the BRD4 inhibitor. The proportion of M1 tumor-associated macrophages (TAMs) increased, and the proportion of M2 TAMs decreased upon BRD4 inhibition. BRD4 inhibitor expanded CD4⁺ and CD8⁺ T cell populations in the tumor microenvironment. Additionally, splenic monocytic myeloid derived suppressor cells, which were increased by RT, were reduced upon the addition of BRD4 inhibitor. Therefore, the addition of BRD4 inhibitor significantly enhanced the systemic antitumor responses of local RT. Full article