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Article: Low-Dose Radiotherapy for Late-Stage COVID-19 Pneumonia?

Koukourakis, Michael I

Dose-response : a publication of International Hormesis Society

2020 Volume 18, Issue 3, Page(s) 1559325820951357

Abstract: Low dose radiotherapy has been used in the pre-antibiotic era for the treatment of all kind of pneumonia, with relative success. The unimaginable daily death toll of thousands of victims dying from COVID-19 pneumonia and the marginal therapeutic value of ...

Abstract	Low dose radiotherapy has been used in the pre-antibiotic era for the treatment of all kind of pneumonia, with relative success. The unimaginable daily death toll of thousands of victims dying from COVID-19 pneumonia and the marginal therapeutic value of agents tested, brings forward the re-evaluation of the position of radiotherapy in the treatment of late stage lethal COVID-induced respiratory failure. A sound biological rationale supports this idea. Immunopathology studies show that excessive inflammation and infiltration of the lung parenchyma by immune cells is the cause of death. Mice lacking IFNαβ receptors remain unaffected by the virus. Radiotherapy at doses of 50-200cG may exert an intense anti-inflammatory effect and reduce the burden of inflammatory cells infiltrating the lungs. Whether radiotherapy, in conjunction with remdesivir and/or macrolides can reduce the dramatic death rates related to COVID-19 is an open challenge, under the absence of an alternative solution.
Keywords	covid19
Language	English
Publishing date	2020-09-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2440820-7
ISSN	1559-3258 ; 1559-3258
ISSN (online)	1559-3258
ISSN	1559-3258
DOI	10.1177/1559325820951357
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Article ; Online: Tumor draining lymph nodes, immune response, and radiotherapy: Towards a revisal of therapeutic principles.

Koukourakis, Michael I / Giatromanolaki, Alexandra

Biochimica et biophysica acta. Reviews on cancer

2022 Volume 1877, Issue 3, Page(s) 188704

Abstract: The tumor-draining lymph nodes (TDLNs) are the primary sites of the development of anti-tumor immunity. Primary tumor irradiation promotes 'radio-vaccination' by enhancing the release of tumor antigens and activating the interferon type-I pathway. ... ...

Abstract	The tumor-draining lymph nodes (TDLNs) are the primary sites of the development of anti-tumor immunity. Primary tumor irradiation promotes 'radio-vaccination' by enhancing the release of tumor antigens and activating the interferon type-I pathway. Activated intratumoral dendritic cells (DCs) enter the lymphatics to reach the TDLNs. The adaptive anti-tumor immune responses are developed, as DCs will present tumor-related antigens to activate CD4+ and CD8+ T-cells. Strong experimental evidence suggests that post-irradiation tumor clearance is strongly dependent on the accumulation of such cytotoxic T-cells in the tumors. However, TDLNs are heavily irradiated during Radiotherapy to eradicate the clinical and subclinical metastatic disease. At the same time, irradiation depletes the critical immune cell population residing in TDLNs and primary tumors, blocking immune response and compromising the effectiveness of immuno-stimulatory interventions. Since TDLNs are essential for T-cell activation by inbound dendritic cells previously activated in the tumor environment, the practice of TDLN-irradiation demands re-evaluation. Interventions to preserve and handle the functional state of regional TDLNs or remote nodes, during or after Radiotherapy, may have great therapeutic importance. TDLNs represent the main playground for educating and expanding tumor-specific cytotoxic immune cells and controlling a delicate balance between immune surveillance and tumor spread. Their activation state may define the outcome of Radiotherapy and the manifestation of abscopal effects. In this critical review, we present the biological and clinical role of TDLNs and propose strategies to include in the design of immuno-radiotherapy trials aiming to eradicate cancer at a local and distant level.
MeSH term(s)	Humans ; Lymph Nodes ; Lymphocyte Activation ; Neoplasms/radiotherapy
Language	English
Publishing date	2022-02-25
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2918802-7
ISSN	1879-2561 ; 0304-419X
ISSN (online)	1879-2561
ISSN	0304-419X
DOI	10.1016/j.bbcan.2022.188704
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Article ; Online: HLA-class-I expression loss, tumor microenvironment and breast cancer prognosis.

Giatromanolaki, Alexandra / Michos, Georgios D / Xanthopoulou, Erasmia / Koukourakis, Michael I

Cellular immunology

2024 Volume 399-400, Page(s) 104816

Abstract: Loss of HLA-class-I molecule expression by cancer cells is a frequent event in human tumors that may lead to immune evasion from cytotoxic T-cells. We examined the expression patterns of HLA-class-I molecules in a series of 175 patients with operable ... ...

Abstract	Loss of HLA-class-I molecule expression by cancer cells is a frequent event in human tumors that may lead to immune evasion from cytotoxic T-cells. We examined the expression patterns of HLA-class-I molecules in a series of 175 patients with operable breast cancer (BCa). Extensive loss of BCa cell HLA-class-I expression was noted 76.6 % of patients (27.5 % complete loss). A significant association of HLA-preservation with high TIL-density (p = 0.001) was documented. Preservation of HLA was evident only in BCa carcinomas with low HIF1α expression and high TIL-density. Cell line experiments (MCF7 and T47D) showed that induction of HLAs in cancer cells following incubation with lymphocytes or IFNγ, was abrogated under hypoxic conditions. HLA-preservation was linked with better distant metastasis-free survival (p = 0.01), which was confirmed also in multivariate analysis (p = 0.02, HR 3.17). Studying the expression of HLA-class-I molecules in parallel with TIL-density and HIF1α expression may identify subgroups of BCa patients who would benefit from immunotherapy.
Language	English
Publishing date	2024-03-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2024.104816
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Article ; Online: Neoplasia-related and treatment-induced lymphopenia: impact on the outcome of chemoradiotherapy in laryngeal cancer.

Koukourakis, Ioannis M / Gkegka, Anastasia G / Giatromanolaki, Alexandra / Koukourakis, Michael I

International journal of radiation biology

2024 Volume 100, Issue 5, Page(s) 736–743

Abstract: Introduction: The role of the immune system in the efficacy of radiotherapy (RT) has been well established. We examined the role of neoplasia-related and treatment-induced lymphopenia in the outcome of RT or chemoradiotherapy (CRT) in squamous cell ... ...

Abstract	Introduction: The role of the immune system in the efficacy of radiotherapy (RT) has been well established. We examined the role of neoplasia-related and treatment-induced lymphopenia in the outcome of RT or chemoradiotherapy (CRT) in squamous cell laryngeal cancer. Materials and methods: We retrospectively analyzed a series of 135 laryngeal carcinomas treated with radical or postoperative RT/CRT. Six lymphocyte-related variables were defined and examined: Results: RT and CRT resulted in a significant decrease of LCs at the end of therapy, and this was significantly more prominent in patients treated with radical intent and neck irradiation (median LC nadir 810/μl vs. 1250/μl; Conclusions: Both neoplasia-related and RT-induced lymphopenia define the outcome of RT in terms of locoregional failure, incidence of metastasis, and, finally, disease-specific survival of patients with laryngeal cancer. Restoration of pre-RT lymphopenia and protection of peripheral lymphocytes during RT emerge as critical issues that demand therapeutic interventions to maximize the efficacy of RT/CRT in patients with laryngeal cancer.
MeSH term(s)	Humans ; Lymphopenia/etiology ; Laryngeal Neoplasms/therapy ; Laryngeal Neoplasms/pathology ; Laryngeal Neoplasms/mortality ; Male ; Female ; Chemoradiotherapy/adverse effects ; Middle Aged ; Aged ; Retrospective Studies ; Treatment Outcome ; Adult ; Aged, 80 and over ; Lymphocyte Count
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ZDB-ID	3065-x
ISSN	1362-3095 ; 0020-7616 ; 0955-3002
ISSN (online)	1362-3095
ISSN	0020-7616 ; 0955-3002
DOI	10.1080/09553002.2024.2316608
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Article ; Online: Using Liquid Biopsy to Predict Relapse After Radiotherapy in Squamous Cell Head-Neck and Esophageal Cancer.

Koukourakis, Ioannis M / Xanthopoulou, Erasmia / Koukourakis, Michael I

Cancer diagnosis & prognosis

2023 Volume 3, Issue 4, Page(s) 403–410

Abstract: Circulating cell-free DNA (cfDNA) in the blood of cancer patients contains tumor-specific mutated genes and viral genome that can be identified and quantified as 'tumor-specific cfDNA' (circulating tumor DNA, ctDNA). Various technologies are available ... ...

Abstract	Circulating cell-free DNA (cfDNA) in the blood of cancer patients contains tumor-specific mutated genes and viral genome that can be identified and quantified as 'tumor-specific cfDNA' (circulating tumor DNA, ctDNA). Various technologies are available that offer reliable detection of ctDNA at a low concentration. Quantitative and qualitative analysis of ctDNA may be of prognostic and predictive value in oncology. Here, we present concisely the experience on the assessment of ctDNA levels and kinetics during therapy in the outcome of radiotherapy (RT) and chemo-radiotherapy (CRT) in squamous cell head-neck cancer and esophageal squamous cell cancer patients. The levels of circulating viral (human papilloma virus or Epstein-Barr) ctDNA, and levels of total, mutated or methylated ctDNA at diagnosis are linked with tumor burden and clinical aggressiveness, and may be of prognostic or even predictive value of RT/CRT efficacy. Persistent ctDNA levels after therapy seem to predict high rates of tumor relapse several months before radiological documentation. This can prove of value for the identification of subgroups of patients who could benefit from RT dose-escalation or consolidation chemotherapy and immunotherapy, a hypothesis that should be tested in clinical trials.
Language	English
Publishing date	2023-07-03
Publishing country	Greece
Document type	Journal Article ; Review
ISSN	2732-7787
ISSN (online)	2732-7787
DOI	10.21873/cdp.10232
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Article ; Online: Hypoxia and acidity regulate immune checkpoint molecule and IFN-β expression in non-small cell lung cancer cell lines.

Mitrakas, Achilleas G / Giatromanolaki, Alexandra / Koukourakis, Michael I

Journal of receptor and signal transduction research

2023 Volume 43, Issue 2, Page(s) 31–36

Abstract: Purpose: Non-small cell lung cancer (NSCLC) is one of the most lethal tumors in humans. Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced diseases. Tumor microenvironment conditions like ... ...

Abstract	Purpose: Non-small cell lung cancer (NSCLC) is one of the most lethal tumors in humans. Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced diseases. Tumor microenvironment conditions like hypoxia and low pH may compromise the efficacy of ICIs. Materials and methods: We report the effect of hypoxia and acidity on the expression levels of the major checkpoint molecules, namely PD-L1, CD80, and CD47, in the A549 and H1299 NSCLC cell lines. Results: Hypoxia induces PD-L1 protein and mRNA expression, represses CD80 mRNA levels, and enhances IFNβ protein expression. An opposite effect was noticed when cells were exposed to acidic conditions. Hypoxia-induced the CD47 molecule at protein and mRNA levels. It is concluded that hypoxia and acidity are important regulators of the expression of PD-L1 and CD80 immune checkpoint molecules. Acidity contributes to the suppression of the interferon type I pathway. Conclusions: These findings suggest that hypoxia and acidity assist cancer cells in the escape from immune surveillance through direct effects on cancer cells' ability to present immune checkpoint molecules and release type I interferons. Targeting hypoxia and acidity may enhance the activity of ICIs in NSCLC.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Immune Checkpoint Proteins ; B7-H1 Antigen ; CD47 Antigen ; Hypoxia ; RNA, Messenger ; Cell Line ; Tumor Microenvironment/genetics
Chemical Substances	Immune Checkpoint Proteins ; B7-H1 Antigen ; CD47 Antigen ; RNA, Messenger
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article
ZDB-ID	1230969-2
ISSN	1532-4281 ; 1079-9893
ISSN (online)	1532-4281
ISSN	1079-9893
DOI	10.1080/10799893.2023.2204944
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Article ; Online: Anti-PD-1 immunotherapy with dose-adjusted ultra-hypofractionated re-irradiation in patients with locoregionally recurrent head and neck cancer.

Koukourakis, Ioannis M / Giakzidis, Axiotis G / Koukourakis, Michael I

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico

2023 Volume 25, Issue 10, Page(s) 3032–3041

Abstract: Introduction: Patients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in ...

Abstract	Introduction: Patients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in 25% of patients. Immunogenic death produced by large radiotherapy (RT) fractions may enhance immune response. Materials and methods: We evaluated the efficacy and tolerance of ultra-hypofractionated immuno-radiotherapy (uhypo-IRT) in 17 patients with recurrent HNSCC and 1 with melanoma. Four of HNSCC patients also had oligometastatic disease. Using a dose/time/toxicity-based algorithm, 7, 7 and 4 patients received 1, 2 and 3 fractions of 8 Gy to the tumor, respectively. Nivolumab anti-PD-1 immunotherapy was administered concurrently with RT and continued for 24 cycles, or until disease progression or manifestation of immune-related adverse events (irAEs). Results: Early and late RT toxicities were minimal. Three patients developed irAEs (16%). After the 12th cycle, 7/17 (41.2%) and 5/17 (29.4%) patients with HNSCC showed complete (CR) and partial response (PR), respectively. CR was also achieved in the melanoma patient. The objective response rates in HNSCC patients were 57%, 86% and 66%, after 1, 2 and 3 fractions, respectively (overall response rate 70.6%). Most responders experienced an increase in peripheral lymphocyte counts. The median time to progression was 10 months. The 3-year projected locoregional progression-free survival was 35%, while the 3-year disease-specific overall survival was 50%. Conclusions: Anti-PD1 uhypo-IRT is safe and effective in patients with recurrent HNSCC. The high objective response rates and the long survival without evidence of disease support further trials on uhypo-IRT.
MeSH term(s)	Humans ; Squamous Cell Carcinoma of Head and Neck/therapy ; Squamous Cell Carcinoma of Head and Neck/etiology ; Re-Irradiation ; Head and Neck Neoplasms/therapy ; Immunotherapy/adverse effects ; Melanoma/drug therapy ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/radiotherapy
Language	English
Publishing date	2023-04-14
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2397359-6
ISSN	1699-3055 ; 1699-048X
ISSN (online)	1699-3055
ISSN	1699-048X
DOI	10.1007/s12094-023-03172-y
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Article ; Online: Combining the past and present to advance immuno-radiotherapy of cancer.

Koukourakis, Ioannis M / Koukourakis, Michael I

International reviews of immunology

2021 Volume 42, Issue 1, Page(s) 26–42

Abstract: Since its first clinical application, 120 years ago, radiotherapy evolved into a major anti-cancer treatment modality, offering high cure rates in many human malignancies. During the past ten years, the establishment of immune checkpoint inhibitors (ICIs) ...

Abstract	Since its first clinical application, 120 years ago, radiotherapy evolved into a major anti-cancer treatment modality, offering high cure rates in many human malignancies. During the past ten years, the establishment of immune checkpoint inhibitors (ICIs) in cancer therapeutics has vigorously reintroduced the immune system's role in the outcome of radiotherapy and, conversely, the role of radio-vaccination in the efficacy of immunotherapy. The knowledge and clinical experience that founded the current era of immuno-radiotherapy started alongside with the birth of radiotherapy, and evolved through exhaustive experimental work, clinical trials on active specific immunotherapy, frustrating attempts to validate the importance of cytokine administration with radiotherapy, and, finally, the encouraging ICI-based clinical trials that opened the door to a far more encouraging perspective; radio-vaccination, through its old and new methods, is rising as a research field that promises to cure, previously incurable, disease. In this critical review, we focus on the scientific knowledge gathered through more than a century of research on radiotherapy interactions with the immune system. Understanding the origins of this promising therapeutic approach will substantially contribute to developing new immuno-radiotherapy policies in the fight against cancer.
MeSH term(s)	Humans ; Neoplasms/radiotherapy ; Immunotherapy ; Cytokines ; Combined Modality Therapy
Chemical Substances	Cytokines
Language	English
Publishing date	2021-09-12
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	632825-8
ISSN	1563-5244 ; 1545-5858 ; 0883-0185
ISSN (online)	1563-5244 ; 1545-5858
ISSN	0883-0185
DOI	10.1080/08830185.2021.1974020
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Article ; Online: Lymphopenia and intratumoral lymphocytic balance in the era of cancer immuno-radiotherapy.

Koukourakis, Michael I / Giatromanolaki, Alexandra

Critical reviews in oncology/hematology

2021 Volume 159, Page(s) 103226

Abstract: Introduction: The immune response has been recognized as a major tumor-eradication component of radiotherapy.: Objective: This review studies, under a clinical perspective, two contrasting effects of radiotherapy, namely immunosuppression and ... ...

Abstract	Introduction: The immune response has been recognized as a major tumor-eradication component of radiotherapy. Objective: This review studies, under a clinical perspective, two contrasting effects of radiotherapy, namely immunosuppression and radiovaccination. Materials and methods: We critically reviewed the available clinical and experimental experience on radiotherapy-induced lymphopenia. Results: Radiation-induced tumor damage promotes radio-vaccination, enhances cytotoxic immune responses, and potentiates immunotherapy. Nevertheless, radiotherapy induces systemic and intratumoral lymphopenia. The above effects are directly related to radiotherapy fractionation and field size/location, and tumor characteristics. Discussion: Hypofractionated stereotactic and accelerated irradiation better promotes radio-vaccination and produces less severe lymphopenia. Adopting cytoprotective policies and combining lympho-stimulatory agents or agents blocking regulatory lymphocyte activity are awaited to unmask the radio-vaccination effect, enhancing the efficacy immuno-radiotherapy. Conclusion: Radiation-induced lymphopenia and immunosuppression are important issues that should be considered in the design of immuno-radiotherapy clinical trials.
MeSH term(s)	Antineoplastic Agents ; Humans ; Immunotherapy/adverse effects ; Lymphocytes ; Lymphopenia/etiology ; Neoplasms/complications ; Neoplasms/radiotherapy
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2021-01-19
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	605680-5
ISSN	1879-0461 ; 0737-9587 ; 1040-8428
ISSN (online)	1879-0461
ISSN	0737-9587 ; 1040-8428
DOI	10.1016/j.critrevonc.2021.103226
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Article ; Online: Low-Dose Radiotherapy for Late-Stage COVID-19 Pneumonia?

Koukourakis, Michael I.

Dose-Response

2020 Volume 18, Issue 3, Page(s) 155932582095135

Abstract	Low dose radiotherapy has been used in the pre-antibiotic era for the treatment of all kind of pneumonia, with relative success. The unimaginable daily death toll of thousands of victims dying from COVID-19 pneumonia and the marginal therapeutic value of agents tested, brings forward the re-evaluation of the position of radiotherapy in the treatment of late stage lethal COVID-induced respiratory failure. A sound biological rationale supports this idea. Immunopathology studies show that excessive inflammation and infiltration of the lung parenchyma by immune cells is the cause of death. Mice lacking IFNαβ receptors remain unaffected by the virus. Radiotherapy at doses of 50-200cG may exert an intense anti-inflammatory effect and reduce the burden of inflammatory cells infiltrating the lungs. Whether radiotherapy, in conjunction with remdesivir and/or macrolides can reduce the dramatic death rates related to COVID-19 is an open challenge, under the absence of an alternative solution.
Keywords	Toxicology ; Public Health, Environmental and Occupational Health ; Health, Toxicology and Mutagenesis ; Chemical Health and Safety ; covid19
Language	English
Publisher	SAGE Publications
Publishing country	us
Document type	Article ; Online
ZDB-ID	2440820-7
ISSN	1559-3258 ; 1559-3258
ISSN (online)	1559-3258
ISSN	1559-3258
DOI	10.1177/1559325820951357
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