Bystander effect and abscopal effect in recurrent thymic carcinoma treated with carbon-ion radiation therapy:A case report

BACKGROUND Although the bystander effect and abscopal effect are familiar in medicine,they are relatively rare in clinical practice.Herein,we report the case of a patient who demonstrated an obvious bystander effect and abscopal effect response following carbon-ion irradiation for recurrent thymic carcinoma.CASE SUMMARY A 44-year-old female presented with shortness of breath.Eleven years prior,she was diagnosed with athymic tumor located in the anterosuperior mediastinum.She underwent extensive tumor resection,and the postoperative pathologic diagnosis was thymic carcinoma.She was administered 50 Gy/25 Fx of postoperative radiation.In 2019,she was diagnosed with a recurrence of thymic carcinoma,with multiple recurrent nodules and masses in the left thoracic chest and peritoneal cavity,the largest of which was in the diaphragm pleura proximal to the pericardium,with a size of 6.7 cm×5.3 cm×4.8 cm.She received carbonion radiotherapy.After carbon-ion radiotherapy treatment,the treated masses and the untreated masses were observed to have noticeably shrunk on the day of carbon-ion radiotherapy completion and on follow-up imaging.We followed the CARE Guidelines for consensus-based clinical case reporting guideline development and completed the CARE Checklist of information to report this case.CONCLUSION This report is the first of obvious abscopal and bystander effects following carbonion irradiation in a human patient,and further research is needed to better elucidate the mechanisms of bystander and abscopal effects.

2-Hexyl-4-Pentylenic Acid(HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages

Objective The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid(HPTA)in combination with radiotherapy(RT)on distant unirradiated breast tumors.Methods Using a rat model of chemical carcinogen(7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer,tumor volume was monitored and treatment response was evaluated by performing HE staining,immunohistochemistry,immunofluorescence,q RT-PCR,and western blot analyses.Results The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant,unirradiated breast tumors.The mechanism of action included tumor-associated macrophage(TAM)infiltration into distant tumor tissues,M1 polarization,and inhibition of tumor angiogenesis by IFN-γ.Conclusion The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs,and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.

Immune blockade inhibitors and the radiation abscopal effect in gastrointestinal cancers

The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.

Radiotherapy,photodynamic therapy,and cryoablation‐induced abscopal effect:Challenges and future prospects

Local therapy modalities such as radiation therapy,photodynamic therapy,photothermal therapy,and cryoablation have been used to treat localized tumors for decades.The discovery of the abscopal effect causes a paradigm shift where local therapy also causes systemic effects and leads to the remission of nonirradiated tumors.The abscopal effect of radiation therapy,alone or in combination with other treatments,has been extensively studied over the last six decades.However,the results are unsatisfactory in producing robust,reproducible,and long‐lasting systemic effects.Although immunotherapy and radiation therapy are promising in producing the abscopal effect,the abscopal effect's mechanism is still unclear,owing to various factors such as irradiation type and dose and cancer type.This article reviews the research progress,clinical and preclinical evidence of the abscopal effect by various local therapies alone and in combination with chemotherapy and immunotherapy,case reports,and the current challenges in producing the abscopal effect by various local therapies,focusing on radiotherapy,photodynamic therapy,cryoablation,and the prospects for obtaining a robust,reproducible,and long‐lasting abscopal effect.

Oncological Hyperthermia: Where to Go from Here?

Oncological hyperthermia is one of the most versatile forms of oncotherapy. It can complement every conventional treatment method and be applied to any tumorous cancer, irrespective of its stages and localization. Numerous technical realizations are conventionally compared by their thermal effect, measured by temperature. However, nonthermal (mainly electric) excitation effects are more recognized nowadays. The technical variants alter the synergy between thermal and nonthermal energy components. Nonthermal energy absorption-induced molecular mechanisms include essential behaviors like selectivity and immunogenicity. The nonthermal electromagnetic effects excite molecular changes, intracellular signals, gene expressions, and many other chemical reactions. Their synergy with thermal conditions is based on the Arrhenius law, which describes the rapid growth of chemical reactions with temperature. A unique technical realization of hyperthermia, modulated electrohyperthermia (mEHT) tries to optimize the thermal and nonthermal effects. The results look very perspective, containing the high accuracy of targeting the tumor cells, the immunogenic cell death, and the activation of tumor-specific immune reactions restoring the healthy immune surveillance to destroy the cancer.

Research progress of radiation induced bystander and abscopal effects in normal tissue

Radiation-induced bystander effect(RIBE)and abscopal effect(RIAE)are non-target cellular responses outside the radiation field.It has been recognized that these effects are of great significance to both radiation protection of environmental low-dose radiation and clinical radiotherapy in which the anti-tumor abscopal effect is even beneficial to patients.However,the mechanisms of them are still obscure.This review briefly introduced the inflammatory signaling factors and immune regulation in RIBE in vitro and RIAE on normal tissues and organisms,and emphasized the genetic consequences of RIAE.Based on a large number of investigation results,we suggest that it’s time to incorporate RIBE and RIAE into the concept of“classic”radiation biology.

The Immunogenic Connection of Thermal and Nonthermal Molecular Effects in Modulated Electro-Hyperthermia

Hyperthermia in oncology is an emerging complementary therapy. The clinical results depend on multiple conditional factors, like the type of cancer, the stage, the applied treatment device, and the complementary conventional therapy. The molecular effect could also be different depending on the temperature, heating dose, kind of energy transfer, and timing sequences compared to the concomitant treatment. This article examines the molecular impacts of a specific technique used in oncological hyperthermia called modulated electro-hyperthermia (mEHT). What sets mEHT apart is its emphasis on harnessing the combined effects of thermal and nonthermal factors. Nonthermal energy absorption occurs through the excitation of molecules, while the thermal component ensures the ideal conditions for this process. The applied radiofrequency current selects the malignant cells, and the modulation drives the nonthermal effects to immunogenic cell death, helping to develop tumor-specific antitumoral immune reactions. The synergy of the thermal and nonthermal components excites the lipid-assembled clusters of transmembrane proteins (membrane rafts) as the channels of transient receptor potentials (TRPs), the heat-shock proteins (HSPs), the voltage-gated channels, and the voltage-sensitive phosphatases (VSPs). All these transmembrane compartments channeling various ionic species (like calcium and proton) interact with the cytoskeleton and are involved in the apoptotic signal pathways.

Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes;therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyteassociated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

Heating Preciosity—Trends in Modern Oncological Hyperthermia

The use of hyperthermia as a treatment in oncology is a common topic for debate. Some researchers expect a breakthrough in oncological treatments with hyperthermia, whereas others have disregarded the method. Serious questions concerning hyperthermia have arisen. Should homogeneous (isothermal) or heterogeneous (selective) heating being used? When we use selective heating (heterogeneity), should the entire tumour be targeted or should the malignant cells be individually selected? Does the mechanism involve thermal cell death or thermally-assisted cell death? Is the goal necrosis or apoptosis? Is hyperthermia safe as a monotherapy or does it have to be combined with conventional treatments? When the selection is local, how do we act on disseminated cells that represent a high risk of life threatening metastases? When local heating is the focus, how should it be carried out with measured and controlled? Our objective is to show how precise, selective heat transfer is necessary to remove malignant cells and, consequently, how hyperthermia as part of the immune-oncology can change the game in this promising field of oncological therapies.

Radiation Induced Bystander Effect: From in Vitro Studies to Clinical Application

In the past 20 years, the classic paradigm in radiobiology recognizing DNA as the main target for the action of radiation has changed. The new paradigm assumes that both targeted and non-targeted effects of radiation determine the final outcome of irradiation. Radiotherapy is one of the main modality treatments of neoplastic diseases with intent to cure, or sometimes to palliate only, thus radiation-induced non-targeted effect, commonly referred to as the radiation-induced bystander effect (RIBE) may have a share in cancer treatment. RIBE is mediated by molecular signaling from radiation targeted cells to their non-irradiated neighbors, and comprises such phenomena as bystander effect, genomic instability, adaptive response and abscopal effect. Whereas first three phenomena may appear both in vitro and in vivo, an abscopal effect is closely related to partial body irradiation and is a systemic effect mediated by immunologic system which synergizes with radiotherapy. From the clinical point of view abscopal effect is particularly interesting due to both its possible valuable contribution to the treatment of metastases, and the potential harmful effects as induction of genetic instability and carcinogenesis. This review summarized the main results of investigations of non-targeted effects coming from in vitro monolayer cultures, 3-dimentional models of tissues, preclinical studies on rodents and clinically observed beneficial abscopal effects with particular emphasis on participation of immunotherapy in the creation of abscopal effects.

Is Use of Radiation Hormesis the Missing Link to a Better Cancer Treatment?

Radiation hormesis is a concept that pervades radiobiological exposures;low doses enhance immune response, while higher doses inhibit immune response. Low-dose Total-Body Irradiation (TBI) therapy offers radiation treatment to cancer patients using the concepts of radiation hormesis and show very good success rates. This phenomenon has been reported elsewhere as the “abscopal effect” and considering the marginal success rates of other treatment agents, like the immunotherapy drug Ipilimumab, TBI therapy may prove to be the missing link to a better cancer treatment.

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

Systematic administration of small molecular drugs often suffered from the low efficacy and systemic toxicity in cancer therapy.In addition,application of single mode drug usually leads to unsatisfactory therapeutic out-comes.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 can-cer 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.

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

Immunotherapy,particularly with immune checkpoint inhibitors,has significantly transformed cancer treatment.Despite its success,many patients struggle to respond adequately or sustain long-lasting clinical improvement.A growing consensus has emerged that radiotherapy(RT)enhances the response rate and overall efficacy of immunotherapy.Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results,establishing itself as a dynamic and thriving area of research,clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results,suggesting the need for a more nuanced understanding.This review provides a balanced and updated analysis of the combination of immunotherapy and RT.We summarized the preclinical mechanisms through which RT boosts antitumor immune responses andmainly 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.

Combination of bacterial-targeted delivery of gold-based AIEgen radiosensitizer for fluorescence-image-guided enhanced radio-immunotherapy against advanced cancer

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 radioimmunotherapy.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.

Combination of immunotherapy-radiotherapy in non-small cell lung cancer: Reality and perspective

The aim of this review was to examine the theoretical,preclinical and clinical bases of the combination radiotherapy immunotherapy in the management of non-small cell lung cancer(NSCLC).Preclinical studies have shown that in addition to its well-established tumoricidal effects,radiotherapy can activate the host immune system and modify the tumor microenvironment.Immunotherapy is currently part of the therapeutic arsenal of the NSCLC given its capacity to restore the host's immune system's ability to recognize and destroy tumor cells.The combination of radiotherapy and immunotherapy seems to be synergistic,particularly with inhibitors of immune checkpoints.This association has become standard in the metastatic stages and especially in consolidation after radiochemotherapy in the locally advanced,unresectable and stable stages.Several questions remain unanswered including the optimal sequence of this combination,the type of radiotherapy(hypo-fractionated or normofractionated),the association of several immunotherapies and the cross-toxicity of the combination.The association of radiotherapy and immunotherapy is a promising treatment.