Tumor Irradiation Research Articles

Role of autophagy in tumor response to radiation: Implications for improving radiotherapy.

Autophagy is an evolutionary conserved, lysosome-involved cellular process that facilitates the recycling of damaged macromolecules, cellular structures, and organelles, thereby generating precursors for macromolecular biosynthesis through the salvage pathway. It plays an important role in mediating biological responses toward various stress, including those caused by ionizing radiation at the cellular, tissue, and systemic levels thereby implying an instrumental role in shaping the tumor responses to radiotherapy. While a successful execution of autophagy appears to facilitate cell survival, abortive or interruptions in the completion of autophagy drive cell death in a context-dependent manner. Pre-clinical studies establishing its ubiquitous role in cells and tissues, and the systemic response to focal irradiation of tumors have prompted the initiation of clinical trials using pharmacologic modifiers of autophagy for enhancing the efficacy of radiotherapy. However, the outcome from the Phase I/II trials in many human malignancies has so far been equivocal. Such observations have not only precluded the advancement of these autophagy modifiers in the Phase III trial but have also raised concerns regarding their introduction as an adjuvant to radiotherapy. This warrants a thorough understanding of the biology of the cancer cells, including its spatio-temporal context, as well as its microenvironment all of which might be the crucial factors that determine the success of an autophagy modifier as an anticancer agent. This review captures the current understanding of the interplay between radiation induced autophagy and the biological responses to radiation damage as well as provides insight into the potentials and limitations of targeting autophagy for improving the radiotherapy of tumors.

Tumor cell-based vaccine contributes to local tumor irradiation by eliciting a tumor model-dependent systemic immune response.

Multimodal treatment approaches, such as radio-immunotherapy, necessitate regimen optimization and the investigation of the interactions of different modalities. The aim of this study was two-fold. Firstly, to select the most effective combination of irradiation and the previously developed tumor cell-based vaccine and then to provide insight into the immune response to the selected combinatorial treatment. The study was performed in immunologically different murine tumor models: B16F10 melanoma and CT26 colorectal carcinoma. The most effective combinatorial treatment was selected by comparing three different IR regimens and three different vaccination regimens. We determined the local immune response by investigating immune cell infiltration at the vaccination site and in tumors. Lastly, we determined the systemic immune response by investigating the amount of tumor-specific effector lymphocytes in draining lymph nodes. The selected most effective combinatorial treatment was 5× 5 Gy in combination with concomitant single-dose vaccination (B16F10) or with concomitant multi-dose vaccination (CT26). The combinatorial treatment successfully elicited a local immune response at the vaccination site and in tumors in both tumor models. It also resulted in the highest amount of tumor-specific effector lymphocytes in draining lymph nodes in the B16F10, but not in the CT26 tumor-bearing mice. However, the amount of tumor-specific effector lymphocytes was intrinsically higher in the CT26 than in the B16F10 tumor model. Upon the selection of the most effective combinatorial treatment, we demonstrated that the vaccine elicits an immune response and contributes to the antitumor efficacy of tumor irradiation. However, this interaction is multi-faceted and appears to be dependent on the tumor immunogenicity.

JS09.6.A Low incidence of radiation-induced brain lesions and stable QoL following proton irradiation for CNS and Skull Base tumors- results from the prospective MedAustron register REGI-MA-002015

Abstract Background Irradiation of intracranial tumors may induce endothelial damage in the surrounding normal brain tissues, resulting in an increase of capillary permeability. These changes can be depicted on magnetic resonance imaging (MRI) as a new contrast medium uptake - not associated with tumor. Radiation-induced brain lesions (RIBL) occur after photon as well as proton irradiation. This study evaluated the incidence of RIBL after proton irradiation and their impact on Quality of Life (QoL). Material and Methods 421 patients treated between 01/2017 and 06/2021 were included. All patients participated in a prospective registry study (ClinicalTrials.gov Identifier: NCT03049072). Follow-up evaluations including MRIs were at 3,6,12 months after treatment completion and annually thereafter. QoL parameters were assessed by EORTC-CTC30 and BN20 questionnaires. Results 48.9% (n=206) patients received therapy for intracranial non-CNS tumors (meningioma, pituitary adenoma, and other), 26.8% (n=113) for head and neck cancer with skull base involvement, 14.5% (n=61) for primary CNS tumors and 9.7% (n=41) for skull base tumor. Median follow-up was 24 months (range 6-54 ), 352 (86%) patients had proton therapy as primary treatment, 59 (14%) had salvage treatment with proton re-irradiation (ReRT). Median prescribed dose was 58.5 Gy (RBE) (range 40-78 Gy (RBE)), median D1% of brain tissue was 54.3 Gy (RBE) (range 30-76 Gy RBE). Local control and overall survival were 91% and 95% at 2 years. The cumulative RIBL incidence was 15.0% (n=63), with significantly lower occurrence in the primary RT group vs. the ReRT group (12.9% vs. 27.1%; p<0.001). According to Grade, the distribution was 10.5% (n=44) Grade I (asymptomatic, MRT finding only), Grade II RIBL, 13 (3.1%) (moderate symptoms) (grade 2) and 1,4% (n=6) developed Grade 3 toxicity. Actuarial 2-year RIBL incidence was 18.2% (95%CI: 14.1-23.2) for the all Grades and the entire, 15.7% (95%CI: 11.6-21) following primary radiation and 34.2% (95%CI: 21.9-50.9) after ReRT. All RIBL developed outside the residual tumor, but inside the Planning Target Volume (PTV), median D1% was 60.3Gy (RBE) (range 46.1- 122.3 Gy(RBE)), median time to development was 11.8 months (range 2.7-37 months) in the total cohort, for primary RT 14.2mo (4.3mo -37.1mo) and 6.0mo (2.7mo -19.3mo) following ReRT. At the time of analysis 26 of the 63 RIBL had resolved (41.3%). General QoL was not compromised. In a matched-pair analysis of 54/50 patients with/without RIBL, only at the 12 month a significant difference in the global health score in favour of non-RIBL patients was observed. At 24 months the score for RIBL patients improved without difference between the groups. Conclusion Overall incidence of RIBL after proton radiotherapy is very low - even for skull base tumors requiring high total doses and it had no significant negative impact on long term QoL.

Radiation dose aspects and establishment of diagnostic reference levels for 90Y radioembolisation during angiographic procedure

90Y radioembolisation (RE) is an angiographic procedure used in patients with both primary and secondary hepatic malignancies. Local tumour control can be achieved by short range tumour irradiation by the regional intra-arterial administration of glass or resin microspheres loaded with 90yttrium that accumulate in the tumorous tissue. The aim of this study was to investigate the radiation exposure of RE and to establish a local diagnostic reference level (DRL). In this retrospective study, dose data from 397 procedures in 306 patients (mean age 67.4 ± 10.6 years, 82 female) who underwent RE between 06/2017 and 01/2022 using one of two different angiography systems were analysed. DRL was set as the 75th percentile of the dose distribution. In the overall population, dose area product (DAP) (median (interquartile range, IQR)) was 26 Gy cm2 (IQR 12–50) with a median fluoroscopy time (FT) of 4.5 min (IQR 2.9–8.0). FT and DAP increased significantly with the number of infusion positions (median, IQR): one position 23 Gy cm2 (12–46), two positions 33 Gy cm2 (14–60), three positions 50 Gy cm2 (24–82) (p < 0.0001). Local DRL is 47 Gy cm2 for RE and 111 Gy cm2 for RE with additional embolisation. Radiation exposure and FT are significantly higher with increasing number of infusion positions as well as additional embolisation. Our established DRLs for RE may serve as a benchmark for dose optimisation.

STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES IN A CHILD WITH EXTRA-SKELETAL EWING'S SARCOMA

Ewing's sarcoma is the second most common oncological disease of bones and soft tissues in children and adolescents, which is characterized by rapid growth and early metastasis. Brain metastases (BMs) occur in 10–12 % of cases and constitute a factor in the unfavorable prognosis of the disease. The possibilities of surgical treatment are often limited by the localization of a metastatic tumor, and the vast majority of chemotherapy drugs don’t penetrate the blood-brain barrier, therefore radiation therapy, particularly stereotactic radiosurgery, the principle of which is a single high dose (15–24 Gy) of ionizing radiation to the pathological focus, is the most important method of treatment. High accuracy of tumor irradiation is ensured by rigid immobilization of the patient (using stereotactic frames or individual three-layer thermoplastic masks) in combination with positioning of the patient and control of his position by orthogonal X-rays. According to various authors, the use of stereotactic radiosurgery provides local control over BMs in 90 % of patients, regardless of the histological type of the primary focus, age and gender of the patient. The article describes a clinical case of successful radiosurgical treatment of a child suffering from extra-skeletal Ewing’s sarcoma, in which following the complex treatment, progression of the disease, represented by multiple metastatic brain damage was revealed; the cumulative volume of metastatic foci was 2.3 cm 3 and due to the proximity of the brain stem, as well as in order to avoid exceeding the tolerant load on healthy brain tissues, the total focal dose did not exceed 16 Gy. A complete response to therapy in the form of regression of all foci was noted six months after the treatment. To date, insufficient data has been published on the use of stereotactic radiosurgery in pediatric oncology, but in the available literature, the authors demonstrate the effectiveness and safety of treatment. Further research is needed to study the effect of the radiosurgical method on the children.

Consensus Recommendations for Managing Childhood Cancer Survivors at Risk for Stroke After Cranial Irradiation: A Delphi Study.

There is insufficient evidence to support stroke prevention guidelines for childhood cancer survivors (CCS) treated with cranial irradiation for CNS tumors or other childhood cancers involving the CNS. We used a systematic consensus-building methodology to develop expert recommendations and define areas of controversy in managing asymptomatic CCS at risk for stroke. A Delphi process was used to query a multispecialty panel of 45 physicians from the United States/Canada, with expertise in CCS, about their stroke screening and management practices (imaging, referrals, laboratory testing, and medications). Three iterative rounds of anonymous, scenario-based questionnaires, building on panelists' aggregate responses, were used to reach consensus (≥90% agreement), agreement (89%-70% agree), or to understand the rationale for disagreement (<70% agree). All 45 physicians participated in the first 2 rounds and 44 in the third. Panelists reached consensus on indications for referral to neurology and laboratory screening for modifiable cerebral vascular disease (CVD) risk factors in most scenarios. Panelists agreed that aspirin therapy is not recommended in the scenario of normal neuroimaging (86% agreed). Decisions about aspirin therapy in scenarios with abnormal neuroimaging were deferred to specialists; almost all agreed with not using aspirin for cavernomas with no evidence for previous hemorrhage (93%) and using aspirin for both large vessel CVD (93%) and small vessel CVD with evidence of previous stroke (86%). Clinical decisions that remain controversial (less than 70% agreement) include neuroimaging to screen asymptomatic CCS for CVD, referral to neurology for cavernomas, aspirin use in the setting of cavernomas with previous hemorrhage, or with evidence for small vessel CVD and no previous stroke, and indications for statins. Overall, pediatric neurologists/neuro-oncologists and radiation oncologists were more likely to advocate for screening and interventions. Despite lack of evidence to guide the management of CCS at risk for stroke, expert recommendations and rationale developed by consensus methodology are helpful to support clinical decision-making.

The Efficacy of Radiation is Enhanced by Metformin and Hyperthermia Alone or Combined Against FSaII Fibrosarcoma in C3H Mice.

The effects of mild-temperature hyperthermia (MTH) and metformin, alone or in combination, on the efficacy of high-dose hypofractionated radiation against experimental tumors were investigated. FSaII fibrosarcoma grown subcutaneously in the hind legs of C3H mice was irradiated with a single 15 Gy dose using a 60Co irradiator. The radio frequency capacitive method was used to heat the tumors at 41.0°C for 30 min. Metformin was intraperitoneally (i.p.) administered daily to tumor-bearing mice at a dose of 150 mg/kg. The expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and programmed cell death-ligand 1 (PD-L1) were determined by immunohistochemical staining of the excised tumor tissues. The apoptosis of tumor cells in vivo was quantified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and cleaved caspase-3 staining of the excised tumor tissues. Irradiation of tumors markedly increased the expression of HIF-1α, VEGF, and PD-L1, and MTH and metformin used either alone or in combination significantly abrogated the radiation-induced upregulation of these proteins. MTH and metformin alone or combined increased the radiation-induced apoptosis in tumor cells and enhanced the radiation-induced suppression of tumor growth. The findings indicated that the increased tumor response to 15 Gy irradiation by MTH and metformin alone or in combination was due, in part, to the abrogation of the radiation-induced upregulation of HIF-1α and its downstream targets VEGF and PD-L1.

P9-7 Treatment outcome following nivolumab therapy administered after radiation therapy for esophageal cancer

Nivolumab is an immune checkpoint inhibitor that has been approved since February 2020 for the treatment of unresectable advanced/recurrent esophageal cancer that has worsened after initial chemotherapy. Although the treatment response rate is low at approximately 20%, it has been reported that the administration of nivolumab after irradiation enhances the antitumor effect in cases of esophageal and head and neck cancers. Therefore, we examined cases of nivolumab administration after irradiation of esophageal tumors in our department.

Enhancement of antitumor immune response by radiation therapy combined with dual immune checkpoint inhibitor in a metastatic model of HER2-positive murine tumor

PurposeTreatments for metastatic human epidermal growth factor receptor 2 (HER2)-positive tumors are improving but remain inadequate. We investigated activating antitumor immune response by combining radiation therapy with immune checkpoint inhibitors using mouse tumors overexpressing HER2, a pivotal driver oncogenic antigen, to develop new immunotherapies for metastatic HER2-positive tumors.Materials and methodsNT2.5 cells were inoculated into the two mammary fat pads of FVB/N mice, which were divided into four groups: no treatment (Non), anti-PD-1 and anti-CTLA4 antibodies (P1C4), irradiation of the large tumor (Rad), and combination (R + P1C4) groups. Tumor growth, immunostaining of tumor-infiltrating lymphocytes, and the proportion of HER2-tumor antigen-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were analyzed.ResultsIn the Rad group, unirradiated and irradiated tumors shrank after treatment. Besides the directly irradiated tumors, the unirradiated tumors in the R + P1C4 group shrank the most. In the unirradiated tumors, CD8-positive T cells and FOXP3-positive T cells accumulated significantly more in the R + P1C4 group than in the P1C4 and the Rad groups (all p < 0.001). CD4-positive helper T cells accumulated significantly more in the R + P1C4 group than in the Rad group (p < 0.05), but this was not significantly different from the P1C4 group. HER2-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were significantly increased in the R + P1C4 group compared to the P1C4 and Rad groups (all p < 0.0001).ConclusionIrradiation of HER2-positive tumors induced an antitumor immune effect against the unirradiated tumor, which was enhanced by the combined use of immune checkpoint inhibitors and was mediated by enhanced recruitment of HER2-tumor antigen-specific cytotoxic T lymphocytes at the tumor site in an HER2-positive mouse tumor model. Harnessing the distant antitumor immune response induced by the combination of radiation therapy and immune checkpoint inhibitors could be a promising treatment strategy for metastatic HER2-positive tumors.

Abstract 6173: Single cell network-based analyses defines the effect of radiation on the tumor immune microenvironment, including the response by and molecular determinants of suppressive myeloid cells

Abstract Background: More than half of all cancer patients undergo radiation therapy (RT), which can be curative or palliative to improve cancer-specific outcomes and quality of life. However, radioresistance emerges and a cure is not always achieved. To date, researchers have studied T-cells and lymphocytes to understand response to RT, but little is known about myeloid cells. This diverse group of cells helps mount immunological responses, but can also be immunosuppressive by lessening the strength of T-cells. We hypothesized that our network-based analyses of single cell proteogenomic data generated from tumor-infiltrating immune cells can identify druggable proteins in pathways driving unwanted immunosuppressive changes, particularly among myeloid cells. Methods: Proteogenomic (CITE-Seq) analysis was conducted on CD45+ immune cells from unirradiated and irradiated orthotopic 4T1 murine mammary tumors three- and ten-days after tumor irradiation. Based on select proteins’ surface expression, CITE-Seq generated eight distinct clusters, including three myeloid cell clusters — monocytes, macrophages, and granulocytes. We used VIPER (virtual inference of protein activity by enriched regulon analysis), a machine learning-based algorithm that infers protein activities by taking regulatory gene expression networks and calculating the weighted expression on each protein’s targets, to create functional subclusters of the eight immune-cell populations. For subclusters enriched by RT, we used OncoTreat to identify active, druggable proteins. Results: Lymphocytes were depleted with radiation, especially ten days post-irradiation. While monocytes appeared homogeneous, one of three subclusters of macrophages appeared more resistant (i.e. enriched with radiation) and had 4 druggable targets (PSMA4, HSP90AB1, PARP1, APEX1) from OncoTreat. Similarly, three of eight subclusters of granulocytes appeared resistant, with two potential targets (PSMA4, S100A9). Conclusion: Suppressive populations were identified among the immune cells, specifically myeloid cells. We plan to experimentally test whether drugging the aforementioned targets in macrophages and granulocytes improves the overall efficacy of RT by augmenting an anti-tumor immune response. Affiliations: Aparna Krishnan1, Aleksandar Obradovic1, Catherine Spina2, Andrea Califano1,3,4,5,6 1 Department of Systems Biology* 2 Department of Radiation Oncology* 3 Herbert Irving Comprehensive Cancer Center* 4 Department of Medicine* 5 Department of Biochemistry &amp; Molecular Biophysics* 6 Department of Biomedical Informatics* * Columbia University Irving Medical Center, New York, NY 10032, USA Citation Format: Aparna Krishnan, Aleksander Obradovic, Catherine Spina, Andrea Califano. Single cell network-based analyses defines the effect of radiation on the tumor immune microenvironment, including the response by and molecular determinants of suppressive myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6173.

Abstract 3196: Focus on adipocytes in the growth, resistance, and lethality of extramedullary leukemic tumors could transform our approach to curing leukemia

Abstract We investigated whether the proposed role of adipocytes in driving solid cancers could apply to breast tumors formed of leukemia cells. This could explain the desmoplastic collagen deposition, metastasis, resistance, and lethality of these tumors that we previously reported. All 290 published cases of breast tumors composed of acute myeloid leukemia (AML) cells were reviewed and extended survivals were solicited from authors. RNA sequencing compared 11 AML breast samples to normal breast. Histology revealed invasion of adipose tissue by AML cells, many of which resided at the adipocyte periphery, accompanied by a shrinkage of adipocytes and the accumulation of collagen and elongated fibroblastic-like cells. Both lymphocytes and macrophages accompanied the infiltration. RNA sequencing showed deregulation of numerous adipose genes, including adiponectin, leptin, FABP4, COL6A3, CD36, and PPARγ, as reported in co-culture studies of breast and other solid cancer cells with adipocytes. Analysis of 210 clinical cases with available followup data revealed a survival benefit of tumor excision and/or irradiation in combination with systemic leukemic agents compared to systemic treatment alone. Two-year survival was achieved with excision +/- RT + systemic agents in 35/88 (40%), with RT + systemic agents in 12/38 (32%) and in 12/84 (14%) given systemic treatment alone. Five-year survival was achieved in 19%, 11%, and 2%, respectively. Eleven patients given surgery +/- RT with systemic treatments survived 10+ to 19+ years. This study reveals for the first time that removal/ablation of leukemic tumors and microenvironment can result in prolonged survival and potentially cure. Agents designed to treat marrow leukemia are ineffective in eradicating cells that have adopted solid tumor phenotype. The observed histologic features and clinical behavior of leukemic breast tumors could result from leukemic cell crosstalk with adipocytes, as reported in solid breast and other cancers. Invasion of fat is correlated with poor prognosis in many cancers. It is very likely that our findings also apply to hematologic tumors in other organs, as most contain or are near adipose tissue. Treating to cure extramedullary leukemia using combined excision/RT and systemic therapy requires confirming that the tumor is isolated and no occult tumors are present. This was not documented in most published cases. Only 10% of reported patients had PET/CT scans, so greater success is expected when body scans are routinely used in staging leukemia, as has been routine in every other cancer for decades. Until pharmacologic agents to interrupt malignant cell-adipocyte crosstalk are available, direct treatment of hematologic tumor after total body scan should be a new standard of care. Citation Format: Isabel Cunningham, James E. Goldman. Focus on adipocytes in the growth, resistance, and lethality of extramedullary leukemic tumors could transform our approach to curing leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3196.

OTHR-31. The molecular profile of secondary meningiomas in survivors of childhood non-central nervous system (CNS) cancers

Abstract INTRODUCTION: Secondary meningiomas are a late effect in children who received cranial irradiation, frequently with a long latency. The molecular genetic profile of primary meningiomas is well studied; however, few studies describe the genomic landscape of radiation-induced meningiomas (RIM). METHODS: Patients followed at the Stollery Children’s Hospital (Edmonton, Canada) with a history of non-CNS malignancies who received cranial irradiation and then developed meningiomas between 1971 and 2013 were identified. Whole exome sequencing (WES), RNA sequencing as well as DNA methylation profiling were performed for patients with available tumor tissue and germline DNA. RESULTS: Of 96 patients who received cranial irradiation for non-CNS tumors, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients identified received 2000-2400 cGy of cranial irradiation, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) of meningiomas infiltrated other tissues. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. NF2 mutations were identified in 50% (8; 4 DNA,4 fusion). Other meningioma related genes with mutations identified in other cohorts were not identified. Copy number alternations were noted in all 16 patients in chromosomes 1p and 22q. 850k methylation analysis with PCA as well as UMAP and tSNE did not demonstrate clustering. Ongoing additional studies include examining tumor mutation burden and the radiation mutational profile. CONCLUSIONS: This study examined the RIM in a cohort of patients having received similar doses of radiation for their childhood cancer. There is increased risk of radiation-induced meningioma in survivors of non-CNS cancers given ≥ 2000 cGy during childhood. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counselling, prognostication, and treatment.

Gamma Irradiation Triggers Immune Escape in Glioma-Propagating Cells.

Simple SummaryStem cell-like glioma-propagating cells (GPCs) are crucial for initiation, growth, and treatment resistance of glioblastoma multiforme. Due to their strong immunosuppressive activities, they essentially limit immunotherapeutic approaches. This study offers a new model of radio-selected patient-derived GPCs mimicking a clinical treatment regime of tumor irradiation which is especially useful for immunotherapeutic studies. We provide evidence that clinically relevant, sub-lethal fractions of γ radiation select for a more radio-resistant GPC phenotype with lower immunogenic potential, potentially hampering the success of adjuvant T-cell-based immunotherapies. The immune evasion in GPCs was characterized by quantitative proteomics. It revealed a marked downregulation of the antigen processing machinery in lipid rafts of these cells, leading to reduced MHC surface expression and weaker cytotoxic T lymphocyte (CTL) recognition.Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, the evasion mechanisms preventing therapy response are largely uncharacterized. Here, we studied the response of glioblastoma-propagating cells (GPCs) to clinically relevant doses of γ radiation. GPCs were treated with 2.5 Gy of γ radiation in seven consecutive cellular passages to select for GPCs with increased colony-forming properties and intrinsic or radiation-induced resistance (rsGPCs). Quantitative proteomic analysis of the cellular signaling platforms of the detergent-resistant membranes (lipid rafts) in GPCs vs. rsGPCs revealed a downregulation of the MHC class I antigen-processing and -presentation machinery. Importantly, the radio-selected GPCs showed reduced susceptibility towards cytotoxic CD8+ T-cell-mediated killing. While previous studies suggested that high-dose irradiation results in enhanced antigen presentation, we demonstrated that clinically relevant sub-lethal fractionated irradiation results in reduced expression of components of the MHC class I antigen-processing and -presentation pathway leading to immune escape.

Safety and potential increased risk of toxicity of radiotherapy combined immunotherapy strategy.

Accumulating interest has emerged in exploring the toxicity profiles of the combination strategy of radiotherapy (RT) and immune checkpoint inhibitors (ICIs). Much remains unknown regarding safety and the potential increased risk of toxicity of acombined treatment. ICI prolongs survival but can induce immune-related adverse events as well. To increase awareness of adverse effect and support immediate and successful management, we go over the literature on the safety of RT combined immunotherapy strategy. Representative evidence relevant to RT combined with ICI in the brain, lung, head and neck, and pelvic malignance was reviewed respectively. Given radiation doses and fractionation, the irradiated volume, the timing of RT, and ICI would significantly affect the safety and efficiency of ICI+RT combination therapy, and no consensus had been reached about how to arrange RT delivery in the combined contexture, we went over the available literature and tried to address these challenges including the timing of RT, optimal dose and fractionations, RT target and target volume, and potential biomarkers to predict toxicity. We found even though RT+ICI combination therapy might augment toxicities, the majority of patients experienced grade 4 or 5 AE are relatively rare and no significant difference could be found between combination group and monotherapy group. Sometimes the acute toxicity with ICI is much less predictable and often life threatening and in some can give rise to permanent effects. Clinicians across disciplines should be aware of these uncommon lethal complications induced by ICI+RT. Early recognition is the key to successful treatment, reversibility of organ dysfunction, and in some cases even prevention of fatal outcome. If recognized early, managed properly, and no fatal AE occurs, the development of irAE indicates a good prognosis. It should be noted that nothing is known about potential late effects because very few studies have 5-year follow-up. The nature of irAE is the attack of activated immune cells on normal tissues. The nature of RT-induced AE is the DNA damage on normal tissue, which is related with the dose delivered and volume irradiated and the tolerance of surrounding normal tissues. The immune-modulating effect of SBRT may augment the damage on normal tissues. To maximize the antitumor immune response, 8-12Gy/fraction is preferred when conducting RT. The available clinical evidence suggest RT of this dose/fractionated strategy combined with ICI have a tolerable AE profile, which need further validation by more clinical trials in the future. The combination strategy of RT with anti-PD1/PDL1 anti-body is supposed to be concurrent or RT followed by anti-PD1/PDL1 antibody. Although RT and ipilimumab combination sequence is controversial, ipilimumab prior to or concurrent with RT might be proper, which need more clinical validation. Under the concept of immunological dose painting, SBRT work as a trigger of immune response. It has been observed that SBRT of partially radiated tumors combined with ICI could induce similar tumor control compared with total tumor irradiation. The side effects of RT may be mitigated potentially due to the reduction of irradiated volume. The antitumor efficiency and safety profile of immunological RT dose painting+ICI deserve further investigation. Clinical predictive factors for irAE risk remain unclear, and more investigation deserves to be conducted about the irAE prediction.

Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A Review

The development of strategies capable of eliminating metastasized cancer cells and preventing tumor recurrence is an exciting and extremely important area of research. In this regard, therapeutic approaches that explore the synergies between nanomaterial-mediated phototherapies and immunostimulants/immune checkpoint inhibitors have been yielding remarkable results in pre-clinical cancer models. These nanomaterials can accumulate in tumors and trigger, after irradiation of the primary tumor with near infrared light, a localized temperature increase and/or reactive oxygen species. These effects caused damage in cancer cells at the primary site and can also (i) relieve tumor hypoxia, (ii) release tumor-associated antigens and danger-associated molecular patterns, and (iii) induced a pro-inflammatory response. Such events will then synergize with the activity of immunostimulants and immune checkpoint inhibitors, paving the way for strong T cell responses against metastasized cancer cells and the creation of immune memory. Among the different nanomaterials aimed for cancer immuno-phototherapy, those incorporating near infrared-absorbing heptamethine cyanines (Indocyanine Green, IR775, IR780, IR797, IR820) have been showing promising results due to their multifunctionality, safety, and straightforward formulation. In this review, combined approaches based on phototherapies mediated by heptamethine cyanine-loaded nanomaterials and immunostimulants/immune checkpoint inhibitor actions are analyzed, focusing on their ability to modulate the action of the different immune system cells, eliminate metastasized cancer cells, and prevent tumor recurrence.

SP-0847 Follow-up after irradiation of primary brain tumours

SP-0847 Follow-up after irradiation of primary brain tumours

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.

Simple SummaryWe present the early results of a novel partial bulky-tumor irradiation using carbon ions and protons. This approach explores the radiation-induced bystander and abscopal effects in patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments including radio-chemotherapy. Early tumor response, symptom relief and minimal toxicity suggest that the partial bulky-tumor irradiation was an effective, safe and well tolerated treatment. Abscopal effects elucidate an immunogenic pathway contribution.Background: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. Methods: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30–45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. Results: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. Conclusions: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment—otherwise previously impossible.

Research Progress on the effect of radiotherapy on immune function of tumor patients

With the cure rate of 21%, radiotherapy is one of the most effective methods for tumor treatment, and about 70% of solid tumors need radiotherapy.With the in-depth study of human impact by radiotherapy and immune system and tumor microenvironment, radiotherapy is no longer used as a local treatment. It is found that irradiation of tumor can activate body immunity. There exist two different views: one is that radiotherapy inhibits immunity, because it can kill tumor cells and normal cells at the same time.The other is that radiotherapy promotes immunity, causing tumor cell necrosis or apoptosis, releasing immune cytokines or promoting immune cell activation, and bystander effect. In recent years, the idea of radiotherapy promoting immunity has been more and more supported by literatures. Whether radiotherapy promotes or inhibits immunity is a research hot spot in recent years. This paper reviews the research progress of the effect of radiotherapy on immune function of tumor patients.

Tumour irradiation in mice with a laser-accelerated proton beam

Recent oncological studies identified beneficial properties of radiation applied at ultrahigh dose rates, several orders of magnitude higher than the clinical standard of the order of Gy min–1. Sources capable of providing these ultrahigh dose rates are under investigation. Here we show that a stable, compact laser-driven proton source with energies greater than 60 MeV enables radiobiological in vivo studies. We performed a pilot irradiation study on human tumours in a mouse model, showing the concerted preparation of mice and laser accelerator, dose-controlled, tumour-conform irradiation using a laser-driven as well as a clinical reference proton source, and the radiobiological evaluation of irradiated and unirradiated mice for radiation-induced tumour growth delay. The prescribed homogeneous dose of 4 Gy was precisely delivered at the laser-driven source. The results demonstrate a complete laser-driven proton research platform for diverse user-specific small animal models, able to deliver tunable single-shot doses up to around 20 Gy to millimetre-scale volumes on nanosecond timescales, equivalent to around 109 Gy s–1, spatially homogenized and tailored to the sample. The platform provides a unique infrastructure for translational research with protons at ultrahigh dose rates.

Non-Cancer Effects following Ionizing Irradiation Involving the Eye and Orbit.

Simple SummaryThe irradiation of tumors involving the eye or orbit represents a complex therapeutic challenge due to the proximity between the tumor and organs that are susceptible to radiation. The challenges include tumor control, as it is often a surrogate for survival; organ (usually the eyeball) preservation; and the minimization of damage of sensitive tissues surrounding the tumor in order to preserve vision. Anticipation of the spectrum and severity of radiation-induced complications is crucial to the decision of which technique to use for a given tumor. The aim of the present review is to report the non-cancer effects that may occur following ionizing irradiation involving the eye and orbit and their specific patterns of toxicity for a given radiotherapy modality. The pros and cons of conventional and advanced forms of radiation techniques and their clinical implementation are provided with a clinical perspective.The eye is an exemplarily challenging organ to treat when considering ocular tumors. It is at the crossroads of several major aims in oncology: tumor control, organ preservation, and functional outcomes including vision and quality of life. The proximity between the tumor and organs that are susceptible to radiation damage explain these challenges. Given a high enough dose of radiation, virtually any cancer will be destroyed with radiotherapy. Yet, the doses inevitably absorbed by normal tissues may lead to complications, the likelihood of which increases with the radiation dose and volume of normal tissues irradiated. Precision radiotherapy allows personalized decision-making algorithms based on patient and tumor characteristics by exploiting the full knowledge of the physics, radiobiology, and the modifications made to the radiotherapy equipment to adapt to the various ocular tumors. Anticipation of the spectrum and severity of radiation-induced complications is crucial to the decision of which technique to use for a given tumor. Radiation can damage the lacrimal gland, eyelashes/eyelids, cornea, lens, macula/retina, optic nerves and chiasma, each having specific dose–response characteristics. The present review is a report of non-cancer effects that may occur following ionizing irradiation involving the eye and orbit and their specific patterns of toxicity for a given radiotherapy modality.