Eye (2018) 32, 287–301 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0950-222X/18 www.nature.com/eye 1,2,3 4 Neuro-ophthalmic side MT Bhatti and AKS Salama REVIEW effects of molecularly targeted cancer drugs Abstract The past two decades has been an amazing time culminated in indescribable violence and in the advancement of cancer treatment. Mole- unspeakable death. However, amazingly within cularly targeted therapy is a concept in which the confines of war have risen some of the specific cellular molecules (overexpressed, greatest advancements in medicine. It is within mutationally activated, or selectively expressed this setting—in particular World War II with the proteins) are manipulated in an advantageous study of mustard gas—that the annals of cancer manner to decrease the transformation, prolif- chemotherapy began touching the lives of eration, and/or survival of cancer cells. In millions of people. It is estimated that in 2016, addition, increased knowledge of the role of the over 1.6 million people in the United States will immune system in carcinogenesis has led to the be diagnosed with cancer and over a half a development of immune checkpoint inhibitors million will die.1 The amount of money being to restore and enhance cellular-mediated anti- spent on research and development of new tumor immunity. The United States Food and cancer therapies is staggering with a record $43 Drug Administration approval of the chimeric billion dollars spent in 2014. Nearly 30% of all monoclonal antibody (mAb) rituximab in 1997 registered clinical trials on the clinicaltrials.gov 1Department of for the treatment of B cell non-Hodgkin lym- website pertain to cancer drugs. Such large Ophthalmology, Duke Eye phoma ushered in a new era of targeted therapy numbers emphasize the urgency of finding a Center, Durham, NC, USA for cancer. A year later, trastuzumab, a huma- cure for cancer. 2 nized mAb, was approved for patients with In the context of co-morbid systemic diseases Department of Neurology, breast cancer. In 2001, imatinib was the first Duke University Medical and patient expectations, the oncologist has a Center, Durham, NC, USA small-molecule kinase inhibitor approved. The wide variety of treatment options to choose from — fi approval of ipilimumab the rst in class based on the histological type, molecular 3Department of — immune checkpoint inhibitor in 2011 serves as marker, and clinical stage of cancer (Table 1). Neurosurgery, Duke a landmark period of time in the resurgence of Since its first clinical application in the early University Medical Center, immunotherapy for cancer. Despite the notion 1940s, cytotoxic chemotherapy has been the Durham, NC, USA that increased tumor specificity results in mainstay of medical treatment for cancer. 4 decreased complications, toxicity remains a Department of Medicine, However, in the past two decades treatment Division of Medical major hurdle in the development and imple- options have expanded dramatically for many Oncology, Duke Cancer mentation of many of the targeted anticancer cancers, allowing oncologists to provide an Center, Durham, NC, USA drugs. This article will provide an overview of increasingly personalized approach.2 Much has the current cellular and immunological under- been learned about normal cell development, Correspondence: – MT Bhatti, Departments of standing of cancer pathogenesis the foundation differentiation, survival, proliferation, and Ophthalmology, Neurology upon which molecularly targeted therapies were ultimate death; which has in turn increased – and Neurosurgery, 2351 developed and a description of the ocular and our knowledge and understanding of Erwin Road, Duke fi neuro-ophthalmic toxicity pro le of mAbs, carcinogenesis. However, there is still much that University Eye Center, immune checkpoint inhibitors, and small- is not understood about the epigenetic DUMC 3802, Durham, NC molecule kinase inhibitors. 27710-3802, USA mechanisms in cellular transformation to + Eye (2018) 32, 287–301; doi:10.1038/eye.2017.222; Tel: 1 919 681 9191; immortality and the complicated interplay Fax: +1 919 684 0547. published online 20 October 2017 between the immune system and cellular E-mail: tariq.bhatti@duke. regulation. It should also be kept in mind that edu the financial impact of targeted cancer therapies has been enormous both in terms of sales (profit) Received: 23 February 2017 Introduction 3 Accepted in revised form: 31 and health care cost. July 2017 War is a recurrent and unfortunate record in the Efficacy is a major goal in cancer drug Published online: history of human civilization that has development. However, safety and toxicity often 20 October 2017 Neuro-ophthalmic side effects of new cancer drugs MT Bhatti and AKS Salama 288 Table 1 Category of cancer therapies of molecularly targeted therapy in cancer.9 Aside from surface receptors, other targets for this novel approach Bolded categories represent therapy modalities discussed in text include intracellular signal proteins and metabolic I. Radiotherapy molecules. Targeted therapy not only affects tumor cells II. Surgery but also immune cells (ie, T and B cells) and vascular- III. Standard (traditional) cytotoxic chemotherapy stromal cells.2,10 IV. Molecularly targeted therapy • Monoclonal antibody ○ Unconjugated (naked) Monoclonal antibodies ○ Conjugated (antibody–drug conjugate) ○ fi Bispeci c The clinical development of mAbs began in earnest in 1972 • Small-molecule kinase inhibitors when Kohler and Meilstein published their ground breaking • Hormonal therapy 11 • Antisense oligodeoxynucleotide technique of producing murine mAbs. This was followed in • Recombinant peptide 1987 with the generation of a chimeric mAb.12 With the use of • Recombinant IgG immunotoxin XenoMouse technology, panitumumab was the first human V. Immunotherapy mAb approved for use in 2006.13 A variety of mAbs exist • Immune checkpoint inhibitors including uncongugated (naked), conjugated (attached to • Biologics Cytokines (ie, interferon, interleukin) • Cell-based therapies effector molecules such as cytotoxic drug, bacterial or plant • Vaccines toxin, or radiopharmaceutical agents),14 and bispecific.15 • Adoptive cellular transfer Other antibody products include antibody-ligand fusion • Oncolytic virus proteins16 and immunoliposomes.14 The nomenclature of mAbs follows a very specific characterization scheme.17 The lead to either limited use of a drug or prevent the elements that make up an antibody name are prefix+target/ utilization of a drug in clinical practice. Despite a very disease class infix+source infix+stem. Some commonly used fi ’ arduous, comprehensive and costly process of drug target/disease class in x s include -tu/-t for tumors, -li/-l for fi research and development culminating in approval by the immunomodulatory, and -ba/-b for bacterial. The source in x – United States Food and Drug Administration (FDA),4 the can be zu for humanized, -o for mouse, -u for fully human, – reporting of adverse events (AEs) from clinical trials and or -xi for chimeric. The stem is either mab for monoclonal or – other databases remains inconsistent and often difficult to pab for polyclonal. interpret.5,6 In a study that reviewed the results of The use of mAbs has become one of the cornerstone treatments in the fight against cancer. There are randomized control trials (RCTs) and updated package currently14 FDA-approved mAbs (not including the inserts (drug label) of targeted cancer drugs, nearly 40% immune checkpoint inhibitors) on the market (Table 2).18 of serious AEs were not published in the initial RCT paper It has been estimated that by the year 2020 the world- and ~ 50% of the serious AEs were not included in the wide sales of mAbs will be approximately $125 billion.19 initial package insert.7 The financial and medical burden The mechanism of action (MOA) by which mAbs exert of cancer drug toxicity and AEs is enormous.8 In many their anticancer effects is varied and includes apoptosis, cases it can be difficult to ascertain the true cause and activation or inhibition of a surface cell receptor, effect of an AE because of its rarity and the fact that there antibody-dependant cellular cytotoxicity (ADCC), and — may be confounding factors such as the combination of complement-dependant cytotoxicity (CDC). In addition — medical or radiation therapy in the treatment regimen of mAbs can target tumor cells, immune cells (ie, T-cell or B patients. cell) or vascular/stromal cells.16,20,21 This review article aims to provide an overview of the The toxicity or AEs of a particular mAb is primarily current cellular and immunological understanding of related to its MOA and/or the unintended targeting of a — carcinogenesis the foundation upon which molecularly cell or organ system.22 Toxicity can be limited if the mAb — targeted therapies were developed within the is directed at a specific target on the neoplastic cell framework of discussing the ocular and neuro- without affecting normal or healthy cells. The four general ophthalmic toxicity profile of selected monoclonal categories of mAb associated AEs are immune reaction antibodies (mAbs), immune checkpoint inhibitors, and (infusion reaction), excessive cytokine release or storm, small-molecule kinase inhibitors. immunosuppression, and autoimmunity.22,23 In general terms, the ocular toxicity profile of mAbs is good. Several review papers have summarized the ocular Molecularly targeted therapy – AEs reported with mAbs.24 28 Neurological side effects The approval of the first