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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
Alemtuzumab
Bevacizumab
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

Lu CS, Liu JH
Pneumonitis in cancer patients receiving anti-PD-1 and radiotherapies: Three case reports.
Medicine (Baltimore). 2017; 96(1):e5747 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: In development of novel therapies for the treatment of patient with cancer, the use of radiotherapy (RT) can produce significant local control and, in recent studies, has also been shown to mediate anti-tumor responses at distant sites by triggering and enhancing the endogenous cellular immune responses. Although RT induces an abscopal effect in some patients due to enhanced immune response to the tumor, immune-escape mechanisms, including up-regulation of programmed death-ligand 1 (PD-L1) on tumor cells, limit this benefit in other patients. Hence, many studies have promoted the synergy of RT and anti-programmed cell death protein 1 (PD-1) treatment for antitumor immunity. However, outcome may be improved when more therapies are combined, but risk of side effects can be increased.
CASE PRESENTATION: We herein present 3 advanced cancer patients with pulmonary metastasis and who received RT. Later, they underwent anti-PD-1 treatment and unfortunately suffered from anti-PD-1-related pneumonitis over the nonirradiated areas after 4 cycles of treatment. The upregulation of cellular PD-1 expression in these areas was considered and the immune overreaction by anti-PD-1 treatment may cause these severe pulmonary adverse effects.
CONCLUSION: Our review of 3 cases warrants careful workup to reduce the risk of side effects by combinative therapy with RT and anti-PD-1 treatment.

Wang S, Jia M
Antibody Therapies in Cancer.
Adv Exp Med Biol. 2016; 909:1-67 [PubMed] Related Publications
Antibody-based immunotherapy has become a standard treatment for a variety of cancers. Many well-developed antibodies disrupt signaling of various growth factor receptors for the treatment of a number of cancers by targeting surface antigens expressed on tumor cells. In recent years, a new family of antibodies is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune-targeted therapies strive to augment antitumor immune responses by antagonizing immunosuppressive pathways or providing exogenous immune-activating stimuli, which have achieved dramatic results in several cancers. The future of cancer therapies is likely to combine these approaches with other treatments, including conventional therapies, to generate more effective treatments.

Schoenhals JE, Seyedin SN, Tang C, et al.
Preclinical Rationale and Clinical Considerations for Radiotherapy Plus Immunotherapy: Going Beyond Local Control.
Cancer J. 2016 Mar-Apr; 22(2):130-7 [PubMed] Related Publications
The use of radiation for cancer therapy has expanded and sparked interest in possible synergistic effects by combining it with current immunotherapies. In this review, we present a case of a patient who responded to programmed cell death 1 (PD1) blockade and radiation therapy and discuss possible mechanisms. We provide background on the blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD1 checkpoints and highlight future immune-based therapies that may synergize with radiation, including cytosine-phosphate-guanine vaccines, OX40 agonists, CD40 agonists, regulatory T-cell depletion, and metabolic "rewiring" of cancer cells. Clinical considerations are noted for combining radiation with immunotherapies to extend the benefit of immunotherapy to more patients. New trials are needed to appropriately investigate the best sequencing and radiation dose to prime an immune response and to identify predictive biomarkers of such responses.

Khalil DN, Smith EL, Brentjens RJ, Wolchok JD
The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.
Nat Rev Clin Oncol. 2016; 13(5):273-90 [PubMed] Related Publications
In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

Weigelin B, Bolaños E, Rodriguez-Ruiz ME, et al.
Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage?
Cancer Immunol Immunother. 2016; 65(5):493-7 [PubMed] Related Publications
CD137(4-1BB) costimulation and adoptive T cell therapy strongly synergize in terms of achieving maximal efficacy against experimental cancers. These costimulatory biological functions of CD137 have been exploited by means of introducing the CD137 signaling domain in clinically successful chimeric antigen receptors and to more efficiently expand T cells in culture. In addition, immunomagnetic sorting of CD137-positive T cells among tumor-infiltrating lymphocytes selects for the fittest antitumor T lymphocytes for subsequent cultures. In mouse models, co-infusion of both agonist antibodies and T cells attains marked synergistic effects that result from more focused and intense cytolytic activity visualized under in vivo microscopy and from more efficient entrance of T cells into the tumor through the vasculature. These several levels of dynamic interaction between adoptive T cell therapy and CD137 offer much opportunity to raise the efficacy of current cancer immunotherapies.

Pistoia V, Pezzolo A
Involvement of HMGB1 in Resistance to Tumor Vessel-Targeted, Monoclonal Antibody-Based Immunotherapy.
J Immunol Res. 2016; 2016:3142365 [PubMed] Free Access to Full Article Related Publications
High mobility group box 1 (HMGB1) is a member of the "danger associated molecular patterns" (DAMPs) than can localize in various compartments of the cell (from the nucleus to the cell surface) and subserve different functions accordingly. HMGB1 is implicated in maintenance of genomic stability, autophagy, immune regulation, and tumor growth. HMGB1-induced autophagy promotes tumor resistance to chemotherapy, as shown in different models of malignancy, for example, osteosarcoma, leukemia, and gastric cancer. To the best of our knowledge, there is virtually no information on the relationships between HMGB1 and resistance to immunotherapy. A recent study from our group has shed new light on this latter issue. We have demonstrated that targeting of tumor-derived endothelial cells with an anti-human CD31 monoclonal antibody in a human neuroblastoma model was unsuccessful due to a complex chain of events involving the participation of HMGB1. These results are discussed in detail since they provide the first evidence for a role of HMGB1 in resistance of tumor cells to monoclonal antibody-based immunotherapy.

Hamanishi J, Mandai M, Matsumura N, et al.
PD-1/PD-L1 blockade in cancer treatment: perspectives and issues.
Int J Clin Oncol. 2016; 21(3):462-73 [PubMed] Free Access to Full Article Related Publications
Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.

Ryan JM, Wasser JS, Adler AJ, Vella AT
Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?
Expert Opin Biol Ther. 2016; 16(5):655-74 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
INTRODUCTION: Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy.
AREAS COVERED: We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR).
EXPERT OPINION: Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.

Carvalho S, Levi-Schaffer F, Sela M, Yarden Y
Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti-cancer antibodies: IUPHAR Review 18.
Br J Pharmacol. 2016; 173(9):1407-24 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models have prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics and highlight mechanisms potentially underlying their enhanced clinical efficacy.

Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, et al.
Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy.
Eur J Immunol. 2016; 46(3):513-22 [PubMed] Related Publications
CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibody-dependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology.

Robert-Tissot C, Speiser DE
Anticancer Teamwork: Cross-Presenting Dendritic Cells Collaborate with Therapeutic Monoclonal Antibodies.
Cancer Discov. 2016; 6(1):17-9 [PubMed] Related Publications
Cross-presentation of tumor antigens represents a key pathway in antitumor immune responses that can be exploited to synergize not only with the already prominent "checkpoint blockade," but also with newer attempts to use T-cell stimulatory monoclonal antibodies in immunotherapy.

Gerber HP, Sapra P, Loganzo F, May C
Combining antibody-drug conjugates and immune-mediated cancer therapy: What to expect?
Biochem Pharmacol. 2016; 102:1-6 [PubMed] Related Publications
Blockade of immune-checkpoints has emerged as one of the most promising approaches to improve the durability of anti-tumor responses in cancer patients. However, the fraction of patients experiencing durable responses to single agent immune checkpoint inhibitor treatment remains limited. Recent clinical reports suggest that patients responding best to checkpoint blockade therapies display higher levels of CD8(+) T-cells in the tumor prior to treatment. Therefore, combination treatments of immune-checkpoint inhibitors with compounds that increase the number of tumor infiltrating CD8(+) T cells may expand the therapeutic benefit of immuno-oncology (IO) drugs. Immunogenic cell death (ICD) of tumor cells is induced by certain classes of cytotoxic compounds and represents a potent stimulator of effector T-cell recruitment to tumors. In addition, several cytotoxics directly stimulate dendritic cell activation and maturation, resulting in improved anti-tumor immune responses when combined with IO compounds. Among them, several cytotoxic agents are currently utilized as payloads for antibody-drug conjugates (ADCs). Therefore, identification of optimal combination regimens between ADC- and IO compounds holds strong promise to overcome the current limitations of immune checkpoint inhibitors, by increasing the recruitment of CD8(+) effector T-cells to the tumor core. Here we review the emerging field of ADC/IO combination research, with a focus on how to optimally combine both modalities. The answer to this question may have a broader impact on oncology drug development, as synergistic activities between IO compounds and ADCs may increase the formation of tumor specific immunological memory, ultimately leading to durable responses in a larger fraction of cancer patients.

Leusen JH
IgA as therapeutic antibody.
Mol Immunol. 2015; 68(1):35-9 [PubMed] Related Publications
This review is focused on the promises of IgA as a new therapeutic antibody. For more than 30 years IgG molecules have been used in the clinic in the fields of oncology, hematology, auto immune diseases and infections. However, IgA might be a good alternative, since it recruits different effector cells, i.e. polymorphonuclear cells or neutrophils, but can also activate monocytes and macrophages. The present knowledge, but also future direction for IgA- based drugs are discussed.

Huang MA, Krishnadas DK, Lucas KG
Cellular and Antibody Based Approaches for Pediatric Cancer Immunotherapy.
J Immunol Res. 2015; 2015:675269 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Progress in the use of traditional chemotherapy and radiation-based strategies for the treatment of pediatric malignancies has plateaued in the past decade, particularly for patients with relapsing or therapy refractory disease. As a result, cellular and humoral immunotherapy approaches have been investigated for several childhood cancers. Several monoclonal antibodies are now FDA approved and commercially available, some of which are currently considered standard of practice. There are also several new cellular immunotherapy approaches under investigation, including chimeric antigen receptor (CAR) modified T cells, cancer vaccines and adjuvants, and natural killer (NK) cell therapies. In this review, we will discuss previous studies on pediatric cancer immunotherapy and new approaches that are currently being investigated in clinical trials.

Chodon T, Koya RC, Odunsi K
Active Immunotherapy of Cancer.
Immunol Invest. 2015; 44(8):817-36 [PubMed] Related Publications
Clinical progress in the field of cancer immunotherapy has been slow for many years but within the last 5 years, breakthrough successes have brought immunotherapy to the forefront in cancer therapy. Promising results have been observed in a variety of cancers including solid tumors and hematological malignancies with adoptive cell therapy using natural host tumor infiltrating lymphocytes, host cells that have been genetically engineered with antitumor T-cell receptors or chimeric antigen receptors, immune checkpoint inhibitors like anti-CTLA-4, anti-PD-1 or PD-L1 monoclonal antibodies and oncolytic virus-based immunotherapy. However, most treatment modalities have shown limited efficacy with single therapy. The complex nature of cancer with intra- and inter-tumor antigen and genomic heterogeneity coupled with the immune suppressive microenvironment emphasizes the prospect of personalized targeted immunotherapy to manipulate the patient's own immune system against cancer. For successful, robust and long-lasting cure of cancer, a multi-modal approach is essential, combining anti-tumor cell therapy with manipulation of multiple pathways in the tumor microenvironment to ameliorate tumor-induced immunosuppression.

Gül N, van Egmond M
Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer.
Cancer Res. 2015; 75(23):5008-13 [PubMed] Related Publications
Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer.

Moussavou G, Ko K, Lee JH, Choo YK
Production of monoclonal antibodies in plants for cancer immunotherapy.
Biomed Res Int. 2015; 2015:306164 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Plants are considered as an alternative platform for recombinant monoclonal antibody (mAb) production due to the improvement and diversification of transgenic techniques. The diversity of plant species offers a multitude of possibilities for the valorization of genetic resources. Moreover, plants can be propagated indefinitely, providing cheap biomass production on a large scale in controlled conditions. Thus, recent studies have shown the successful development of plant systems for the production of mAbs for cancer immunotherapy. However, their several limitations have to be resolved for efficient antibody production in plants.

Sharabi AB, Lim M, DeWeese TL, Drake CG
Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.
Lancet Oncol. 2015; 16(13):e498-509 [PubMed] Related Publications
Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.

Vinay DS, Kwon BS
Therapeutic potential of anti-CD137 (4-1BB) monoclonal antibodies.
Expert Opin Ther Targets. 2016; 20(3):361-73 [PubMed] Related Publications
INTRODUCTION: 4-1BB (CD137) is an important T-cell stimulating molecule. The 4-1BB mAb or its variants have shown remarkable therapeutic activity against autoimmunity, viral infections, and cancer. Antibodies to 4-1BB have recently entered clinical trials for the treatment of cancer with favorable toxicity profile. In this article, we present a review documenting the efficacy and pitfalls of 4-1BB therapy.
AREAS COVERED: An extensive literature search has been made on 4-1BB, spanning two decades, and a comprehensive report is presented here highlighting the origins, biological effects, therapeutic potential, and mechanistic basis of targeting 4-1BB as well as the side effects associated with such therapy.
EXPERT OPINION: Research so far indicates that 4-1BB is highly protective against various pathological conditions including cancer. However, a few important side effects of 4-1BB therapy such as liver toxicity, thrombocytopenia, anemia, and suppressive effects on certain immune competent cells should be taken into consideration before it is used for human therapy.

Koster BD, de Gruijl TD, van den Eertwegh AJ
Recent developments and future challenges in immune checkpoint inhibitory cancer treatment.
Curr Opin Oncol. 2015; 27(6):482-8 [PubMed] Related Publications
PURPOSE OF REVIEW: In this review, we focus on the recent findings and future challenges in cancer treatment with immune checkpoint inhibitors.
RECENT FINDINGS: Major progress has been made in recent years as the first immune checkpoint inhibitors are approved by the US Food and Drug Administration for the treatment of cancer patients. Anticytotoxic T-lymphocyte-associated protein 4 and antiprogrammed death protein 1/programmed death-ligand 1 (PD-L1) monoclonal antibodies are being extensively studied in many different tumor types, often showing impressive response rates, but also a typical serious toxicity profile in the form of auto-immunity. Unfortunately, it is not yet possible to prevent or predict these immune-related adverse events. Studies on mutational load, neo-epitopes, lactate dehydrogenase, PD-L1 expression, and T-cell infiltration suggest that these markers are correlating with efficacy, but have not yet reached the status of a validated biomarker for checkpoint inhibitors. Other immune checkpoints are being investigated and new checkpoint inhibitors are on the brink of being evaluated in clinical trials.
SUMMARY: The main challenge for the near future will be to predict efficacy of immune checkpoint blockade and to predict and prevent immune-related adverse events. More research should be done in order to find potential biomarkers that predict treatment response and/or toxicity; the optimal administration route, dosage, and frequency; and possible combinations of therapies that have an added or synergetic effect.

Seyedin SN, Schoenhals JE, Lee DA, et al.
Strategies for combining immunotherapy with radiation for anticancer therapy.
Immunotherapy. 2015; 7(9):967-80 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint-based strategies and adoptive immunotherapies with radiation.

Geng X, Kong X, Hu H, et al.
Research and development of therapeutic mAbs: An analysis based on pipeline projects.
Hum Vaccin Immunother. 2015; 11(12):2769-76 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
As the subject of active research and development (R&D) in recent decades, monoclonal antibodies have emerged among the major classes of therapeutic agents for treatment of many human diseases, especially cancers, infections, and immunological disorders. This article surveys the landscape of R&D projects of therapeutic monoclonal antibodies (mAbs), which are mostly used for disease immunotherapy, from a number of perspectives, including therapeutic indications, development phases, participants, and citation of related patents. The results of this research can be used as a reference resource for pharmaceutical researchers, investors, and policymakers in the field of therapeutic mAbs.

Cuneo KC, Nyati MK, Ray D, Lawrence TS
EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection.
Pharmacol Ther. 2015; 154:67-77 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The epidermal growth factor receptor (EGFR) plays an important role in tumor progression and treatment resistance for many types of malignancies including head and neck, colorectal, and nonsmall cell lung cancer. Several EGFR targeted therapies are efficacious as single agents or in combination with chemotherapy. Given the toxicity associated with chemoradiation and poor outcomes seen in several types of cancers, combinations of EGFR targeted agents with or without chemotherapy have been tested in patients receiving radiation. To date, the only FDA approved use of an anti-EGFR therapy in combination with radiation therapy is for locally advanced head and neck cancer. Given the important role EGFR plays in lung and colorectal cancer and the benefit of EGFR inhibition combined with chemotherapy in these disease sites, it is perplexing why EGFR targeted therapies in combination with radiation or chemoradiation have not been more successful. In this review we summarize the clinical findings of EGFR targeted therapies combined with radiation and chemoradiation regimens. We then discuss the interaction between EGFR and radiation including radiation induced EGFR signaling, the effect of EGFR on DNA damage repair, and potential mechanisms of radiosensitization. Finally, we examine the potential pitfalls with scheduling EGFR targeted therapies with chemoradiation and the use of predictive biomarkers to improve patient selection.

Vigneron N
Human Tumor Antigens and Cancer Immunotherapy.
Biomed Res Int. 2015; 2015:948501 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
With the recent developments of adoptive T cell therapies and the use of new monoclonal antibodies against the immune checkpoints, immunotherapy is at a turning point. Key players for the success of these therapies are the cytolytic T lymphocytes, which are a subset of T cells able to recognize and kill tumor cells. Here, I review the nature of the antigenic peptides recognized by these T cells and the processes involved in their presentation. I discuss the importance of understanding how each antigenic peptide is processed in the context of immunotherapy and vaccine delivery.

Kovacević A, Dragojević-Simić V, Rancić N, et al.
End-of-life costs of medical care for advanced stage cancer patients.
Vojnosanit Pregl. 2015; 72(4):334-41 [PubMed] Related Publications
BACKGROUND/AIM: Cancer, one of the leading causes of mortality in the world, imposes a substantial economic burden on each society, including Serbia. The aim of this study was to evaluate the major cancer cost drivers in Serbia.
METHODS: A retrospective, in-depth, bottom-up analysis of two combined databases was performed in order to quantify relevant costs. End-of-life data were obtained from patients with cancer, who deceased within the first year of the established diagnose, including basic demographics, diagnosis, tumour histology, medical resource use and related costs, time and cause of death. All costs were allocated to one of the three categories of cancer health care services: primary care (included home care), hospital outpatient and hospital inpatient care.
RESULTS: Exactly 114 patients were analyzed, out of whom a high percent (48.25%) had distant metastases at the moment of establishing the diagnosis. Malignant neoplasms of respiratory and intrathoracic organs were leading causes of morbidity. The average costs per patient were significantly different according to the diagnosis, with the highest (13,114.10 EUR) and the lowest (4.00 EUR) ones observed in the breast cancer and melanoma, respectively. The greatest impact on total costs was observed concerning pharmaceuticals, with 42% of share (monoclonal antibodies amounted to 34% of all medicines and 14% of total costs), followed by oncology medical care (21%), radiation therapy and interventional radiology (11%), surgery (90%), imaging diagnostics (9%) and laboratory costs (8%). CONCLUSION. Cancer treatment incurs high costs, especially for end-of-life pharmaceutical expenses, ensued from medical personnel tendency to improve such patients' quality of life in spite of nearing the end of life. Reimbursement policy on monoclonal antibodies, in particular at end-stage disease, should rely on cost-effectiveness evidence as well as documented clinical efficiency.

Teng F, Kong L, Meng X, et al.
Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges.
Cancer Lett. 2015; 365(1):23-9 [PubMed] Related Publications
To date, several kinds of immunomodulating monoclonal antibodies (mAbs) have been applied in clinical trials, such as anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) mAb and anti-programmed death-1 (anti-PD-1) mAb. With the recent success of cancer immunotherapy, especially the checkpoint inhibitors, the renewed interest in immunotherapy as a treatment modality has gained extensive attention. The irradiated tumor cell death can enhance antitumor immunity by inducing antigen expression on tumor cells and activating lymphocytes. Radiotherapy (RT) combined with immunotherapy has revealed promising outcomes in various animal models. However, this new paradigm is often considered as a medical spectacle without a unifying model, and its mechanisms have yet to be elucidated. The purpose of this review is to investigate previously published studies of radiotherapy combined with checkpoint blockades by the following aspects: exploring the potential mechanisms; identifying the most beneficial dose, fraction and target site for RT; finding an appropriate time window to combine these two treatments; and discussing the toxicity and suitable treatment evaluating criteria.

Starodub AN, Ocean AJ, Shah MA, et al.
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors.
Clin Cancer Res. 2015; 21(17):3870-8 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
PURPOSE: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.
EXPERIMENTAL DESIGN: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.
RESULTS: Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.
CONCLUSIONS: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies.

Karlitepe A, Ozalp O, Avci CB
New approaches for cancer immunotherapy.
Tumour Biol. 2015; 36(6):4075-8 [PubMed] Related Publications
Immunotherapy is a promising field that offers alternative methods for treatment of cancer. The current strategy consists of cancer vaccines, monoclonal antibodies, and cellular therapies. Cancer vaccines aim to eradicate cancer cells via immune system. Thus, they may attack these cells derived from any type of cancer, besides their role in preventing cancer. Lymphocytes and dendritic cells are often used in cellular therapy. In addition, monoclonal antibodies are designed to target specific antigens found in cancer cells. Currently, at least 12 clinically approved monoclonal antibodies are being used and many cancer vaccines are being developed with ongoing phase studies for cancer therapy. Relevant studies are focused on glioma and several other cancer types. Correspondingly, the combination of effective methods may enhance the efficacy of immunotherapy. It is thought that particularly immune checkpoint inhibitors will play a crucial role in immunotherapeutic approaches.

Redman JM, Hill EM, AlDeghaither D, Weiner LM
Mechanisms of action of therapeutic antibodies for cancer.
Mol Immunol. 2015; 67(2 Pt A):28-45 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

Yamaguchi A, Usami K, Shimabe M, et al.
The novel CA IX inhibition antibody chKM4927 shows anti-tumor efficacy in vivo.
Anticancer Res. 2015; 35(4):1997-2004 [PubMed] Related Publications
Carbonic anhydrase IX (CA IX) is an attractive target for cancer therapy. Many anti-CA IX antibodies have been reported but few have been shown to possess inhibition activity. Furthermore, effective use of CA IX-inhibition antibodies for cancer immunotherapy has not been well-validated since data are mainly limited to in vitro assays. In this study, we established that chKM4927, an anti-CA IX chimeric antibody, recognizes CA IX and has CA IX-specific inhibition activity. ChKM4927 also retains antibody-dependent cellular cytotoxicity (ADCC) activity against CA IX-expressing cancer cells. Compared to controls, chKM4927 treatment (10 mg/kg) showed anti-tumor activity in the VMRC-RCW xenograft model in vivo. ChKM4927-attenuated ADCC activity showed equally effective anti-tumor activity. These results suggest that the CA IX-inhibition antibody chKM4927 has an anti-tumor effect in the VMRC-RCW xenograft model via an ADCC-independent mechanism.

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