Journal Articles

Checkpoint modulation

Cancer immunotherapeutic approaches that target stimulatory or inhibitory immune checkpoint pathways as well as immune related adverse events associated with these therapies

Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (2) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (3) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (4) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (5) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (6) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (7) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (8) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (9) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. (10) Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA. tim.greten@nih.gov. National Cancer Institute, Center for Cancer Research, Liver Cancer Program, Bethesda, USA. tim.greten@nih.gov.

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Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes

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PURPOSE: Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM). MATERIALS AND METHODS: Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan-Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT+immunotherapy groups. Significance was defined as a P value

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (4) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (5) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (6) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (7) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (8) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (9) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (10) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (11) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (12) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. Electronic address: cabraham@wustl.edu.

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It is finally time for adjuvant therapy in melanoma

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Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitor+MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients' selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (2) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (3) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (4) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (5) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (6) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (7) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. Electronic address: teresa.troiani@unicampania.it.

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Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma

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The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8(+) T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3(Y705) and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.

Author Info: (1) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital

Author Info: (1) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (2) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (3) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (4) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (5) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. (6) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (7) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (8) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (9) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (10) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. zhangwf59@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. zhangwf59@whu.edu.cn. (11) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. sunzj@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. sunzj@whu.edu.cn.

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PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy

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Cancer immunotherapy has greatly advanced in recent years, and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy. Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients, which promoted the Food and Drug Administration (FDA) approval of PD-1/PD-L1 blocking drugs. In this review, we provide a detailed introduction of five PD-1/PD-L1 blocking drugs, with indications and studies, as a valuable reference for doctors and medical investigators. Moreover, the characteristics of PD-1/PD-L1 blocking therapies, including their universality and sustainability, are discussed in this review. Furthermore, we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment, and the current status of combination therapies.

Author Info: (1) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational

Author Info: (1) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry, Tianjin Medical University, Tianjin 300070, China. (2) Institute of Integrative Medicines for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin 300100, China. (3) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry, Tianjin Medical University, Tianjin 300070, China. Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.

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Vaccine and immune cell therapy in non-small cell lung cancer

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Despite new advances in therapeutics, lung cancer remains the first cause of mortality among different types of malignancies. To improve survival, different strategies have been developed such as chemotherapy combinations, targeted therapies and more recently immunotherapy. Immunotherapy is based on the capability of the immune system to differentiate cancer cells from normal cells to fight against the tumor. The two main checkpoint inhibitors that have been widely studied in non-small cell lung cancer (NSCLC) are PD-1/PD-L1 and CTLA-4. However, interactions between tumor and immune system are much more complex with several different elements that take part and probably many new interactions to be discovered and studied for a better comprehension of those pathways. Vaccines are part of the prophylaxis and of the treatment for different infectious diseases. For that reason, they have allowed us to improve global survival worldwide. This same idea can be used for cancer treatment. First reports in clinical trials that used therapeutic vaccines in NSCLC were discouraging, but currently vaccines have a new chance in cancer therapy with the identification of new targetable antigens, adjuvant treatments and most interestingly, the combination of vaccines with anti-PD-1/PD-L1 and anti-CTLA-4 drugs. The aim of this article is to describe the scientific evidence that has been reported for the different types of vaccines and their mechanisms of action in the fight against NSCLC tumors to improve disease control.

Author Info: (1) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Oncology, Parc Tauli Hospital, Sabadell, Spain. (2) Oncology Department, Clinica Alemana Santiago

Author Info: (1) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Oncology, Parc Tauli Hospital, Sabadell, Spain. (2) Oncology Department, Clinica Alemana Santiago, Santiago, Chile. (3) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology Palermo, University of Palermo, Palermo, Italy. (4) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Center for Oncological Research Antwerp, University of Antwerp, Antwerp, Belgium. (5) Center for Oncological Research Antwerp, University of Antwerp, Antwerp, Belgium. Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium. (6) University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.

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Do immune checkpoint inhibitors need new studies methodology

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Immune checkpoint inhibitors (ICI) have widely reshaped the treatment paradigm of advanced cancer patients. Although multiple studies are currently evaluating these drugs as monotherapies or in combination, the choice of the most accurate statistical methods, endpoints and clinical trial designs to estimate the benefit of ICI remains an unsolved methodological issue. Considering the unconventional patterns of response or progression [i.e., pseudoprogression, hyperprogression (HPD)] observed with ICI, the application in clinical trials of novel response assessment tools (i.e., iRECIST) able to capture delayed benefit of immunotherapies and/or to quantify tumor dynamics and kinetics over time is an unmet clinical need. In addition, the proportional hazard model and the conventional measures of survival [i.e., median overall or progression free survival (PFS) and hazard ratios (HR)] might usually result inadequate in the estimation of the long-term benefit observed with ICI. For this reason, innovative methodologies such as milestone analysis, restricted mean survival time (RMST), parametric models (i.e., Weibull distribution, weighted log rank test), should be systematically investigated in clinical trials in order to adequately quantify the fraction of patients who are "cured", represented by the tails of the survival curves. Regarding predictive biomarkers, in particular PD-L1 expression, the integration and harmonization of the existing assays are urgently needed to provide clinicians with reliable diagnostic tests and to improve patient selection for immunotherapy. Finally, developing original and high-quality study designs, such as adaptive or basket biomarker enriched clinical trials, included in large collaborative platforms with multiple active sites and cross-sector collaboration, represents the successful strategy to optimally assess the benefit of ICI in the next future.

Author Info: (1) Department of Medical Oncology, Gustave Roussy, Villejuif, France. (2) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. (3)

Author Info: (1) Department of Medical Oncology, Gustave Roussy, Villejuif, France. (2) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. (3) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. (4) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. (5) Regina Elena National Cancer Institute, Roma, Italy. (6) Regina Elena National Cancer Institute, Roma, Italy. (7) Regina Elena National Cancer Institute, Roma, Italy. (8) Department of Medical Oncology, Gustave Roussy, Villejuif, France. (9) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. (10) U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

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Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients

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Immune checkpoint inhibitors (ICIs) have revolutionized treatment landscape among non-small cell lung cancer (NSCLC) patients in first- and second-line setting, and may become soon new treatment options in other thoracic malignancies such as small cell lung cancer (SCLC) or mesothelioma. The use of these drugs has indubitably changed the toxicity profile the oncologists are familiar with, and new spectra of immune-related adverse events are being reported with the widespread use of immunotherapies in solid tumors. Clinical management and understanding of immune-related adverse events is new and complex but expertise is still limited. In this review, we are summarizing the incidence and management of main side effects related to ICIs focusing on NSCLC patients.

Author Info: (1) Medical Oncology Department, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, Barcelona, Spain. (2) Gustave Roussy, Departement de Medecine Oncologique, Universite Paris-Saclay, Villejuif, France

Author Info: (1) Medical Oncology Department, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, Barcelona, Spain. (2) Gustave Roussy, Departement de Medecine Oncologique, Universite Paris-Saclay, Villejuif, France. (3) Oncoavanze-Quiron Sevilla, Sevilla, Spain. (4) Medical Oncology Department, Hospital Clinic Barcelona, Villarroel, Barcelona, Spain. (5) Medical Oncology Department, Hospital Clinic Barcelona, Villarroel, Barcelona, Spain.

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Blood cell count indexes as predictors of outcomes in advanced non-small-cell lung cancer patients treated with Nivolumab

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Lung cancer is the most common malignancy worldwide. Despite significant advances in diagnosis and treatment, mortality rates remain extremely high, close to incidence rates. Several targeted therapies have been recently introduced for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. Nivolumab, a monoclonal antibody that targets programmed death-1 (PD-1), was the first immune checkpoint inhibitor approved for the treatment of patients with advanced/metastatic NSCLC not responding to platinum-based chemotherapy. Biomarkers predicting response to these therapies would allow early identification of non-responders and timely implementation of appropriate combination strategies, avoiding inadequate and expensive therapies. The role of the neutrophil to lymphocyte ratio and other blood cell count indexes as possible biomarkers of response has been recently investigated. We discuss the encouraging results reported on the topic, provide new data from our personal experience, and discuss opportunities for further research.

Author Info: (1) Medical Oncology Unit, University Hospital of Sassari (AOU), Viale San Pietro 43, 07100, Sassari, Italy. (2) Medical Oncology Unit, San Gerardo Hospital, Via Pergolesi

Author Info: (1) Medical Oncology Unit, University Hospital of Sassari (AOU), Viale San Pietro 43, 07100, Sassari, Italy. (2) Medical Oncology Unit, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy. (3) Medical Oncology Unit, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy. (4) Medical Oncology Unit, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy. (5) Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy. (6) Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy. (7) Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy. ppaliogiannis@uniss.it.

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Complete Local and Abscopal Responses from a Combination of Radiation and Nivolumab in Refractory Hodgkin's Lymphoma

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Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.

Author Info: (1) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (2) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas

Author Info: (1) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (2) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (3) b Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (4) c Department of Radiology, Houston Methodist Research Institute, Houston, Texas (5) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (6) f Department of Medical Oncology, University of Toledo Medical Center, Toledo, Ohio, 43614. (7) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (8) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. f Department of Medical Oncology, University of Toledo Medical Center, Toledo, Ohio, 43614. (9) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (10) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (11) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (12) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. e Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, Texas 77030. g University of Texas MD Anderson Cancer Center, Houston, Texas 77030.

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