Begell House Inc.
Onco Therapeutics
OT
2694-4642
5
1-2
2014
Eulogy for My Friend Michio Nishida
iv
10.1615/ForumImmunDisTher.2015014035
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Michio Nishida
Memoriam
In Memoriam: Michio Nishida
v-vi
10.1615/ForumImmunDisTher.2015014046
Roland
Newman
Tanabe Research Labs USA, 4540 Towne Centre Court, San Diego, California 92121
In Memoriam of My Friend Michio Nishida
vii
10.1615/ForumImmunDisTher.2015014076
Nabil
Hanna
None
Preface: New Immunological Approaches to Cancer Therapy Dedicated to Dr. Michio Nishida
viii-ix
10.1615/ForumImmunDisTher.2015014036
Roland
Newman
Tanabe Research Labs USA, 4540 Towne Centre Court, San Diego, California 92121
Rituxan: The First 20 Years
1-5
10.1615/ForumImmunDisTher.2015013931
Roland
Newman
Tanabe Research Labs USA, 4540 Towne Centre Court, San Diego, California 92121
antibody
cancer
CD20
non-Hodgkin's lymphoma
Rituxan
rituximab
Rituximab (Rituxan) was the first chimeric monoclonal antibody approved by the Food and Drug Administration (FDA) and the first approved for the treatment of cancer. Since then, combination therapy with various chemotherapeutic agents has increased response rates in lymphoma to almost 100% and has resulted in many cures. After its approval in 1997 for "relapsed or refractory, B-cell, low-grade, or follicular non-Hodgkin's lymphoma", Rituxan has subsequently been approved for other hematological indications as well as for use in several autoimmune diseases, including rheumatoid arthritis. Not only was Rituxan successful in treating lymphoma, but it also overcame the prevailing myth at that time, that monoclonal antibodies were not useful as therapeutics. It also opened the door for future development of many more monoclonal antibodies for treating cancer.
CD20 and Its Antibodies: Past, Present, and Future
7-23
10.1615/ForumImmunDisTher.2015014073
Robert J.
Oldham
The Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, General Hospital, Southampton, SO16 6YD, UK.
Kirstie L.S.
Cleary
The Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, General Hospital, Southampton, SO16 6YD, UK.
Mark S.
Cragg
The Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, General Hospital, Southampton, SO16 6YD, UK.
ADCC
ADCP
CD20
FcγR
lymphoma
Rituxan
rituximab
The pan B-cell marker CD20 was cloned more than 3 decades ago. It has been intensively studied ever since, allowing the specific identification and targeting of B cells facilitating the development of antibody-mediated immunotherapy. In this review, we document the current understanding of how CD20 regulates B-cell biology. We also describe the emerging knowledge of how anti-CD20 antibodies elicit their therapeutic responses, revealing how this has changed and matured throughout the decades of their use.
The New Generation of Antibody Drug Conjugates
25-45
10.1615/ForumImmunDisTher.2015013964
Vincent
Blot
Tanabe Research Laboratories USA Inc., San Diego CA 92121
Robyn
Richardson
Tanabe Research Laboratories USA Inc., San Diego CA 92121
Julia
Coronella
Tanabe Research Laboratories USA Inc., San Diego CA 92121
ADC
antibody drug conjugate
auristatin
conjugation
linker
maytansine
off-target toxicity
on-target toxicity
pyrrolobenzodiazepine
site-directed conjugation
toxin
The concept of antibody drug conjugates (ADCs) has existed for some decades, but advances in toxin and linker technology and improved target selection have only recently enabled the construction of molecules with significant clinical activity. Like all oncology drugs, the current generation of ADCs was built on the successes of the previous generation, with improvements in their liabilities. In many cases, the ADCs now in the clinic have impressive efficacy, but there is clearly room for future improvements to extend the therapeutic index and the duration and breadth of clinical responses. In this review, we examine emerging concepts based on recent data and technologies that may provide the basis of increased clinical efficacy.
Adoptive Immunotherapy of Cancer Using Chimeric Antigen Receptor−Engineered T Cells
47-67
10.1615/ForumImmunDisTher.2015013955
Daniela
Achkova
King's College London, King's Health Partners Integrated Cancer Centre, Department of Research Oncology, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK
John
Maher
King's College London, King's Health Partners Integrated Cancer Centre, Department of Research Oncology, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK; Department of Immunology, Barnet Hospital, Royal Free London NHS Foundation Trust, Barnet
adoptive immunotherapy
cancer
chimeric antigen receptor
leukemia
lymphoma
The use of chimeric antigen receptors (CARs) to redirect T cells against tumor-associated antigen targets is a powerful new approach to cancer immunotherapy. Recently, published phase I clinical trials and case reports suggest that this strategy has the potential to transform modern management of patients with B-cell-derived hematologic malignancies. Indeed, few precedents for novel therapies have achieved comparable therapeutic efficacy when evaluated for the first time in patients with otherwise untreatable malignant disease. One of several arising questions is how this impressive "proof of concept" can be extended to the treatment of solid tumors, which account for the vast majority of the cancer burden. Additional issues about the safety and potential for widespread use of this approach also remain to be addressed. Here, we summarize recent developments in the preclinical and early-phase clinical evaluation of CAR T-cell immunotherapy. We also discuss some of the obstacles to the broader clinical development of this exciting new therapeutic modality and how current preclinical studies are attempting to address these shortcomings.
Checkpoint Modulators in Cancer Immunotherapy
69-82
10.1615/ForumImmunDisTher.2015013940
Jean
Sathish
MRC Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
antibodies
cancer therapy
checkpoint activators
checkpoint inhibitors
CTLA-4
cytotoxic T cells
immunosuppression
PD-1
Enhancing the T-cell-mediated immune response against cancers is currently an attractive therapeutic approach, particularly for cancers that are intractable to conventional chemotherapy. Immune checkpoints are molecules that control the degree of T-cell activation and effector functions. These checkpoint molecules are comprised of costimulatory receptors (e.g., 4-1BB, glucocorticoid-induced T-cell-receptor [GITR]-related [protein], and OX40), co-inhibitory receptors (e.g., programmed cell death-1 [PD-1], cytotoxic T-lymphocyte-associated protein-4 [CTLA-4,] and T-cell immunoglobulin mucin-3 [TIM-3]), and enzymes (e.g., indoleamine 2,3-dioxygenase [IDO] and CD73). There has been a surge in the development of antibody- (and small-molecule)-based therapy aimed at enhancing the antitumor T-cell response by targeting immune checkpoints. The clinical experience with modulators of CTLA-4 and PD-1 has been highly positive and has stimulated the development of modulators of other immune checkpoints. This review describes the role of some key checkpoint molecules in governing the antitumor immune response and assesses the evidence for the therapeutic utility of checkpoint modulation. The rationale for combining a checkpoint modulator with other approaches (such as chemotherapy or radiation) or indeed with other checkpoint modulators is discussed. The safety concerns that arise with checkpoint modulation and the strategies used to mitigate safety risk are also considered. Finally, the challenges in the development and clinical deployment of safe, new checkpoint modulators are outlined.
Immunocytokines for Cancer Therapy
83-99
10.1615/ForumImmunDisTher.2015014013
Philipp
Probst
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), CH-8093 Zurich, Switzerland
Dario
Neri
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), CH-8093 Zurich, Switzerland
Cancer
cytokines
immunocytokines
immunotherapy
monoclonal antibodies
The ability of cytokines to boost the immune system's activity against tumors has been of pharmaceutical interest for many years, and a number of different cytokines have been investigated in clinical trials. However, complete cures were rarely observed upon systemic administration of recombinant cytokine products, because severe dose-limiting toxicities and unfavorable pharmacokinetic properties prevented the escalation to therapeutically relevant dose regimens. Antibody-cytokine fusion proteins (termed immunocytokines) represent an elegant strategy to improve the therapeutic index of cytokine payloads. The immunoglobulin moiety, used either as a full-size monoclonal antibody or an antibody fragment, serves as a selective delivery vehicle to the site of disease, thereby allowing a preferential accumulation in the malignant environment while sparing healthy tissue. In the past few years, a large number of immunocytokines have been developed and tested in preclinical cancer models, and 10 immunocytokines have further been evaluated in clinical trials for oncological indications. In this review, we discuss the main structural and functional features of immunocytokines, which are relevant for in vivo performance, and outline emerging trends for product development.
Alternative Scaffolds as Therapeutics in Cancer and Other Diseases
101-114
10.1615/ForumImmunDisTher.2015014027
Ulrich
Wuellner
Covagen AG, a Janssen Pharmaceutical Companies of Johnson & Johnson, CH-8952 Zurich-Schlieren, Switzerland
Dragan
Grabulovski
Covagen AG, a Janssen Pharmaceutical Companies of Johnson & Johnson, CH-8952 Zurich-Schlieren, Switzerland
oncology
protein engineering
scaffold
selection
Alternative scaffold proteins are a growing class of engineered binding proteins that can be identified using modern protein-engineering technologies. From large combinatorial libraries, high-quality binders can be generated essentially against any target protein of interest. Typically, these binding proteins have favorable properties in terms of size, stability, or ease of production. In this review, we focus on alternative scaffold binders for applications mainly in oncology. We highlight recent advances in the field and provide a perspective on the potentials and challenges in the drug development process of these molecules.