Journal Articles

Experimental Immunotherapy

Preclinical and clinical cancer immunotherapy approaches

The route of administration dictates the immunogenicity of peptide-based cancer vaccines in mice

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Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.

Author Info: (1) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Washington University School of

Author Info: (1) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Washington University School of Medicine, Saint Louis, MO, USA. (2) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan. Department of Innovative Head and Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, Asahikawa, Japan. (3) Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan. Department of Pathology, Asahikawa Medical University, Asahikawa, Japan. (4) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. (5) Oncovir, Inc., Washington, DC, USA. (6) Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4142, Augusta, GA, 30912, USA. ecelis@augusta.edu.

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Current status of immune checkpoint inhibitors in treatment of non-small cell lung cancer

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Lung cancer remains a leading cause of cancer mortality worldwide, including in Korea. Systemic therapy including platinum-based chemotherapy and targeted therapy should be provided to patients with stage IV non-small cell lung cancer (NSCLC). Applications of targeted therapy, such as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors, in patients with NSCLC and an EGFR mutation or ALK gene rearrangement has enabled dramatic improvements in efficacy and tolerability. Despite advances in research and a better understanding of the molecular pathways of NSCLC, few effective therapeutic options are available for most patients with NSCLC without druggable targets, especially for patients with squamous cell NSCLC. Immune checkpoint inhibitors such as anti-cytotoxic T lymphocyte antigen-4 or anti-programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have demonstrated durable response rates across a broad range of solid tumors, including NSCLC, which has revolutionized the treatment of solid tumors. Here, we review the current status and future approaches of immune checkpoint inhibitors that are being investigated for NSCLC with a focus on pembrolizumab, nivolumab, atezolizumab, durvalumab, and ipilimumab.

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (2) Division of Hematology-Oncology, Department of Medicine, Samsung

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (2) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy

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Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-cis-retinoic acid) has a US Food and Drug Administration (FDA)-registered indication for treating high-risk NB patients who achieved at least a partial response to prior first-line multi-agent, multimodality therapy. The FDA registration resulted from a prospective randomized trial assessing the benefit of adding dinutuximab + cytokines to post-myeloablative maintenance therapy for high-risk NB. Dinutuximab has also shown promising antitumor activity when combined with temozolomide and irinotecan in treating NB progressive disease. Clinical activity of dinutuximab and other GD2-targeted therapies relies on the presence of the GD2 antigen on NB cells. Some NBs have been reported as GD2 low or negative, and such tumor cells could be nonresponsive to anti-GD2 therapy. As dinutuximab relies on complement and effector cells to mediate NB killing, factors affecting those components of patient response may also decrease dinutuximab effectiveness. This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB, and the potential mechanisms of resistance to dinutuximab.

Author Info: (1) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. (2) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. Department of Internal Medicine, Patrick.Reynolds@ttuhsc.edu. Department of Cell Biology

Author Info: (1) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. (2) Cancer Center, Patrick.Reynolds@ttuhsc.edu. Department of Pediatrics, Patrick.Reynolds@ttuhsc.edu. Department of Internal Medicine, Patrick.Reynolds@ttuhsc.edu. Department of Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA, Patrick.Reynolds@ttuhsc.edu.

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Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial

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BACKGROUND: Sintilimab (Innovent Biologics, Suzhou, China), a highly selective, fully humanised, monoclonal antibody, blocks the interaction between PD-1 and its ligands. We aimed to assess the activity and safety profile of sintilimab in Chinese patients with relapsed or refractory classical Hodgkin lymphoma. METHODS: In this ongoing, single-arm, phase 2 study, we recruited patients with histopathologically diagnosed classical Hodgkin lymphoma that was relapsed or refractory after two or more lines of therapy from 18 hospitals in China. Patients were given intravenous sintilimab (200 mg, once every 3 weeks) until progression, death, unacceptable toxicity, or withdrawal of consent. The primary outcome was the proportion of patients in the full analysis set (ie, those with classical Hodgkin lymphoma confirmed by the central pathology laboratory) who had an objective response, as assessed by an independent radiological review committee (IRRC), by 24 weeks after enrolment of the last patient. Tumour response was assessed by enhanced CT scan or MRI at baseline, at weeks 6, 15, and 24, every 12 weeks from weeks 24 to 48, and every 16 weeks beyond week 48. Safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03114683, and is ongoing. FINDINGS: Between April 19, 2017, and Nov 1, 2017, 96 patients were enrolled and commenced treatment. Four patients, whose diagnosis was not subsequently confirmed by the central pathology laboratory, were excluded from the full analysis set. Ten patients discontinued treatment. Median duration of follow-up was 10.5 months. In the full analysis set (n=92), 74 patients (80.4%; 95% CI 70.9-88.0) had an IRRC-assessed objective response before the analysis cutoff date of April 16, 2018. 89 (93%) of 96 patients had treatment-related adverse events, and 17 patients (18%) had grade 3 or 4 treatment-related adverse events, the most common being pyrexia (three [3%] patients). 14 (15%) patients had serious adverse events of any cause. No patient died during the study. INTERPRETATION: Sintilimab could be a new treatment option for patients with relapsed or refractory classical Hodgkin lymphoma in China. FUNDING: Innovent Biologics, Eli Lilly and Company, National New Drug Innovation Programme, and the National Key Scientific Programme Precision Medicine Research Fund of China.

Author Info: (1) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: syuankai@cicams.ac.cn

Author Info: (1) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: syuankai@cicams.ac.cn. (2) Department of Lymphoma, 307th Hospital of Chinese People's Liberation Army, Beijing, China. (3) Department of Haematology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China. (4) Sun Yat-Sen University Cancer Centre, Guangzhou, Guangdong, China. (5) Department of Oncology, Second Hospital of Dalian Medical University, Dalian, Liaoning, China. (6) Department of Haematology, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China. (7) Department of Haematology, Peking Union Medical College Hospital, Beijing, China. (8) Department of Haematology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. (9) Department of Haematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. (10) Department of Haematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. (11) Department of Oncology, Cancer Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong, China. (12) Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. (13) Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. (14) Department of Oncology, First Hospital of Jilin University, Changchun, Jilin, China. (15) Department of Haematology, Changhai Hospital, Shanghai, China. (16) Department of Haematology, Qilu Hospital of Shandong University, Jinan, Shandong, China. (17) Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China. (18) Department of Oncology, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, China. (19) Department of Haematology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China. (20) Innovent Biologics (Suzhou) Co, Suzhou, Jiangsu, China. (21) Innovent Biologics (Suzhou) Co, Suzhou, Jiangsu, China. (22) National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

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Immune defects in pancreatic cancer

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Pancreatic cancer is resistant to the immunotherapy. This resistance is caused by any of the four immune "defects" that occur in pancreatic cancer, including lack of "high quality" T cells, stromal barriers to T cells getting access to tumor cells, immunosuppressive cells such as M2 macrophages, myeloid derivative suppressor cells, and T regulatory cells, in the tumor microenvironment of pancreatic cancer. One or more defects may occur in an individual pancreatic cancer. To overcome the resistance to the immunotherapy such as immune checkpoint inhibitors, a rational combination of agents that target multiple immune defects is highly demanded.

Author Info: (1) The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Author Info: (1) The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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Prostate Cancer-Specific of DD3-driven Oncolytic Virus-harboring mK5 Gene

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Prostate cancer (PCa) is the second most diagnosed cancer in Western male population. In this study, we insert mK5 (the mutational kringle5 of human plasminogen) into a DD3-promoted (differential display code 3) oncolytic adenovirus to construct OncoAd.mK5.DD3. E1A.dE1B, briefly, O(Ad).DD3.mK5. DD3 is one of the most prostate cancer specific promoters which can transcriptionally control adenoviral replication. mK5 has been proved to be able to inhibit the tumor angiogenesis and inhibit cell proliferation. Our results suggested that targeting PCa with O(Ad).DD3.mK5 elicited strong antitumor effect.

Author Info: (1) Xinyuan Institute of Medicine and Biotechnology, Zhejiang SciTech University, Hangzhou 310018, China. (2) Xinyuan Institute of Medicine and Biotechnology, Zhejiang SciTech University, Hangzhou 310018

Author Info: (1) Xinyuan Institute of Medicine and Biotechnology, Zhejiang SciTech University, Hangzhou 310018, China. (2) Xinyuan Institute of Medicine and Biotechnology, Zhejiang SciTech University, Hangzhou 310018, China. (3) Shanghai Yuansong biotechnology Co., Ltd., Shanghai, China. (4) Key Laboratory of Contraceptive Drugs and Devices of NPFPC, Shanghai Institute of Planned Parenthood Research, Shanghai, China.

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Melanoma and autoimmunity: spontaneous regressions as a possible model for new therapeutic approaches

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Until now, malignancy has been considered a cellular problem represented by the perturbed (uncontrolled) division of the cells associated with invasion and metastasis. Contrary to this classical approach, a new perspective suggests that cancerous disease is, in fact, a supracellular problem represented by inadequate evolution of complex supracellular processes (embryogenesis, development, regeneration, etc.). Such complex processes would be disconnected from the real needs of the body, inducing unnecessary or even dangerous events such as an exacerbated rate of the cell division, angiogenesis, immunosuppression (specific to embryogenesis and melanoma), invasion (mediated by trophoblastic/placental factors in melanoma), and migration (specific to neural crest cells, which generate melanocytes - the most common origin for melanoma). As a result, a correct and comprehensive interpretation of cancer (causes, evolution, therapy, and prevention) should be conducted from a supracellular perspective. After presenting the supracellular perspective, this article further investigates the favorable evolution of malignant melanoma in two distinct situations: in patients receiving no therapy and in patients treated with immune-checkpoint inhibitors. In patients receiving no therapy, spontaneous regressions of melanoma could be the result of several autoimmune reactions (inducing not only melanoma regression but also vitiligo, an autoimmune event frequently associated with melanoma). Patients treated with immune-checkpoint inhibitors develop similar autoimmune reactions, which are clearly correlated with better therapeutic results. The best example is vitiligo, which is considered a positive prognostic factor for patients receiving immune-checkpoint inhibitors. This finding indicates that immune-checkpoint inhibitors induce distinct types of autoimmune events, some corresponding to specific favorable autoimmune mechanisms (favoring tumor regression) and others to common unfavorable adverse reactions (which should be avoided or minimized). In conclusion, the spectrum of autoimmune reactions induced by immune-checkpoint inhibitors should be restricted in the near future to only these specific favorable autoimmune mechanisms. In this way, the unnecessary autoimmune reactions/autoaggressions could be avoided (a better quality of life), and treatment specificity and efficiency should increase (a higher response rate for melanoma therapy).

Author Info: (1) Department of Surgery/Oncology, St Pantelimon Hospital, Carol Davila University, Bucharest, Romania.

Author Info: (1) Department of Surgery/Oncology, St Pantelimon Hospital, Carol Davila University, Bucharest, Romania.

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Expression of cancer/testis antigens in cutaneous melanoma: a systematic review

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The cancer/testis antigen (CTA) family is a group of antigens whose expression is restricted to male germline cells of the testis and various malignancies. This expression pattern makes this group of antigens potential targets for immunotherapy. The aim of this study was to create an overview of CTA expressed by melanoma cells at mRNA and protein level. A systematic literature search was performed in Medline (PubMed) and Embase from inception up to and including February 2018. Studies were screened for eligibility by two independent reviewers. A total of 65 full-text articles were included in the final analysis. A total of 48 CTA have been studied in melanoma. Various CTA show different expression rates in primary and metastatic tumours. Of the 48 CTA, the most studied were MAGE-A3, MAGE-A1, NY-ESO-1, MAGE-A4, SSX2, MAGE-A2, MAGE-C1/CT7, SSX1, MAGE-C2/CT10 and MAGE-A12. On average, MAGE-A3 mRNA is present in 36% of primary tumours, whereas metastatic tumours have an expression rate of 55-81%. The same applies to the protein expression rate of MAGE-A3 in primary tumours, which is reported to be at 15-37%, whereas metastatic tumours have a higher expression rate of 25-70%. This trend of increased expression in metastases compared with primary tumours is observed with MAGE-A1, MAGE-A2, MAGE-A4, MAGE-A12 and NY-ESO-1. Many CTA are expressed on melanoma. This review provides an overview of the expression frequency of CTAs in melanoma and may aid in identifying CTA as the therapeutic target for immunotherapy.

Author Info: (1) Department of Dermatology, Amsterdam University Medical Centers, VU University. (2) Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of

Author Info: (1) Department of Dermatology, Amsterdam University Medical Centers, VU University. (2) Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam. Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute Amsterdam. (3) Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam. Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute Amsterdam. (4) Department of Dermatology. (5) Medical Library, Leiden University Medical Center, Leiden, The Netherlands. (6) Department of Dermatology, Amsterdam University Medical Centers, VU University. Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam. (7) Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam. Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute Amsterdam. (8) Department of Dermatology, Amsterdam University Medical Centers, VU University. Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam.

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Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma

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Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.

Author Info: (1) Department of Pediatrics, New York Medical College, Valhalla, NY, USA. (2) Department of Pediatrics, New York Medical College, Valhalla, NY, USA. (3) Department of

Author Info: (1) Department of Pediatrics, New York Medical College, Valhalla, NY, USA. (2) Department of Pediatrics, New York Medical College, Valhalla, NY, USA. (3) Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA. (4) Department of Pediatrics, New York Medical College, Valhalla, NY, USA. Department of Medicine, New York Medical College, Valhalla, NY, USA. Department of Pathology, New York Medical College, Valhalla, NY, USA. Department of Microbiology & Immunology, New York Medical College, Valhalla, NY, USA. Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA.

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Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies

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BACKGROUND: Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line. METHODS: A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered. RESULTS: 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n=10), reintroduction (n=4), sequence (n=5), dose escalation (n=1) and mixed (n=6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR=0.0-53.8%; disease control rate, DCR=24.0-89.7%), with best results in the setting of rechallenge (ORR=2.9-53.8%; DCR=40.0-89.7%). CONCLUSIONS: Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.

Author Info: (1) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. (2) Niguarda Cancer

Author Info: (1) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. (2) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. (3) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (4) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (5) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (6) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (7) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (8) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (9) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (10) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. (11) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (12) Candiolo Cancer Insitute - FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin, Italy. (13) Candiolo Cancer Insitute - FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin, Italy. (14) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. (15) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Universita degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy. Electronic address: andrea.sartorebianchi@unimi.it.

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