Journal Articles

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

PURPOSE: Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ES-SCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiation therapy (TRT) after induction chemotherapy for SCLC. METHODS: ES-SCLC patients who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity (DLTs) in the 35 days following initiation of treatment. RESULTS: Thirty-eight ES-SCLC patients (median age 65 years, range, 37-79) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100-200 mg with no DLTs in the 35-day window. There were no grade 4-5 toxicities; two (6%) experienced grade 3 events (n=1 rash, n=1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range 1-13); median progression-free and overall survival were 6.1 months (95% confidence interval [CI] 4.1-8.1) and 8.4 months (95% CI 6.7-10.1). CONCLUSIONS: Concurrent pembrolizumab-TRT was tolerated well, with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g. enrolling progressors on induction chemotherapy). Although randomized studies have illustrated benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.

Author Info: (1) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: jwelsh@mdanderson.org. (2) Department of Thoracic Head & N

Author Info: (1) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: jwelsh@mdanderson.org. (2) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (3) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, JN, CN. (4) Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA. (5) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (6) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. (7) Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX. (8) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (9) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (10) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (11) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (12) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (13) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (14) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (15) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (16) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (17) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (18) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (19) Department of Thoracic Head & Neck Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Neoantigen Dissimilarity to the Self-Proteome Predicts Immunogenicity and Response to Immune Checkpoint Blockade

Despite improved methods for MHC affinity prediction, the vast majority of computationally predicted tumor neoantigens are not immunogenic experimentally, indicating that high-quality neoantigens are beyond current algorithms to discern. To enrich for neoantigens with the greatest likelihood of immunogenicity, we developed an analytic method to parse neoantigen quality through rational biological criteria across five clinical datasets for 318 cancer patients. We explored four quality metrics, including analysis of dissimilarity to the non-mutated proteome that was predictive of peptide immunogenicity. In patient tumors, neoantigens with high dissimilarity were unique, enriched for hydrophobic sequences, and correlated with survival after PD-1 checkpoint therapy in patients with non-small cell lung cancer independent of predicted MHC affinity. We incorporated our neoantigen quality analysis methodology into an open-source tool, antigen.garnish, to predict immunogenic peptides from bulk computationally predicted neoantigens for which the immunogenic "hit rate" is currently low.

Author Info: (1) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic

Author Info: (1) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rhv@upenn.edu. (3) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rech@rech.io.

Preclinical models of breast cancer: Two-way shuttles for immune checkpoint inhibitors from and to patient bedside

The Food and Drug Administration has lately approved atezolizumab, anti-programmed death ligand 1 (PD-L1), to be used together with nanoparticle albumin-bound (nab) paclitaxel in treating patients with triple negative breast cancer (BC) expressing PD-L1. Nonetheless, immune checkpoint inhibitors (ICIs) are still challenged by the resistance and immune-related adverse effects evident in a considerable subset of treated patients without conclusive comprehension of the underlying molecular basis, biomarkers and tolerable therapeutic regimens capable of unleashing the anti-tumour immune responses. Stepping back to preclinical models is thus inevitable to address these inquiries. Herein, we comprehensively review diverse preclinical models of BC exploited in investigating ICIs underscoring their pros and cons as well as the learnt and awaited lessons to allow full exploitation of ICIs in BC therapy.

Author Info: (1) Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams Universi

Author Info: (1) Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: AmalAbdel-Aziz@pharma.asu.edu.eg. (2) Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Faculty of Biotechnology, October University for Modern Sciences and Arts, 6th October City, Cairo, Egypt. (3) Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy. (4) Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. (5) Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. (6) Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy. Electronic address: giuseppe.curigliano@ieo.it. (7) Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy. Electronic address: saverio.minucci@ieo.it.

Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor

Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4(+) and CD8(+) T cells, and Tregs, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.

Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA. Electronic address: eruffo@pitt.edu. (2) Department of Immuno

Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA. Electronic address: eruffo@pitt.edu. (2) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA; Division of Hematology-Oncology, UPMC Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA; Hematology/Oncology Fellowship Program, University of Pittsburgh Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA. Electronic address: wurc@upmc.edu. (3) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Electronic address: tbruno@pitt.edu. (4) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Electronic address: cworkman@pitt.edu. (5) Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Electronic address: dvignali@pitt.edu.

CTLA-4 (CD152): A versatile receptor for immune-based therapy

Coreceptor-based immunotherapy is a rapidly developing approach to treat cancer patients. Among those targeted receptors, CTLA-4 is the primary attenuator of adaptive immune responses and the most prominent and extensively investigated molecule in this field. CTLA-4 is involved in broad range of mechanisms that regulate and control immune cell functions and therefore provides versatile strategies for therapeutic interventions. Despite being successfully harnessed in clinical treatments the different facets of CTLA-4 biology still remain incompletely understood. Here, we review the various aspects of CTLA-4 functions and CTLA-4-based immunotherapies and discuss challenges to improve current approaches.

Author Info: (1) Department of Experimental Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 4

Author Info: (1) Department of Experimental Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. (2) Department of Experimental Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Electronic address: monika.brunner-weinzierl@med.ovgu.de.

Tim-3: A co-receptor with diverse roles in T cell exhaustion and tolerance

T cell inhibitory co-receptors play a crucial role in maintaining the balance between physiologic immune responses and maladaptive ones. T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is a unique inhibitory co-receptor in that its expression is chiefly restricted to interferon (IFN)gamma-producing CD4(+) and CD8(+) T cells. Early reports firmly established its importance in maintaining peripheral tolerance in transplantation and autoimmunity. However, it has become increasingly clear that Tim-3 expression on T cells, together with other check-point molecules, in chronic infections and cancers can hinder productive immune responses. In this review, we outline what is currently known about the regulation of Tim-3 expression, its ligands and signaling. We discuss both its salutary and deleterious function in immune disorders, as well as the T cell-extrinsic and -intrinsic factors that regulate its function.

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, 60 Fenwood Rd., Boston, MA, 021

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, 60 Fenwood Rd., Boston, MA, 02115, USA. (2) Department of Neurosciences, Centre de Recherche du CHU de Quebec - Universite Laval, Pavillon CHUL, 2705 Boul Laurier, Quebec City, QC, G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, 1050 Ave de la Medecine, Quebec City, Canada. (3) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, 60 Fenwood Rd., Boston, MA, 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu.

Cellular therapy approaches harnessing the power of the immune system for personalized cancer treatment

Cancer development often implies failure of the immune system to recognize tumor antigens and kill malignant cells. While the whole immune cell repertoire is broad, that of immune cells with the ability to react to individual tumor antigens is usually very limited. The purpose of cancer immunotherapy is to augment the power, quantitative and qualitative, of the immune system such that it readily recognizes and eliminates cancer cells. As immune therapy is shifting toward more personalized medicine, different types of tumor antigens can be used as target antigens to allow T cells to destroy tumor cells. These antigens are mostly defined as tumor associated antigens (TAA), neoantigens or minor histocompatibility antigens. Their clinical usage involve either direct injection of TAA and neoantigens, administration of peptide-loaded dendritic cells in vaccination approaches, or infusion of ex vivo expanded tumor-specific T cells. However, such cellular therapies are facing several challenges including immune suppressive tumor microenvironment, lack of persistence of ex vivo expanded antigen specific T cells and potential off-target toxicity of these therapies. In this review, we will discuss recent advances allowing for better expansion of tumor reactive T cells and novel strategies used to overcome the challenges facing cellular therapy for cancer.

Author Info: (1) Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, Canada; Department of Medicine, Universite de Montreal, Montreal, Canada. (2) Division

Author Info: (1) Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, Canada; Department of Medicine, Universite de Montreal, Montreal, Canada. (2) Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, Canada; Department of Medicine, Universite de Montreal, Montreal, Canada. (3) Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, Canada; Department of Medicine, Universite de Montreal, Montreal, Canada; Department of Microbiology, Infectiology and Immunology, Universite de Montreal, Canada. (4) Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, Canada; Department of Medicine, Universite de Montreal, Montreal, Canada. Electronic address: denis-claude.roy@umontreal.ca.

Common gamma chain cytokines and CD8 T cells in cancer

Overcoming exhaustion-associated dysfunctions and generating antigen-specific CD8 T cells with the ability to persist in the host and mediate effective long-term anti-tumor immunity is the final aim of cancer immunotherapy. To achieve this goal, immuno-modulatory properties of the common gamma-chain (gammac) family of cytokines, that includes IL-2, IL-7, IL-15 and IL-21, have been used to fine-tune and/or complement current immunotherapeutic protocols. These agents potentiate CD8 T cell expansion and functions particularly in the context of immune checkpoint (IC) blockade, shape their differentiation, improve their persistence in vivo and alternatively, influence distinct aspects of the T cell exhaustion program. Despite these properties, the intrinsic impact of cytokines on CD8 T cell exhaustion has remained largely unexplored impeding optimal therapeutic use of these agents. In this review, we will discuss current knowledge regarding the influence of relevant gammac cytokines on CD8 T cell differentiation and function based on clinical data and preclinical studies in murine models of cancer and chronic viral infection. We will restate the place of these agents in current immunotherapeutic regimens such as IC checkpoint blockade and adoptive cell therapy. Finally, we will discuss how gammac cytokine signaling pathways regulate T cell immunity during cancer and whether targeting these pathways may sustain an effective and durable T cell response in patients.

Author Info: (1) Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Faculty of Medicine, Univer

Author Info: (1) Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. (2) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada. (4) Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. Electronic address: helene.decaluwe@umontreal.ca.

VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity

V-domain Ig suppressor of T cell activation (VISTA) is a novel checkpoint regulator with limited homology to other B7 family members. The constitutive expression of VISTA on both the myeloid and T lymphocyte lineages coupled to its important role in regulating innate and adaptive immune responses, qualifies VISTA to be a promising target for immunotherapeutic intervention. Studies have shown differential impact of agonistic and antagonistic targeting of VISTA, providing a unique landscape for influencing the outcome of cancer and inflammatory diseases.

Author Info: (1) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, United States. (2) Department of Microbiolog

Author Info: (1) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, United States. (2) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, United States. (3) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, United States; Immunext Corp., Lebanon, NH, United States. Electronic address: Randolph.J.Noelle@dartmouth.edu. (4) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, United States. Electronic address: Janet.L.Lines@dartmouth.edu.

Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-target Effects with Reduced Off-tumor Toxicity for Use in Immuno-Oncology

The deep and durable antitumor effects of antibody-based immunotherapies such as immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the therapeutic landscape for many cancers. Several anti-programmed death receptor 1 and anti-programmed death receptor ligand 1 antibodies have been approved for use in advanced solid tumors, including melanoma, non-small cell lung cancer (NSCLC), bladder cancer, and other cancers. ICIs are under development across many tumor types and preliminary results are compelling. However, ICIs have been associated with severe immune-related adverse events (irAEs), including rash, diarrhea, colitis, hypophysitis, hepatotoxicity, and hypothyroidism, which in some cases lead to high morbidity, are potentially life-threatening, and limit the duration of treatment. The incidence of severe irAEs increases further when programmed cell death-1 and programmed cell death ligand-1 inhibitors are combined with anti-CTLA-4 and/or other multi-drug regimens. Probody therapeutics, a new class of recombinant, proteolytically activated antibody prodrugs are in early development and are designed to exploit the hallmark of dysregulation of tumor protease activity to deliver their therapeutic effects within the tumor microenvironment (TME) rather than peripheral tissue. TME targeting, rather than systemic targeting, may reduce irAEs in tissues distant from the tumor. Probody therapeutic technology has been applied to multiple antibody formats, including immunotherapies, Probody drug conjugates, and T-cell-redirecting bispecific Probody therapeutics. In preclinical models, Probody therapeutics have consistently maintained anti-cancer activity with improved safety in animals compared with the non-Probody parent antibody. In the clinical setting, Probody therapeutics may expand or create therapeutic windows for anti-cancer therapies.

Author Info: (1) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center autiok@mskcc.org. (2) Department of Oncology, START Madrid-CIOCC HM University Ho

Author Info: (1) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center autiok@mskcc.org. (2) Department of Oncology, START Madrid-CIOCC HM University Hospital Sanchinarro. (3) Immuno-oncology Department, CytomX Therapeutics, Inc. (4) Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center.

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