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Partnership of Radiotherapy and Immunotherapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 71924

Special Issue Editors

Head of Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
Interests: immune modulation by radiation; tumor immunology; hyperthermia; vaccination; osteoimmunological mechanisms of low-dose radiation therapy; translational immune monitoring; combined radio- immunotherapies; prognostic and predictive immune biomarkers
Special Issues, Collections and Topics in MDPI journals
Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 27, 91054 Erlangen, Germany
Interests: radiotherapy; immunotherapy; vaccination; immune checkpoints; hyperthermia; tumor immunology; immunogenic cancer cell death; immunomonitoring; inflammatory and degenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the last years it has become obvious that radiotherapy acts as immune modulator besides its local mode of action of DNA damage induction. DNA damage and stress responses are interconnected and may result in an immune stimulatory and/or immune suppressive micro-environment. A strong interplay between the radiation-modified tumour cells, stromal cells, secreted factors and immune cells exists. This individual condition calls for adjusted immunotherapies to reach efficient and specific anti-tumour immune responses.

This Special Issue will focus on immune biological consequences of radiotherapy, both in malign and benign (inflammatory) situations as basis for combination with selected immunotherapies including vaccination, immune checkpoint inhibition, hyperthermia, adoptive immune cell transfer and further innovative approaches. Biomarkers, solid and liquid ones, will be needed to improve radio-immunotherapy protocols and are also intensely considered here. Input of the huge multidisciplinary, basic and translational field of oncology and inflammation science is very welcome in this Special Issue.

Prof. Dr. Udo S. Gaipl
Dr. Benjamin Frey
Guest Editors

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Keywords

  • Radiotherapy
  • Immunotherapy
  • Cancer
  • Inflammatory diseases
  • Immune checkpoint inhibition
  • Vaccination
  • Adoptive immune cell transfer
  • Hyperthermia
  • Biomarkers
  • Immunomonitoring
  • DNA damage and stress responses

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Published Papers (13 papers)

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Research

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9 pages, 540 KiB  
Article
Neutrophil-to-Lymphocyte Ratio in Rectal Cancer—Novel Biomarker of Tumor Immunogenicity During Radiotherapy or Confounding Variable?
by Lore Helene Braun, David Baumann, Kerstin Zwirner, Ewald Eipper, Franziska Hauth, Andreas Peter, Daniel Zips and Cihan Gani
Int. J. Mol. Sci. 2019, 20(10), 2448; https://doi.org/10.3390/ijms20102448 - 17 May 2019
Cited by 31 | Viewed by 3319
Abstract
The aim of this study was to investigate the predictive value of blood-derived makers of local and systemic inflammatory responses on early and long-term oncological outcomes. A retrospective analysis of patients with locally advanced rectal cancer treated with preoperative long-course 5-fluorouracil-based radiochemotherapy was [...] Read more.
The aim of this study was to investigate the predictive value of blood-derived makers of local and systemic inflammatory responses on early and long-term oncological outcomes. A retrospective analysis of patients with locally advanced rectal cancer treated with preoperative long-course 5-fluorouracil-based radiochemotherapy was performed. Differential blood counts before neoadjuvant treatment were extracted from the patients’ electronic charts. Optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were determined. Potential clinical and hematological prognostic factors for disease-free survival (DFS) were studied using uni- and multivariate analysis. A total of 220 patients were included in the analysis. Median follow-up was 67 months. Five-year DFS and overall survival (OS) were 70% and 85%, respectively. NLR with a cut-off value of 4.06 was identified as optimal to predict DFS events. In multivariate analysis, only tumor volume (HR 0.33, 95% CI (0.14–0.83), p = 0.017) and NLR (HR 0.3, 95% CI (0.11–0.81), p = 0.017) remained significant predictors of DFS. Patients with a good histological response (Dworak 3 and 4) to radiotherapy also had a lower NLR than patients with less pronounced tumor regression (3.0 vs. 4.2, p = 0.015). A strong correlation between primary tumor volume and NLR was seen (Pearson’s r = 0.64, p < 0.001). Moreover, patients with T4 tumors had a significantly higher NLR than patients with T1–T3 tumors (6.6 vs. 3.3, p < 0.001). An elevated pretherapeutic NLR was associated with higher T stage, inferior DFS, and poor pathological response to neoadjuvant radiochemotherapy. A strong correlation between NLR and primary tumor volume was seen. This association is important for the interpretation of study results and for the design of translational studies which are warranted. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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13 pages, 5337 KiB  
Article
Preliminary Study of the Effect of Stereotactic Body Radiotherapy (SBRT) on the Immune System in Lung Cancer Patients Unfit for Surgery: Immunophenotyping Analysis
by Arturo Navarro-Martín, Isabel Linares Galiana, Miguel A. Berenguer Frances, Jon Cacicedo, Rut Cañas Cortés, Silvia Comas Anton, Susana Padrones Sánchez, Santiago Bolívar Cuevas, Renate Parry and Ferran Guedea Edo
Int. J. Mol. Sci. 2018, 19(12), 3963; https://doi.org/10.3390/ijms19123963 - 09 Dec 2018
Cited by 34 | Viewed by 4319
Abstract
An immunophenotyping analysis was performed in peripheral blood samples from seven patients with lung cancer unfit for surgery treated with stereotactic body radiotherapy (SBRT). The objective was to characterize the effect of SBRT on the host immune system. Four patients received 60 Gy [...] Read more.
An immunophenotyping analysis was performed in peripheral blood samples from seven patients with lung cancer unfit for surgery treated with stereotactic body radiotherapy (SBRT). The objective was to characterize the effect of SBRT on the host immune system. Four patients received 60 Gy (7.5 Gy × 8) and three 50 Gy (12.5 Gy × 4). Analyses were performed before SBRT, 72 h after SBRT, and at one, three, and six months after the end of SBRT. Of note, there was a specific increase of the immunoactive component of the immune system, with elevation of CD56+highCD16+ natural killer (NK) cells (0.95% at baseline to 1.38% at six months), and a decrease of the immunosuppressive component of the immune system, with decreases of CD4+CD25+Foxp3+CDA5RA− regulatory T cells (4.97% at baseline to 4.46% at six months), granulocytic myeloid-derived suppressor cells (G-MDSCs) (from 66.1% at baseline to 62.6% at six months) and monocytic (Mo-MDSCs) (8.2% at baseline to 6.2% at six months). These changes were already apparent at 72 h and persisted over six months. SBRT showed an effect on systemic immune cell populations, which is a relevant finding for supporting future combinations of SBRT with immunotherapy for treating lung cancer patients. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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16 pages, 2012 KiB  
Article
Clinically Relevant Radiation Exposure Differentially Impacts Forms of Cell Death in Human Cells of the Innate and Adaptive Immune System
by Sylvia E. Falcke, Paul F. Rühle, Lisa Deloch, Rainer Fietkau, Benjamin Frey and Udo S. Gaipl
Int. J. Mol. Sci. 2018, 19(11), 3574; https://doi.org/10.3390/ijms19113574 - 13 Nov 2018
Cited by 61 | Viewed by 5558
Abstract
In cancer treatments, especially high-dose radiotherapy (HDRT) is applied. Patients suffering from chronic inflammatory diseases benefit from low-dose radiation therapy (LDRT), but exposure to very low radiation doses can still steadily increase for diagnostic purposes. Yet, little is known about how radiation impacts [...] Read more.
In cancer treatments, especially high-dose radiotherapy (HDRT) is applied. Patients suffering from chronic inflammatory diseases benefit from low-dose radiation therapy (LDRT), but exposure to very low radiation doses can still steadily increase for diagnostic purposes. Yet, little is known about how radiation impacts on forms of cell death in human immune cells. In this study, the radiosensitivity of human immune cells of the peripheral blood was examined in a dose range from 0.01 to 60 Gy with regard to induction of apoptosis, primary necrosis, and secondary necrosis. Results showed that immune cells differed in their radiosensitivity, with monocytes being the most radioresistant. T cells mainly died by necrosis and were moderately radiosensitive. This was followed by B and natural killer (NK) cells, which died mainly by apoptosis. X-radiation had no impact on cell death in immune cells at very low doses (≤0.1 Gy). Radiation doses of LDRT (0.3–0.7 Gy) impacted on the more radiosensitive NK and B cells, which might contribute to attenuation of inflammation. Even single doses applied during RT of tumors did not erase the immune cells completely. These in vitro studies can be considered as the basis to optimize individual radiation therapy schemes in multimodal settings and to define suited time points for further inclusion of immunotherapies. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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13 pages, 2058 KiB  
Article
The Optimal Radiation Dose to Induce Robust Systemic Anti-Tumor Immunity
by Jan Poleszczuk and Heiko Enderling
Int. J. Mol. Sci. 2018, 19(11), 3377; https://doi.org/10.3390/ijms19113377 - 29 Oct 2018
Cited by 41 | Viewed by 5139
Abstract
The synergy of radiation and the immune system is currently receiving significant attention in oncology as numerous studies have shown that cancer irradiation can induce strong anti-tumor immune responses. It remains unclear, however, what are the best radiation fractionation protocols to maximize the [...] Read more.
The synergy of radiation and the immune system is currently receiving significant attention in oncology as numerous studies have shown that cancer irradiation can induce strong anti-tumor immune responses. It remains unclear, however, what are the best radiation fractionation protocols to maximize the therapeutic benefits of this synergy. Here, we present a novel mathematical model that can be used to predict and dissect the complexity of the immune-mediated response at multiple tumor sites after applying focal irradiation and systemic immunotherapy. We successfully calibrate the proposed framework with published experimental data, in which two tumors were grown in mice at two spatially-separated sites from which only one was irradiated using various radiation fractionation protocols with and without concurrent systemic immunotherapy. The proposed model is calibrated to fit the temporal dynamics of tumor volume at both sites and can predict changes in immune infiltration in the non-irradiated tumors. The model was then used to investigate additional radiation fractionation protocols. Model simulations suggest that the optimal radiation doses per fraction to maximize anti-tumor immunity are between 10 and 13 Gy, at least for the experimental setting used for model calibration. This work provides the framework for evaluating radiation fractionation protocols for radiation-induced immune-mediated systemic anti-tumor responses. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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12 pages, 1837 KiB  
Article
Robotic Stereotactic Radiosurgery in Melanoma Patients with Brain Metastases under Simultaneous Anti-PD-1 Treatment
by Maike Trommer-Nestler, Simone Marnitz, Martin Kocher, Daniel Rueß, Max Schlaak, Sebastian Theurich, Michael Von Bergwelt-Baildon, Janis Morgenthaler, Karolina Jablonska, Eren Celik, Maximilian I. Ruge and Christian Baues
Int. J. Mol. Sci. 2018, 19(9), 2653; https://doi.org/10.3390/ijms19092653 - 07 Sep 2018
Cited by 33 | Viewed by 3973
Abstract
Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with [...] Read more.
Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone (n = 13; 20 lesions) or in combination with anti-PD-1 therapy (n = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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10 pages, 2569 KiB  
Article
Enhancement of Radiation Effectiveness in Cervical Cancer Cells by Combining Ionizing Radiation with Hyperthermia and Molecular Targeting Agents
by Marloes IJff, Bregje Van Oorschot, Arlene L. Oei, Przemek M. Krawczyk, Hans M. Rodermond, Lukas J. A. Stalpers, H. Petra Kok, Johannes Crezee and Nicolaas A. P. Franken
Int. J. Mol. Sci. 2018, 19(8), 2420; https://doi.org/10.3390/ijms19082420 - 16 Aug 2018
Cited by 13 | Viewed by 3314
Abstract
Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1-i; DNA-dependent protein [...] Read more.
Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1-i; DNA-dependent protein kinase catalytic subunit inhibitor, DNA-PKcs-i and Heat Shock Protein 90 inhibitor, HSP90-i) in cervical cancer cell lines. Survival curves of SiHa and HeLa cells, concerning the combined effects of radiation with hyperthermia and PARP1-i, DNA-PKcs-i or HSP90-i, were analyzed using the linear-quadratic model: S(D)/S(0) = exp − (αD + βD2). The values of the linear-quadratic (LQ) parameters α and β, determine the effectiveness at low and high doses, respectively. The effects of these sensitizing agents on the LQ parameters are compared to evaluate dose-dependent differences in radio enhancement. Combination of radiation with hyperthermia, PARP1-i and DNA-PKcs-i significantly increased the value of the linear parameter α. Both α and β were significantly increased for HSP90-i combined with hyperthermia in HeLa cells, though not in SiHa cells. The Homologous Recombination pathway is inhibited by hyperthermia. When hyperthermia is combined with DNA-PKcs-i and PARP1-i, the Non-Homologous End Joining or Alternative Non-Homologous End Joining pathway is also inhibited, leading to a more potent radio enhancement. The observed increments of the α value imply that significant radio enhancement is obtained at clinically-used radiotherapy doses. Furthermore, the sensitizing effects of hyperthermia can be even further enhanced when combined with other molecular targeting agents. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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16 pages, 1805 KiB  
Article
In Vivo Irradiation of Mice Induces Activation of Dendritic Cells
by Eszter Persa, Tünde Szatmári, Géza Sáfrány and Katalin Lumniczky
Int. J. Mol. Sci. 2018, 19(8), 2391; https://doi.org/10.3390/ijms19082391 - 14 Aug 2018
Cited by 19 | Viewed by 4404
Abstract
It is becoming clear that ionizing radiation positively influences certain immune parameters, which opens the possibility for combining radio- and immunotherapies in cancer treatment. The presence of functionally competent dendritic cells (DCs) is crucial in mounting a successful antitumor immune response. While it [...] Read more.
It is becoming clear that ionizing radiation positively influences certain immune parameters, which opens the possibility for combining radio- and immunotherapies in cancer treatment. The presence of functionally competent dendritic cells (DCs) is crucial in mounting a successful antitumor immune response. While it has been shown that DCs are relatively radioresistant, few and contradictory data are available on how ionizing radiation alters the functional integrity of these cells. Therefore, our objective was to investigate the effect of whole-body irradiation on the function of splenic DCs. C57Bl/6 mice were irradiated with 0.1, 0.25, and 2 Gy X-rays and changes in the phenotype of splenic DCs were compared to unirradiated controls. An increase was seen in DC surface markers influencing DC-T cell interactions. In vivo cytokine production was determined by direct intracellular cytokine staining. Irradiation with 2 Gy induced a 1.6-fold increase in IL-1α production, while the combination of irradiation and lipopolysaccharide (LPS) treatment induced a 3.9-fold increase, indicating a strong synergism between irradiation and LPS stimulation. Interaction of DCs with effector and regulatory T cells was investigated in a mixed lymphocyte reaction. While DCs from control animals induced stronger proliferation of regulatory T cells, DCs from animals irradiated with 2 Gy induced stronger proliferation of effector T cells. Antigen uptake and presentation was investigated by measuring the capacity of DCs to internalize and present ovalbumine (OVA)-derived peptides on their major histocompatibility complex (MHCI) molecules. Irradiation with 2 Gy did not influence antigen uptake or presentation, while low doses stimulated antigen uptake and reduced the level of antigen presentation. In conclusion, high-dose in vivo irradiation induced increased expression of T cell costimulatory markers, enhanced production of proinflammatory cytokines and a stronger stimulation of effector T cell proliferation than that of regulatory T cells. However, it did not influence DC antigen uptake or presentation. On the other hand, low-dose irradiation increased antigen uptake and lowered antigen presentation of DCs, indicating that low- and high-dose irradiation act on different pathways in DCs. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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Review

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17 pages, 1871 KiB  
Review
Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review
by Rodolfo Chicas-Sett, Ignacio Morales-Orue, Juan Castilla-Martinez, Juan Zafra-Martin, Andrea Kannemann, Jesus Blanco, Marta Lloret and Pedro C Lara
Int. J. Mol. Sci. 2019, 20(9), 2173; https://doi.org/10.3390/ijms20092173 - 02 May 2019
Cited by 64 | Viewed by 5270
Abstract
Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in [...] Read more.
Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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27 pages, 1810 KiB  
Review
Realizing the Clinical Potential of Immunogenic Cell Death in Cancer Chemotherapy and Radiotherapy
by Bernardo L. Rapoport and Ronald Anderson
Int. J. Mol. Sci. 2019, 20(4), 959; https://doi.org/10.3390/ijms20040959 - 22 Feb 2019
Cited by 101 | Viewed by 8852
Abstract
Immunogenic cell death (ICD), which is triggered by exposure of tumor cells to a limited range of anticancer drugs, radiotherapy, and photodynamic therapy, represents a recent innovation in the revitalized and burgeoning field of oncoimmunnotherapy. ICD results in the cellular redistribution and extracellular [...] Read more.
Immunogenic cell death (ICD), which is triggered by exposure of tumor cells to a limited range of anticancer drugs, radiotherapy, and photodynamic therapy, represents a recent innovation in the revitalized and burgeoning field of oncoimmunnotherapy. ICD results in the cellular redistribution and extracellular release of damage-associated molecular patterns (DAMPs), which have the potential to activate and restore tumor-targeted immune responses. Although a convincing body of evidence exists with respect to the antitumor efficacy of ICD in various experimental systems, especially murine models of experimental anticancer immunotherapy, evidence for the existence of ICD in the clinical setting is less compelling. Following overviews of hallmark developments, which have sparked the revival of interest in the field of oncoimmunotherapy, types of tumor cell death and the various DAMPs most prominently involved in the activation of antitumor immune responses, the remainder of this review is focused on strategies which may potentiate ICD in the clinical setting. These include identification of tumor- and host-related factors predictive of the efficacy of ICD, the clinical utility of combinatorial immunotherapeutic strategies, novel small molecule inducers of ICD, novel and repurposed small molecule immunostimulants, as well as the critical requirement for validated biomarkers in predicting the efficacy of ICD. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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21 pages, 1078 KiB  
Review
Combining Radiotherapy and Immunotherapy in Lung Cancer: Can We Expect Limitations Due to Altered Normal Tissue Toxicity?
by Florian Wirsdörfer, Simone De Leve and Verena Jendrossek
Int. J. Mol. Sci. 2019, 20(1), 24; https://doi.org/10.3390/ijms20010024 - 21 Dec 2018
Cited by 76 | Viewed by 8489
Abstract
In recent decades, technical advances in surgery and radiotherapy, as well as breakthroughs in the knowledge on cancer biology, have helped to substantially improve the standard of cancer care with respect to overall response rates, progression-free survival, and the quality of life of [...] Read more.
In recent decades, technical advances in surgery and radiotherapy, as well as breakthroughs in the knowledge on cancer biology, have helped to substantially improve the standard of cancer care with respect to overall response rates, progression-free survival, and the quality of life of cancer patients. In this context, immunotherapy is thought to have revolutionized the standard of care for cancer patients in the long term. For example, immunotherapy approaches such as immune checkpoint blockade are currently increasingly being used in cancer treatment, either alone or in combination with chemotherapy or radiotherapy, and there is hope from the first clinical trials that the appropriate integration of immunotherapy into standard care will raise the success rates of cancer therapy to a new level. Nevertheless, successful cancer therapy remains a major challenge, particularly in tumors with either pronounced resistance to chemotherapy and radiation treatment, a high risk of normal tissue complications, or both, as in lung cancer. Chemotherapy, radiotherapy and immunotherapy have the capacity to evoke adverse effects in normal tissues when administered alone. However, therapy concepts are usually highly complex, and it is still not clear if combining immunotherapy with radio(chemo)therapy will increase the risk of normal tissue complications, in particular since normal tissue toxicity induced by chemotherapy and radiotherapy can involve immunologic processes. Unfortunately, no reliable biomarkers are available so far that are suited to predict the unique normal tissue sensitivity of a given patient to a given treatment. Consequently, clinical trials combining radiotherapy and immunotherapy are attracting major attention, not only regarding efficacy, but also with regard to safety. In the present review, we summarize the current knowledge of radiation-induced and immunotherapy-induced effects in tumor and normal tissue of the lung, and discuss the potential limitations of combined radio-immunotherapy in lung cancer with a focus on the suspected risk for enhanced acute and chronic normal tissue toxicity. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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18 pages, 1153 KiB  
Review
Combining PARP Inhibition, Radiation, and Immunotherapy: A Possible Strategy to Improve the Treatment of Cancer?
by Mathieu Césaire, Juliette Thariat, Serge M. Candéias, Dinu Stefan, Yannick Saintigny and François Chevalier
Int. J. Mol. Sci. 2018, 19(12), 3793; https://doi.org/10.3390/ijms19123793 - 28 Nov 2018
Cited by 57 | Viewed by 6603
Abstract
Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of [...] Read more.
Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of improving the efficacy of immunotherapy. Because the value of immunotherapy is amplified with the expression of tumor antigens, coupling poly(ADP-ribose) polymerase (PARP) inhibitors and immunotherapy might be a promising treatment for cancer. Further, PARP inhibitors (PARPis) are being combined with radiation therapy to inhibit DNA repair functions, thus enhancing the effects of radiation; this association might interact with the antitumor immune response. Cytotoxic T lymphocytes are central to the antitumor immune response. PARP inhibitors and ionizing radiation can enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, but they can also enhance PD-1/PDL-1 expression. Thus, the addition of immune checkpoint inhibitors with PARP inhibitors and/or ionizing radiation could counterbalance such immunosuppressive effects. With the present review article, we proposed to evaluate some of these associated therapies, and we explored the biological mechanisms and medical benefits of the potential combination of radiation therapy, immunotherapy, and PARP inhibitors. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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18 pages, 1641 KiB  
Review
Stereotactic Radiosurgery and Immune Checkpoint Inhibitors in the Management of Brain Metastases
by Eric J. Lehrer, Heather M. McGee, Jennifer L. Peterson, Laura Vallow, Henry Ruiz-Garcia, Nicholas G. Zaorsky, Sonam Sharma and Daniel M. Trifiletti
Int. J. Mol. Sci. 2018, 19(10), 3054; https://doi.org/10.3390/ijms19103054 - 07 Oct 2018
Cited by 41 | Viewed by 5809
Abstract
Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive [...] Read more.
Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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21 pages, 1101 KiB  
Review
Immunogenic Effect of Hyperthermia on Enhancing Radiotherapeutic Efficacy
by Sungmin Lee, Beomseok Son, Gaeul Park, Hyunwoo Kim, Hyunkoo Kang, Jaewan Jeon, HyeSook Youn and BuHyun Youn
Int. J. Mol. Sci. 2018, 19(9), 2795; https://doi.org/10.3390/ijms19092795 - 17 Sep 2018
Cited by 40 | Viewed by 6080
Abstract
Hyperthermia is a cancer treatment where tumor tissue is heated to around 40 °C. Hyperthermia shows both cancer cell cytotoxicity and immune response stimulation via immune cell activation. Immunogenic responses encompass the innate and adaptive immune systems, involving the activation of macrophages, natural [...] Read more.
Hyperthermia is a cancer treatment where tumor tissue is heated to around 40 °C. Hyperthermia shows both cancer cell cytotoxicity and immune response stimulation via immune cell activation. Immunogenic responses encompass the innate and adaptive immune systems, involving the activation of macrophages, natural killer cells, dendritic cells, and T cells. Moreover, hyperthermia is commonly used in combination with different treatment modalities, such as radiotherapy and chemotherapy, for better clinical outcomes. In this review, we will focus on hyperthermia-induced immunogenic effects and molecular events to improve radiotherapy efficacy. The beneficial potential of integrating radiotherapy with hyperthermia is also discussed. Full article
(This article belongs to the Special Issue Partnership of Radiotherapy and Immunotherapy)
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