Journal Articles

Cytokine therapy

Treatment strategies based on cytokines, including cytokine gene therapy and immunocytokines

Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-beta, in advanced solid tumors

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PURPOSE: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-beta (TGF-beta) "trap." Experimental DesignIn the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. RESULTS: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade >/=3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-beta1, -beta2, and -beta3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). CONCLUSIONS: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging and multiple expansion cohorts are ongoing in a range of tumors.

Author Info: (1) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (2) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National

Author Info: (1) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (2) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (3) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (4) Genitourinary Malignancies Branch, National Cancer Institute. (5) Genetics Branch, National Cancer Institute. (6) Genetic Branch, National Cancer Institute. (7) Office of Research Nursing, National Cancer Institute, National Institutes of Health. (8) Laboratory of Tumor Immunology and Biology, National Cancer Institute. (9) Laboratory of Tumor Immunology and Biology, National Cancer Institute. (10) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (11) Genitourinary Malignancies Branch,, Center for Cancer Research, National Cancer Institute. (12) EMD Serono. (13) Global Exploratory Development, EMD Serono. (14) Merck KGaA. (15) Genitourinary Malignancies Branch, ational Cancer Institute, National Institutes of Health gulleyj@mail.nih.gov.

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Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors

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Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFNgamma, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFNgamma and TNFalpha in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8(+) T cells within tumors, reduced tumor burden and prolonged survival. Notably, treatment with TCR+iIL-12 but not iIL-18 T cells resulted in enhanced intra-tumoral accumulation of macrophages, which was accompanied by a decreased frequency of therapeutic T cells, in particular of the CD8 subset. In addition, when administered to mice, iIL-18 but not iIL-12 demonstrated a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.

Author Info: (1) Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. (2) Department I of Internal Medicine, University Hospital Cologne

Author Info: (1) Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. (2) Department I of Internal Medicine, University Hospital Cologne and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. (3) Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. (4) Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. (5) Department I of Internal Medicine, University Hospital Cologne and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. (6) Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

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Th17 immune microenvironment in Epstein-Barr virus-negative Hodgkin lymphoma: implications for immunotherapy

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Classical Hodgkin lymphoma (CHL) is a neoplasm characterized by robust inflammatory infiltrates and heightened expression of the immunosuppressive PD-1/PD-L1 pathway. Although anti-PD-1 therapy can be effective in >60% of patients with refractory CHL, improved treatment options are needed for CHLs which are resistant to anti-PD-1 or relapse after this form of immunotherapy. A deeper understanding of immunologic factors in the CHL microenvironment might support the design of more effective treatment combinations based on anti-PD-1. In addition, because the Epstein-Barr virus (EBV) residing in some CHL tumors is strongly immunogenic, we hypothesized that characteristics of the tumor immune microenvironment in EBV(+) CHL would be distinct from EBV(-) CHL, with specific implications for designing combination treatment regimens. Employing immunohistochemistry for immune cell subsets and checkpoint molecules, as well as gene expression profiling, we characterized 32 CHLs from the Johns Hopkins archives, including 12 EBV(+) and 20 EBV(-) tumors. Our results revealed a dichotomous cellular and cytokine immune milieu in EBV(+) vs EBV(-) CHL. EBV(+) tumors displayed a T helper 1 (Th1) profile typical of effective antitumor immunity, with increased infiltration of CD8(+) T cells and coordinate expression of the canonical Th1 transcription factor Tbet (TBX21), interferon-gamma (IFNG), and the IFN-gamma-inducible immunosuppressive enzyme indoleamine 2,3-dioxygenase. In contrast, EBV(-) tumors manifested a pathogenic Th17 profile and ongoing engagement of the interleukin-23 (IL-23)/IL-17 axis, with heightened phosphorylated signal transducer and activator of transcription 3 expression in infiltrating lymphocytes. These findings suggest that drugs blocking the IL-23/IL-17 axis, which are already in the clinic for treating certain autoimmune disorders, may enhance the therapeutic impact of anti-PD-1 therapy in EBV(-) CHL.

Author Info: (1) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. (2) Bloomberg-Kimmel

Author Info: (1) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. (2) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Oncology. (3) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. (4) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Dermatology. (5) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. (6) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Surgery, and. (7) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Surgery, and. (8) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Surgery, and. (9) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Dermatology. (10) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Dermatology. (11) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD. (12) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Oncology. (13) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Surgery, and. (14) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD; and. Department of Oncology.

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Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models

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Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients.

Author Info: (1) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (2) Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA. (3) Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ

Author Info: (1) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (2) Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA. (3) Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ. (4) Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA. (5) Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ. (6) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (7) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (8) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (9) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. (10) Drug Safety Evaluation, Bristol-Myers Squibb, Mt. Vernon, IN. (11) Early Clinical Development, Bristol-Myers Squibb, Princeton, NJ. (12) Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA. (13) Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ. (14) Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA.

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Generation and Functional In Vitro Analysis of Semliki Forest Virus Vectors Encoding TNF-alpha and IFN-gamma

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Cytokine gene delivery by viral vectors is a promising novel strategy for cancer immunotherapy. Semliki Forest virus (SFV) has many advantages as a delivery vector, including the ability to (i) induce p53-independent killing of tumor cells via apoptosis, (ii) elicit a type-I interferon (IFN) response, and (iii) express high levels of the transgene. SFV vectors encoding cytokines such as interleukin (IL)-12 have shown promising therapeutic responses in experimental tumor models. Here, we developed two new recombinant SFV vectors encoding either murine tumor necrosis factor-alpha (TNF-alpha) or murine interferon-gamma (IFN-gamma), two cytokines with documented immunostimulatory and antitumor activity. The SFV vector showed high infection rate and cytotoxicity in mouse and human lung carcinoma cells in vitro. By contrast, mouse and human macrophages were resistant to infection with SFV. The recombinant SFV vectors directly inhibited mouse lung carcinoma cell growth in vitro, while exploiting the cancer cells for production of SFV vector-encoded cytokines. The functionality of SFV vector-derived TNF-alpha was confirmed through successful induction of cell death in TNF-alpha-sensitive fibroblasts in a concentration-dependent manner. SFV vector-derived IFN-gamma activated macrophages toward a tumoricidal phenotype leading to suppressed Lewis lung carcinoma cell growth in vitro in a concentration-dependent manner. The ability of SFV to provide functional cytokines and infect tumor cells but not macrophages suggests that SFV may be very useful for cancer immunotherapy employing tumor-infiltrating macrophages.

Author Info: (1) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Cancer Gene Therapy Group, Latvian Biomedical Research and Study

Author Info: (1) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia. (2) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Department of Biosciences, University of Oslo, Oslo, Norway. (3) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (4) Department of Laboratory Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (5) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (6) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (7) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (8) Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia.

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TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma

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Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor alpha (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.

Author Info: (1) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. (2) INSERM UMR 1037, CRCT, 31037, Toulouse, France

Author Info: (1) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. (2) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. (3) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. (4) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. (5) Institut Universitaire du Cancer, 31059, Toulouse, France. (6) Institut Universitaire du Cancer, 31059, Toulouse, France. (7) Institut Universitaire du Cancer, 31059, Toulouse, France. (8) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. (9) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. Laboratoire de Biochimie, Institut Federatif de Biologie, CHU Purpan, 31059, Toulouse, France. (10) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. Institut Universitaire du Cancer, Toulouse, Hopital Larrey et Oncopole, 31059, Toulouse, France. (11) INSERM UMR 1037, CRCT, 31037, Toulouse, France. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. (12) INSERM UMR 1037, CRCT, 31037, Toulouse, France. bruno.segui@inserm.fr. Equipe Labellisee Ligue Contre Le Cancer, 31037, Toulouse, France. bruno.segui@inserm.fr. Universite Toulouse III - Paul Sabatier, 31062, Toulouse, France. bruno.segui@inserm.fr. Universite Federale de Toulouse Midi-Pyrenees, 41 Allee Jules Guesde, 31000, Toulouse, France. bruno.segui@inserm.fr.

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Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIM(SM) registry

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BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM(SM) registry data base from 2008 to 2016 (NCT01415167, August 9, 2011). METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIM(SM) patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact. CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

Author Info: (1) Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR, 97213, USA. (2) Moores Cancer Center, University of California San Diego, 9500 Gilman Drive

Author Info: (1) Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR, 97213, USA. (2) Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. (3) Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. (4) Loyola University Medical Center, 2160 S First Avenue, Maywood, IL, 60153, USA. (5) Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. (6) Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, 46202, USA. (7) Primary Biostatistical Solutions, 2042 Carnarvon Ct, Victoria, BC, V8R2V3, Canada. (8) Primary Biostatistical Solutions, 2042 Carnarvon Ct, Victoria, BC, V8R2V3, Canada. (9) Prometheus Laboratories, 9410 Carroll Park Drive, San Diego, CA, 92121, USA. (10) Prometheus Laboratories, 9410 Carroll Park Drive, San Diego, CA, 92121, USA. (11) Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27705, USA. (12) MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. (13) Cancer Research Foundation of NY, 43 Longview Lane, Chappaqua, NY, 10514, USA. jpd4401@aol.com.

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Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

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BACKGROUND: Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT(R)) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas. METHODS: We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted. RESULTS: Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0-1 in 48 patients (96%); median number of prior therapies was 3 (0-12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9-3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%). CONCLUSION: Immunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted.

Author Info: (1) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Author Info: (1) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (3) Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (4) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (5) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (6) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (7) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (8) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (9) Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (10) Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (11) Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (12) Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (13) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. (14) Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Unit 455, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. VSubbiah@mdanderson.org.

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The current status of immunobased therapies for metastatic renal-cell carcinoma

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The management of metastatic renal-cell carcinoma (mRCC) represents an important clinical challenge. Since being approved in the early 1990s, aspecific immunotherapy has been a mainstay of treatment for mRCC and the only therapy that has demonstrated long-term cures for mRCC. However, in recent times there have been landmark advances made in the field of specific immunotherapy for a number of malignancies, including kidney cancer. This review outlines the range of immunobased agents currently available for the treatment of mRCC.

Author Info: (1) Department of Urology. (2) Department of Urology. (3) Department of Urology. Masonic Cancer Center. (4) Department of Urology. Masonic Cancer Center. (5) Masonic Cancer

Author Info: (1) Department of Urology. (2) Department of Urology. (3) Department of Urology. Masonic Cancer Center. (4) Department of Urology. Masonic Cancer Center. (5) Masonic Cancer Center. Division of Hematology, Oncology, and Transplantation. (6) Department of Urology. Masonic Cancer Center. (7) Department of Urology. Masonic Cancer Center. Center for Immunology. Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA.

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Evolution of the magic bullet: Single chain antibody fragments for the targeted delivery of immunomodulatory proteins

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Immunocytokines are fusion proteins that combine the specific antigen binding capacities of an antibody or derivative thereof and the potent bioactivity of a cytokine partner. These novel biopharmaceuticals have been directed to various targets of oncological as well as non-oncological origin and a handful of promising constructs are currently advancing in the clinical trial pipeline. Several factors such as the choice of a disease specific antigen, the antibody format and the modulatory nature of the payload are crucial, not only for therapeutic efficacy and safety but also for the commercial success of such a product. In this review, we provide an overview of the basic principles and obstacles in immunocytokine design with a specific focus on single chain antibody fragment-based constructs that employ interleukins as the immunoactive component. Impact statement Selective activation of the immune system in a variety of malignancies represents an attractive approach when existing strategies have failed to provide adequate treatment options. Immunocytokines as a novel class of bifunctional protein therapeutics have emerged recently and generated promising results in preclinical and clinical studies. In order to harness their full potential, multiple different aspects have to be taken into consideration. Several key points of these fusion constructs are discussed here and should provide an outline for the development of novel products based on an overview of selected formats.

Author Info: (1) 1 School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia. (2) 2 Inflammatory Diseases Biology and Therapeutics, Mater

Author Info: (1) 1 School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia. (2) 2 Inflammatory Diseases Biology and Therapeutics, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia. (3) 2 Inflammatory Diseases Biology and Therapeutics, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia. (4) 1 School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia. 3 Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, St. Lucia, QLD 4072, Australia.

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