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Monoclonal Antibodies

The immune system produces antibodies when we are exposed to infections and other antigens. When exposed to the same antigen again, these antibodies will recognise it and the immune system can fight it more quickly. Monoclonal antibodies are antibodies made in a laboratory and are designed to attach to receptors on the surface of cancer cells. As such they are more targeted to the cancer cells compared to standard chemotherapy drugs, which are toxic to the body's healthy cells and tissues.

There are different types of monoclonal antibodies and approaches to using them in cancer treatment (some are still at the early stages of evaluation in laboratory and clinical studies). For example they may:

  • signal the body´s immune system to attack the cancer cells
  • cause the cell to destroy itself (apoptosis)
  • block the receptor from binding with another protein, stopping cancer cell growth
  • be used with in conjunction with chemotherapy drugs or radioactive substances which bind to the monoclonal antibody; delivering the treatment direct to the cancer cell.
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Web Resources: Monoclonal antibodies
Latest Research Publications
Cetuximab (Erbitux)
Gemtuzumab (Mylotarg)
Iodine131 tositumomab (Bexxar)
Ipilimumab (Yervoy)
Obinutuzumab (Gazyva)
Panitumumab (Vectibix)
Rituximab (Mabthera)
Trastuzumab (Herceptin)
90Y-Ibritumomab tiuxetan (Zevalin)

Web Resources: Monoclonal antibodies (4 links)

Latest Research Publications

Zappasodi R, Sirard C, Li Y, et al.
Rational design of anti-GITR-based combination immunotherapy.
Nat Med. 2019; 25(5):759-766 [PubMed] Related Publications
Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses

Sanchez-Correa B, Lopez-Sejas N, Duran E, et al.
Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy.
Cancer Immunol Immunother. 2019; 68(5):861-870 [PubMed] Related Publications
The incidence of some types of tumours has increased progressively in recent years and is expected to continue growing in the coming years due in part to the aging of the population. The design of new therapies based on natural killer (NK) cells opens new possibilities especially for the treatment of elderly patients who are particularly susceptible to the toxicity of conventional chemotherapy treatments. In recent years, the potential use of NK cells in cancer immunotherapy has been of great interest thanks to advances in the study of NK cell biology. The identification of key points (checkpoints) in the activation of NK cells that can be regulated by monoclonal antibodies has allowed the design of new therapeutic strategies based on NK cells. However, there are still limitations for its use and the first clinical trials blocking KIR inhibitory receptors have shown little efficacy by inhibiting the maturation of NK cells. Blockade of other inhibitory receptors such as TIGIT, TIM3, LAG3 and PD1 may represent novel strategies to increase NK function in cancer patients. Altogether, the identification of NK cell and tumour cell markers of resistance or susceptibility to the action of NK cells will contribute to identifying those patients that will most likely benefit from NK cell-based immunotherapy.

Kamimura N, Wolf AM, Iwai Y
Development of Cancer Immunotherapy Targeting the PD-1 Pathway.
J Nippon Med Sch. 2019; 86(1):10-14 [PubMed] Related Publications
Immune checkpoint inhibitors are causing a paradigm shift in cancer treatment. Immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) dampen T cell activation to avoid autoimmunity and the destructive effects of an excessive inflammatory response. Immune checkpoint signaling can be exploited by tumors to escape host immune surveillance, and immune checkpoint inhibitors enhance antitumor immunity by releasing the brakes on the immune system. PD-1 was identified in 1992 by Honjo and colleagues at Kyoto University. Studies in animal models revealed that PD-1 blockade can inhibit tumorigenesis and tumor metastasis. In addition, PD-1 blockade showed fewer adverse effects than CTLA-4 blockade. Based on these findings, a humanized monoclonal antibody against human PD-1 called nivolumab was developed. Since PD-1 blockade targets lymphocytes rather than tumor cells, the therapeutic effects last longer, even if mutations occur during tumorigenesis. Furthermore, because it does not depend on specific tumor antigens, PD-1 blockade can be applied to various kinds of tumors.

Sun L, Chen L, Li H
Checkpoint-modulating immunotherapies in tumor treatment: Targets, drugs, and mechanisms.
Int Immunopharmacol. 2019; 67:160-175 [PubMed] Related Publications
Tumor immunotherapy, as a new treatment of cancer, has been developing on the basis of tumor immunology. Tumor immunotherapy stimulates and enhances the function of immune system in human bodies, in order to control and kill tumor cells. It is often used as an adjuvant therapy combined with surgery, chemotherapy, radiotherapy and other conventional methods. Cancer immunotherapies involve cells, antibodies and cytokines, etc. Some immunotherapies are widely used to activate the immune system, while some others precisely target at different tumor antigens. With the development of tumor immunotherapy, immune regulation activities of small molecules and biological agents have been gradually becoming a hot research area these years. In this review, we summarize the therapeutic targets, drugs, biologics, and their mechanisms in tumor immunotherapies.

Darvin P, Toor SM, Sasidharan Nair V, Elkord E
Immune checkpoint inhibitors: recent progress and potential biomarkers.
Exp Mol Med. 2018; 50(12):165 [PubMed] Free Access to Full Article Related Publications
Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

Marrocco I, Romaniello D, Yarden Y
Cancer Immunotherapy: The Dawn of Antibody Cocktails.
Methods Mol Biol. 2019; 1904:11-51 [PubMed] Related Publications
Since the approval of the first monoclonal antibody (mAb), rituximab, for hematological malignancies, almost 30 additional mAbs have been approved in oncology. Despite remarkable advances, relatively weak responses and resistance to antibody monotherapy remain major open issue. Overcoming resistance might require combinations of drugs blocking both the major target and the emerging secondary target. We review clinically approved combinations of antibodies and either cytotoxic regimens (chemotherapy and irradiation) or kinase inhibitors. Thereafter, we focus on the most promising and currently very active arena that combines mAbs inhibiting immune checkpoints or growth factor receptors. Clinically approved and experimental oligoclonal mixtures of mAbs targeting different antigens (hetero-combinations) or different epitopes of the same antigen (homo-combinations) are described. Effective oligoclonal mixtures of antibodies that mimic the polyclonal immune response will likely become a mainstay of cancer therapy.

Li B, Jiang Z, Xie D, et al.
Cetuximab-modified CuS nanoparticles integrating near-infrared-II-responsive photothermal therapy and anti-vessel treatment.
Int J Nanomedicine. 2018; 13:7289-7302 [PubMed] Free Access to Full Article Related Publications
Background: Photothermal therapy (PTT) has received extensive attention owing to its non-invasive nature and highly therapeutic outcomes. PTT agents and near-infrared (NIR) laser are essential elements in PTT. However, most PTT agents are composed of heavy metals, characterized by serious cytotoxicity and side effects, and NIR irradiation often damages normal tissue owing to the high dose, thus limiting the clinical application of PTT.
Purpose: In this regard, exploring new perspectives enabling more PTT agents to be enriched into the tumor and NIR laser irradiation decay in PTT is vital.
Methods: In this study, cetuximab (Ab), an anti-angiogenic antibody which targets the EGFR, was modified on CuS NPs (CuS-Ab NPs) to improve the aggregation of CuS NPs in the tumor.
Results: The cellular uptake data and the biodistribution results showed comparable accumulation of CuS-Ab NPs in tumor, thus decreasing the cytotoxicity and side effects in normal tissues. More importantly, the modification of Ab in CuS-Ab NPs impressively inhibited the formation and progression of tumor vessels, as demonstrated by immunohistochemistry staining. The introduction of anti-vessel treatment requires CuS-Ab NPs to provide weak PTT, which means that a small amount of laser energy is required, inevitably causing negligible damage to normal tissue.
Conclusion: Therefore, our tailor-made CuS-Ab NPs have promising potential in clinical applications.

Zhang M, Xia L, Yang Y, et al.
PD-1 blockade augments humoral immunity through ICOS-mediated CD4
Int Immunopharmacol. 2019; 66:127-138 [PubMed] Related Publications
Successful applications of PD-1/PD-L1 blockade in multiple cancers highlight the efficacy of immunotherapy mediated by enhancing CD8

Zhu J, Petit PF, Van den Eynde BJ
Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism.
Cancer Immunol Immunother. 2019; 68(5):835-847 [PubMed] Related Publications
Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid-derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of "cold" tumors that fail to respond to immunotherapy. Interfering with the Fas-FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy.

Zhao H, Li Y, Wei D, Luo H
The Application of Nanoparticle-Based Drug Delivery Systems in Checkpoint Blockade Cancer Immunotherapy.
J Immunol Res. 2018; 2018:3673295 [PubMed] Free Access to Full Article Related Publications
Tumor is the most serious threat to human beings. Although war against cancer has been launched over forty years, cancer treatment is still far away from being satisfactory. Immunotherapy, especially checkpoint blockade immunotherapy, is a rising star that shows a promising future. To fulfill the requirement of depleting primary tumor and inhibiting tumor metastasis and recurrence, many researchers combined checkpoint blockade immunotherapy with other treatment strategies to extend the treatment outcome. Photodynamic therapy could induce immunogenic cell death, and checkpoint blockade could further accelerate the immunity; therefore, combining these two strategies publishes many papers. Additionally, photothermal therapy and immunotherapy were also utilized for combining with checkpoint blockade, which were also reviewed in this paper. Furthermore, antibodies, siRNA, and small molecule inhibitors are developed to block the checkpoint; therefore, we categorized the papers into three sections, combination nanoparticles with checkpoint blockade antibody, combination nanoparticles with checkpoint blockade siRNA, and combination nanoparticles with small molecule checkpoint inhibitors, and related researches were summarized. In conclusion, the combination nanoparticle with checkpoint blockade cancer immunity is a promising direction that may fulfill the requirement of cancer treatment.

De Santis F, Del Vecchio M, Castagnoli L, et al.
Innovative therapy, monoclonal antibodies, and beyond: Highlights from the eighth annual meeting.
Cytokine Growth Factor Rev. 2018; 44:1-10 [PubMed] Related Publications
The eighth annual conference of "Innovative therapy, monoclonal antibodies, and beyond" was held in Milan on Jan. 26, 2018, and hosted by Fondazione IRCCS-Istituto Nazionale dei Tumori (Fondazione IRCCS INT). The conference was divided into two main scientific sessions, of i) pre-clinical assays and novel biotargets, and ii) clinical translation, as well as a third session of presentations from young investigators, which focused on recent achievements within Fondazione IRCCS INT on immunotherapy and targeted therapies. Presentations in the first session addressed the issue of cancer immunotherapy activity with respect to tumor heterogeneity, with key topics addressing: 1) tumor heterogeneity and targeted therapy, with the definition of the evolutionary Index as an indicator of tumor heterogeneity in both space and time; 2) the analysis of cancer evolution, with the introduction of the TRACERx Consortium-a multi-million pound UK research project focused on non-small cell lung cancer (NSCLC); 3) the use of anti-estrogen agents to boost immune recognition of breast cancer cells; and 4) the high degree of functional plasticity within the NK cell repertoire, including the expansion of adaptive NK cells following viral challenges. The second session addressed: 1) the effectiveness of radiotherapy to enhance the proportion of patients responsive to immune-checkpoint blockers (ICBs); 2) the use of MDSC scores in selecting melanoma patients with high probability to be responsive to ICBs; and 3) the relevance of the gut microbiome as a predictive factor, and the potential of its perturbation in increasing the immune response rate to ICBs. Overall, a picture emerged of tumor heterogeneity as the main limitation that impairs the effectiveness of anti-cancer therapies. Thus, the choice of a specific therapy based on reproducible and selective predictive biomarkers is an urgent unmet clinical need that should be addressed in order to increase the proportion of long-term responding patients and to improve the sustainability of novel drugs.

Vinay DS, Kwon BS
Harnessing immune checkpoints for cancer therapy.
Immunotherapy. 2018; 10(14):1265-1284 [PubMed] Related Publications
Immunomodulatory antibodies that directly trigger and reawaken suppressed T-cell effector function are termed 'checkpoint inhibitors'. CTLA-4 and PD-1/PD-L1 molecules are the most studied inhibitory immune check points against cancer and because of this therapeutic property have entered the clinic for treating a variety of tumor types. The results so far demonstrate a positive impact on cancer remission. Preclinical studies have demonstrated that targeting a number of other T-cell surface molecules including both positive and negative immune regulators, also possesses strong antitumor activity. Some of these molecules have already entered clinical trials. In this report, we briefly highlight the status of these immune checkpoint inhibitors and discuss their side effects and future directions for their use.

Kimiz-Gebologlu I, Gulce-Iz S, Biray-Avci C
Monoclonal antibodies in cancer immunotherapy.
Mol Biol Rep. 2018; 45(6):2935-2940 [PubMed] Related Publications
Nowadays, in cancer treatments, immunotherapy which can be classified as a cancer type specific therapy is more popular than non-specific therapy methods such as surgery, radiotherapy and chemotherapy. The main aim of immunotherapy is to enable patients' immune system to target cancer cells and destroy them. The mainly used treatment methods in cancer immunotherapy are cancer vaccines, adoptive cell therapy, cytokines and monoclonal antibodies. In this review, we discuss the immunotherapy approaches, especially monoclonal antibodies which are mostly used in cancer immunotherapy in clinical applications.

Cristescu R, Mogg R, Ayers M, et al.
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
Science. 2018; 362(6411) [PubMed] Related Publications
Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.

Wei R, Guo L, Wang Q, et al.
Targeting PD-L1 Protein: Translation, Modification and Transport.
Curr Protein Pept Sci. 2019; 20(1):82-91 [PubMed] Related Publications
Programmed death ligand 1 (PD-L1) is a cell membrane protein that binds to programmed cell death protein 1 (PD-1) on the effector T cells and transduces immunosuppressive signals. It is now clear that the expression of the PD-L1 protein on the tumor cell surface is critical for tumor cells to escape immunosuppression. At present, more attention is focused on the transcriptional regulation of PDL1 mRNA. However, PD-L1 protein is the functional unit involved in immunotherapy response. It is essential to deeply understand how this membrane protein is regulated post-transcriptionally in tumors and immune cells. In this review, we summarize the recent progress on the translation, modification and transport of PD-L1 protein.

Dahal LN, Schwarz H, Ward FJ
Hiding in Plain Sight: Soluble Immunomodulatory Receptors.
Trends Immunol. 2018; 39(10):771-774 [PubMed] Related Publications
Alternatively spliced natural soluble isoforms of immunomodulatory receptors [cytotoxic T lymphocyte antigen-4 (CTLA-4), 4-1BB, and programmed death-1 (PD-1)/PD-L1] have been overlooked in favor of their cell-surface-bound counterparts that have generated blockbuster antibodies for the treatment of cancer. We propose that the soluble variants of these receptors contribute to immune regulation and offer potential as targets for immunotherapy.

Wahid B, Ali A, Rafique S, et al.
An overview of cancer immunotherapeutic strategies.
Immunotherapy. 2018; 10(11):999-1010 [PubMed] Related Publications
Artificially boosting body's immune response is one of the most exciting, effective and promising advancements in the treatment of cancers. Cancer immunotherapeutics consist of variety of treatment approaches such as cytokine therapy, adoptive T-cell transfer therapy, and antibodies that stimulate innate and adoptive immune responses. In addition to this, development of HPV vaccine has paved way toward the development of other cancer vaccines. Checkpoint blockade inhibitors, for example, anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated antigen-4, chimeric antigen receptor T-cell therapy and monoclonal antibodies are emerging as other major breakthroughs that are highly effective against cancer. This review addresses the current status of immunotherapeutic strategies against cancer and provides baseline data for future research.

Shi Y
Regulatory mechanisms of PD-L1 expression in cancer cells.
Cancer Immunol Immunother. 2018; 67(10):1481-1489 [PubMed] Related Publications
Immunotherapy targeting the PD-L1/PD-1 pathway using antibodies is effective in the clinical treatment of a multitude of cancers. This makes research of the regulatory mechanisms of PD-1 expression in cancer cells intriguing. PD-L1 expression can be categorized into inducible expression, attributed to extrinsic factors in the microenvironment, and constitutive expression, attributed to intrinsic cancer-driving gene alteration. The mechanisms of PD-L1 expression in cancer cells operate at multiple levels, including gene amplification, chromatin modification, transcription, posttranscription, translation and posttranslation. Moreover, some open questions in this field that need to be answered in future research are proposed. Studies of regulatory mechanisms of PD-L1 expression pave the way for the application of more effective approaches in the future of cancer immunotherapy.

Lin CH, Chen KH, Chen KY, et al.
Immune checkpoint inhibitor therapy-induced hypophysitis ∼ a case series of Taiwanese patients.
J Formos Med Assoc. 2019; 118(1 Pt 3):524-529 [PubMed] Related Publications
Immune checkpoint blockade-based immunotherapy is a new modality of cancer treatment with a unique mechanism that has gained increased numbers of indication and is now used in several cancer types. However, immune-related adverse events (irAEs) emerge as a new entity of diseases involving one or multiple organ systems. irAEs could result in interruption of immunotherapy, morbidities or even death. Among various manifestations of irAEs, immune-mediated hypophysitis is rare but important, requiring prompt diagnosis and treatment to avoid life-threatening conditions. We report seven cases of immune-mediated hypophysitis in Taiwan. They suffered from various types of advanced cancer and received different regimens of immune checkpoint inhibitors. The time of onset after initiation of immunotherapy ranged from 5 to 36 weeks. All seven subjects were diagnosed of central adrenal insufficiency, while four of them had primary hypothyroidism. There was no typical finding of infiltrative hypophysitis on the pituitary MRI. There was no documented hormone recovery after diagnosis of hypophysitis, and the tumor responses to immunotherapy were variable in these seven patients. In conclusion, immune-mediated hypophysitis is often irreversible. Fortunately, it can be managed adequately with hormone replacements. Further investigations are warranted to unveil underlying mechanisms and ethnic differences to guide the solutions.

Chung V, Kos FJ, Hardwick N, et al.
Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.
Clin Transl Oncol. 2019; 21(3):363-372 [PubMed] Related Publications
BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors.
PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression.
RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8
CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Bernard-Tessier A, Baldini C, Martin P, et al.
Outcomes of long-term responders to anti-programmed death 1 and anti-programmed death ligand 1 when being rechallenged with the same anti-programmed death 1 and anti-programmed death ligand 1 at progression.
Eur J Cancer. 2018; 101:160-164 [PubMed] Related Publications
BACKGROUND: Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined timeframe.
PATIENTS AND METHODS: We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred.
RESULTS: Patients were treated for colorectal microsatellite instability-high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non-small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6-12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8-49). The median time free-treatment after discontinuation was 12.6 months (range 4-39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5-35.4). No grade 3/4 events occurred during the study period.
CONCLUSION: Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results.

Miranda Poma J, Ostios Garcia L, Villamayor Sanchez J, D'errico G
What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events.
Allergol Immunopathol (Madr). 2019 May - Jun; 47(3):303-308 [PubMed] Related Publications
Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL-1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors.

Jacob W, James I, Hasmann M, Weisser M
Clinical development of HER3-targeting monoclonal antibodies: Perils and progress.
Cancer Treat Rev. 2018; 68:111-123 [PubMed] Related Publications
The human epidermal growth factor receptor (HER) family consists of four transmembrane receptor tyrosine kinases: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. They are part of a complex signalling network and stimulate intracellular pathways regulating cell growth and differentiation. So far, monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors targeting EGFR and HER2 have been developed and approved. Recently, focus has turned to HER3 as it may play an important role in resistance to EGFR- and HER2-targeting therapies. HER3-targeting agents have been undergoing clinical evaluation for the last 10 years and currently thirteen mAbs are in phase 1 or 2 clinical studies. Single agent activity has proven to be limited, however, the tolerability was favourable. Thus, combinations of HER3-binding mAbs with other HER-targeting therapies or chemotherapies have been pursued in various solid tumor entities. Data indicate that the HER3-binding ligand heregulin may serve as a response prediction marker for HER3-targeting therapy. Within this review the current status of clinical development of HER3-targeting compounds is described.

Mayes PA, Hance KW, Hoos A
The promise and challenges of immune agonist antibody development in cancer.
Nat Rev Drug Discov. 2018; 17(7):509-527 [PubMed] Related Publications
Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.

Hafeez U, Gan HK, Scott AM
Monoclonal antibodies as immunomodulatory therapy against cancer and autoimmune diseases.
Curr Opin Pharmacol. 2018; 41:114-121 [PubMed] Related Publications
Since Nobel laureate Paul Ehrlich proposed the concept of magic bullet in 1906, Köhler and Milstein discovered Hybridoma technology in 1975, and Greg Winter pioneered the technique to humanize monoclonal antibodies in 1988, monoclonal antibodies have been successfully developed to treat medical illnesses. Monoclonal antibodies are effective treatments for inhibition of alloimmune reactivity, haematological malignancies, solid organ malignancies, viral illnesses and are also used as antiplatelet therapy. Their successful use in cancer and autoimmune diseases in humans have made them one of the fastest growing classes of new drugs approved for these indications in last few decades. This review focuses on the role of monoclonal antibodies as an immunomodulatory therapy against cancer and autoimmune diseases, the strategies used to enhance efficacy, and how resistance mechanisms are being addressed to improve therapeutic outcomes for patients.

Mølgaard K, Harwood SL, Compte M, et al.
Bispecific light T-cell engagers for gene-based immunotherapy of epidermal growth factor receptor (EGFR)-positive malignancies.
Cancer Immunol Immunother. 2018; 67(8):1251-1260 [PubMed] Related Publications
The recruitment of T-cells by bispecific antibodies secreted from adoptively transferred, gene-modified autologous cells has shown satisfactory results in preclinical cancer models. Even so, the approach's translation into the clinic will require incremental improvements to its efficacy and reduction of its toxicity. Here, we characterized a tandem T-cell recruiting bispecific antibody intended to benefit gene-based immunotherapy approaches, which we call the light T-cell engager (LiTE), consisting of an EGFR-specific single-domain V

Yu XY, Qiu WY, Long F, et al.
A novel fully human anti-CD47 antibody as a potential therapy for human neoplasms with good safety.
Biochimie. 2018; 151:54-66 [PubMed] Related Publications
Strategies for targeting CD47 are becoming a hot spot of cancer immunotherapy. However the ubiquitous expression of CD47, especially on the RBC, makes the targeted therapy facing safety risk issues. So, how to balance the safety and efficacy during CD47 inhibition is currently a major question. We had reported an anti-CD47 antibody ZF1 with potent anti-tumor effect. In this study, we further developed and assessed a novel fully human anti-CD47 antibody, AMMS4-G4, derived from ZF1 using affinity maturation. AMMS4-G4 exhibited equivalent anticancer effects with Hu5F9-G4, a humanized anti-CD47 antibody in clinical trial, on the potential of inducing significant phagocytosis of tumor cells in vitro and prolonging the survival of leukemia xenografted mice. Additionally, AMMS4-G4 significantly inhibited the growth of grafted solid tumors by enhancing macrophage infiltration and modestly enhanced the anti-tumor activity of opsonizing antibody and antiangiogenic therapy. In cynomolgus monkeys, AMMS4-G4 was safely administered, was well tolerated at doses of 30 and 60 mg/kg, and did not produce serious adverse events, except for the reversible anemia, which was observed after 3 days and started to recover from 9 days later. Remarkably, it was proved by in vitro assay that Hu5F9-G4 induced RBC hemagglutination which wasn't observed in AMMS4-G4. On the whole, AMMS4-G4 was demonstrated to be a promising candidate with great potential and safe profile for cancer immunotherapy.

Dalziel M, Beers SA, Cragg MS, Crispin M
Through the barricades: overcoming the barriers to effective antibody-based cancer therapeutics.
Glycobiology. 2018; 28(9):697-712 [PubMed] Related Publications
Since the turn of the century, cancer therapy has undergone a transformation in terms of new treatment modalities and renewed optimism in achieving long-lived tumor control and even cure. This is, in large part, thanks to the widespread incorporation of monoclonal antibodies (mAbs) into standard treatment regimens. These new therapies have, across many settings, significantly contributed to improved clinical responses, patient quality of life and survival. Moreover, the flexibility of the antibody platform has led to the development of a wide range of innovative and combinatorial therapies that continue to augment the clinician's armory. Despite these successes, there is a growing awareness that in many cases mAb therapy remains suboptimal, primarily due to inherent limitations imposed by the immune system's own homeostatic controls and the immunosuppressive tumor microenvironment. Here, we discuss the principal barriers that act to constrain the tumor-killing activity of antibody-based therapeutics, particularly those involving antibody glycans, using illustrative examples from both pre-clinical and market approved mAbs. We also discuss strategies that have been, or are in development to overcome these obstacles. Finally, we outline how the growing understanding of the biological terrain in which mAbs function is shaping innovation and regulation in cancer therapeutics.

Koury J, Lucero M, Cato C, et al.
Immunotherapies: Exploiting the Immune System for Cancer Treatment.
J Immunol Res. 2018; 2018:9585614 [PubMed] Free Access to Full Article Related Publications
Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers.

Wang Y, Abu-Sbeih H, Mao E, et al.
Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis.
Inflamm Bowel Dis. 2018; 24(8):1695-1705 [PubMed] Related Publications
Background: Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes.
Methods: We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves.
Results: Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis.
Conclusion: 10.1093/ibd/izy104_video1izy104.video15808053084001.

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