Therapeutic Antibodies in Cancer Therapy.

The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the clinical relevance of this approach.Targeted cancer therapies , also referred to as personalized medicine, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The use of monoclonal antibodies in colorectal and gastric cancer for example have shown best outcome when combined with chemotherapy, even though single agent anti-EGFR antibodies seem to be active in particular setting of metastatic colorectal cancer patients. However, it is not well defined whether the addition of anti-VEGF - and anti-EGFR strategies to chemotherapy could improve outcome in those patients susceptible to colorectal cancer-related metastases resection. Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints, exemplified by the recently FDA-approved agent, Ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of Ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. This section attempts to discuss recent progress of targeted agents and in tackling a more general target applicable to gastrointestinal cancer .

[1]  H. Burris,et al.  A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies. , 2007, Gynecologic oncology.

[2]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[3]  Clive R. Taylor,et al.  Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[5]  M. Azuma,et al.  Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer , 2005, Clinical Cancer Research.

[6]  P Kelly Marcom,et al.  Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Berlin,et al.  Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer , 2007, Cancer.

[8]  F. Thistlethwaite,et al.  High-dose Interleukin-2 Can Produce a High Rate of Response and Durable Remissions in Appropriately Selected Patients With Metastatic Renal Cancer , 2011, Journal of immunotherapy.

[9]  Carsten Reinhardt,et al.  Bispecific T-cell engaging antibodies for cancer therapy. , 2009, Cancer research.

[10]  Helen X. Chen,et al.  A Randomized Phase 2 Trial of Bevacizumab with or without Daily Low-Dose Interferon Alfa-2b in Metastatic Malignant Melanoma , 2007, Annals of Surgical Oncology.

[11]  A. Rosenwald,et al.  Expression of Foxp3 in Colorectal Cancer but Not in Treg Cells Correlates with Disease Progression in Patients with Colorectal Cancer , 2013, PloS one.

[12]  G. Adams,et al.  High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. , 2001, Cancer research.

[13]  R. Kontermann Recombinant bispecific antibodies for cancer therapy , 2005, Acta Pharmacologica Sinica.

[14]  A. Hinke,et al.  Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[16]  C. Hudis Trastuzumab--mechanism of action and use in clinical practice. , 2007, The New England journal of medicine.

[17]  A. Dachman,et al.  Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Hermann Einsele,et al.  Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  P. Catalano,et al.  Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Yoshimasa Tanaka,et al.  Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer , 2007, Proceedings of the National Academy of Sciences.

[21]  T. Okazaki,et al.  Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma , 2010, Cancer.

[22]  K. Swenerton,et al.  A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer , 2004, International Journal of Gynecologic Cancer.

[23]  G. Adams,et al.  Monoclonal antibody therapy of cancer , 1999, Nature Biotechnology.

[24]  M. Friedrich,et al.  Antitumor Activity of an EpCAM/CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release , 2009, Journal of immunotherapy.

[25]  Louis M. Weiner,et al.  Monoclonal antibodies: versatile platforms for cancer immunotherapy , 2010, Nature Reviews Immunology.

[26]  E. Van Cutsem,et al.  Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  A. D. Van den Abbeele,et al.  Efficacy and Safety of Single-Agent Pertuzumab, a Human Epidermal Receptor Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer , 2007, Clinical Cancer Research.

[28]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[29]  J. Bergh,et al.  Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  N. Hanna,et al.  Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  C. Davis,et al.  Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. , 1999, Cancer research.

[32]  M. Gonen,et al.  Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  M. Grimm,et al.  T-cell response to p53 tumor-associated antigen in patients with colorectal carcinoma. , 2006, International journal of oncology.

[34]  R. Lechler,et al.  Cutting Edge: CTLA-4 (CD152) Differentially Regulates Mitogen-Activated Protein Kinases (Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase) in CD4+ T Cells from Receptor/Ligand-Deficient Mice1 , 2002, The Journal of Immunology.

[35]  Lyndsay N Harris,et al.  Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  P. Murawa,et al.  The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial , 2010, International journal of cancer.

[37]  R. Barroso-Sousa,et al.  Biological therapies in breast cancer: common toxicities and management strategies. , 2013, Breast.

[38]  J. Wolchok,et al.  Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab , 2011, Proceedings of the National Academy of Sciences.

[39]  C. Germer,et al.  The role of FOXP3 in disease progression in colorectal cancer patients , 2013, Oncoimmunology.

[40]  M. Lubeck,et al.  Human macrophages armed with murine immunoglobulin G2a antibodies to tumors destroy human cancer cells. , 1983, Science.

[41]  C. Bokemeyer,et al.  A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  R. Fisher,et al.  High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  N. Xu,et al.  Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. , 2006, Acta histochemica.

[45]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[46]  P. Zimmerman,et al.  Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. , 2007, Oncology.

[47]  Dongsheng Tu,et al.  Cetuximab for the treatment of colorectal cancer. , 2007, The New England journal of medicine.

[48]  D. Pfister,et al.  A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors , 2007, Cancer Immunology, Immunotherapy.

[49]  Heather L. Mulder,et al.  Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. , 2014, The New England journal of medicine.

[50]  R. Amato Everolimus for the treatment of advanced renal cell carcinoma , 2011, Expert opinion on pharmacotherapy.

[51]  J. Bluestone,et al.  Interactions between programmed death-1 and programmed death ligand-1 promote tolerance by blocking the T cell receptor-induced stop signal , 2009, Nature Immunology.

[52]  P. Soares,et al.  The mTOR Signalling Pathway in Human Cancer , 2012, International journal of molecular sciences.

[53]  E. Perez,et al.  Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. , 2007, The New England journal of medicine.

[54]  F. Rojo,et al.  Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer , 2006, British Journal of Cancer.

[55]  F. Hagemeister,et al.  Denileukin diftitox: a novel immunotoxin , 2009, Expert opinion on biological therapy.

[56]  J. Berek,et al.  Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  R. Motzer,et al.  Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  R. Figlin,et al.  Targeting angiogenesis in renal cell carcinoma , 2013, Expert opinion on pharmacotherapy.

[59]  P. Sharma,et al.  CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients , 2008, Proceedings of the National Academy of Sciences.

[60]  B. Fenton,et al.  Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment. , 1998, Cancer research.

[61]  L. Mazzucchelli,et al.  Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  G. Perlemuter,et al.  Gastrointestinal toxicities of novel agents in cancer therapy. , 2009, European journal of cancer.

[63]  J. Bourhis,et al.  Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  Sylvia Janetzki,et al.  Improved Endpoints for Cancer Immunotherapy Trials , 2010, Journal of the National Cancer Institute.

[65]  M. Melamed,et al.  Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[66]  F. Kabbinavar,et al.  Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  T. Okazaki,et al.  PD-1 and PD-1 ligands: from discovery to clinical application. , 2007, International immunology.

[68]  R. Figlin,et al.  Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  J. Kirkwood,et al.  Next generation of immunotherapy for melanoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  P. Linsley,et al.  Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[71]  G. Viani,et al.  Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials , 2007, BMC Cancer.

[72]  G. Gasparini,et al.  Pancreatic cancer: from molecular signature to target therapy. , 2008, Critical reviews in oncology/hematology.

[73]  C. Fuchs,et al.  Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  John M Lambert,et al.  Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. , 2008, Cancer research.

[75]  C. O’Bryant,et al.  Oncology; Everolimus: A New Treatment Option for Advanced Pancreatic Neuroendocrine Tumors , 2012, The Annals of pharmacotherapy.

[76]  D. Sargent,et al.  Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  G. Freeman,et al.  Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production 1 , 2003, The Journal of Immunology.

[78]  B. Liu,et al.  The development of potential antibody-based therapies for myeloma. , 2015, Blood reviews.

[79]  R. Figlin,et al.  Kidney cancer: Progress and controversies in neoadjuvant therapy , 2014, Nature Reviews Urology.

[80]  E. Winer,et al.  Trastuzumab plus vinorelbine or taxane chemotherapy for HER2‐overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study , 2007, Cancer.

[81]  J. Egen,et al.  Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. , 2002, Immunity.

[82]  B Nebiyou Bekele,et al.  Cetuximab and Irinotecan Interact Synergistically to Inhibit the Growth of Orthotopic Anaplastic Thyroid Carcinoma Xenografts in Nude Mice , 2006, Clinical Cancer Research.

[83]  J N Weinstein,et al.  A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[84]  A. Lobuglio,et al.  Human immune response to monoclonal antibodies. , 1994, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[85]  E. Van Cutsem,et al.  Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  R. Marcus,et al.  CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. , 2005, Blood.

[87]  F. Kabbinavar,et al.  Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[89]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[90]  I. Bernstein,et al.  Treatment of malignancy with unmodified antibody. , 1987, Pathology and immunopathology research.

[91]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[92]  G. Bebb,et al.  Nimotuzumab: a novel anti-EGFR monoclonal antibody that retains anti-EGFR activity while minimizing skin toxicity , 2009, Expert opinion on biological therapy.

[93]  M. Brown,et al.  Could bystander killing contribute significantly to the antitumor activity of brentuximab vedotin given with standard first-line chemotherapy for Hodgkin lymphoma? , 2014, Immunotherapy.

[94]  A. Avilés,et al.  Interferon and low doses of methotrexate versus interferon and retinoids in the treatment of refractory/relapsed cutaneous T-cell lymphoma , 2015, Hematology.

[95]  Seta Shahin,et al.  A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  J. Weber Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. , 2007, The oncologist.

[97]  April M. Kloxin,et al.  Metastatic melanoma - a review of current and future treatment options. , 2015, Acta dermato-venereologica.

[98]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[99]  M. Saif Pancreatic neoplasm in 2011: an update. , 2011, JOP : Journal of the pancreas.

[100]  J. Wolchok,et al.  Antibody therapy of cancer , 2012, Nature Reviews Cancer.

[101]  E. Kimby Biological Therapy Doublets: Pairing Rituximab with Interferon, Lenalidomide, and Other Biological Agents in Patients with Follicular Lymphoma , 2012, Current Hematologic Malignancy Reports.

[102]  H. Schneider,et al.  CD28 and CTLA‐4 coreceptor expression and signal transduction , 2009, Immunological reviews.

[103]  Rui-Ru Ji,et al.  An immune-active tumor microenvironment favors clinical response to ipilimumab , 2012, Cancer Immunology, Immunotherapy.

[104]  M. Bueter,et al.  Influence of p53 on anti-tumor immunity (review). , 2006, International journal of oncology.

[105]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[106]  David S Mendelson,et al.  Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[107]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[108]  M. Ghielmini,et al.  Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. , 2004, Blood.

[109]  Marc Peeters,et al.  Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[110]  P. Rochaix,et al.  In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR , 2006, Cancer Chemotherapy and Pharmacology.

[111]  L. Siu,et al.  Cardiovascular toxicity of molecularly targeted agents. , 2009, European journal of cancer.

[112]  J. Byrd,et al.  Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. , 2002, Blood.

[113]  F. Penault-Llorca,et al.  Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification , 2007, Clinical Cancer Research.

[114]  J. Sakamoto,et al.  Efficacy of molecular response at 1 or 3 months after the initiation of dasatinib treatment can predict an improved response to dasatinib in imatinib-resistant or imatinib-intolerant Japanese patients with chronic myelogenous leukemia during the chronic phase. , 2014, Journal of clinical and experimental hematopathology : JCEH.

[115]  J. Baselga,et al.  Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[116]  M. Ebinger,et al.  Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab , 2014, Haematologica.

[117]  P. Möller,et al.  Monoclonal antibody-mediated tumor regression by induction of apoptosis. , 1989, Science.

[118]  D. Yardley Adverse event management of mTOR inhibitors during treatment of hormone receptor-positive advanced breast cancer: considerations for oncologists. , 2014, Clinical breast cancer.

[119]  C. Hudis,et al.  A phase I study of cetuximab/paclitaxel in patients with advanced-stage breast cancer. , 2006, Clinical breast cancer.

[120]  M. Goldwasser,et al.  Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[121]  Bethan Hughes Antibody–drug conjugates for cancer: poised to deliver? , 2010, Nature Reviews Drug Discovery.

[122]  J. Koropatnick,et al.  Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[123]  B. Ramaswamy,et al.  Phase II Trial of Bevacizumab in Combination with Weekly Docetaxel in Metastatic Breast Cancer Patients , 2006, Clinical Cancer Research.

[124]  G. Adams,et al.  Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies. , 1998, Cancer research.

[125]  R. Herbst,et al.  Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[126]  S. Khozin,et al.  U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. , 2014, The oncologist.

[127]  A. Lanfranco,et al.  CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms , 2004, Molecular and Cellular Biology.

[128]  A. Lièvre,et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[129]  R. Figlin,et al.  Systemic therapy in renal cell carcinoma: advancing paradigms. , 2012, Oncology.

[130]  K. Weiss Safety profile of interferon-alpha therapy. , 1998, Seminars in oncology.

[131]  S. O’Day,et al.  Phase I/II study of ipilimumab for patients with metastatic melanoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[132]  Paul Garside,et al.  Reversal of the TCR Stop Signal by CTLA-4 , 2006, Science.

[133]  J. Allison,et al.  Enhancement of Antitumor Immunity by CTLA-4 Blockade , 1996, Science.

[134]  Raetasha S. Dabney,et al.  New agents in renal cell carcinoma , 2014, Targeted Oncology.

[135]  Alison P. Klein,et al.  Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape , 2012, Science Translational Medicine.

[136]  Haidong Dong,et al.  Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion , 2002, Nature Medicine.

[137]  Mahitosh Mandal,et al.  Concurrent Cetuximab and Bevacizumab Therapy in a Murine Orthotopic Model of Anaplastic Thyroid Carcinoma , 2007, The Laryngoscope.

[138]  Qing Chen,et al.  Diseases at the crossroads: chronic myelogenous leukemia and tuberculosis. , 2015, Archives of Iranian medicine.

[139]  S. Ramalingam,et al.  Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced‐stage nonsmall cell lung cancer , 2008, Cancer.

[140]  D. Teachey,et al.  Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017-4023. , 2016, Blood.

[141]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[142]  J. Berek,et al.  CA125 Velocity at Relapse is a Highly Significant Predictor of Survival Post Relapse: Results of a 5-year Follow-up Survey to a Randomized Placebo-controlled Study of Maintenance Oregovomab Immunotherapy in Advanced Ovarian Cancer , 2008, Journal of immunotherapy.

[143]  David C. Smith,et al.  Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[144]  M. Namer,et al.  Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[145]  Israel Lowy,et al.  Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[146]  P. Keegan,et al.  FDA drug approval summary: panitumumab (Vectibix). , 2007, The oncologist.

[147]  K. Ang,et al.  Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[148]  V. Sondak,et al.  The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma , 2013, Nature Reviews Clinical Oncology.

[149]  Molly Brewer,et al.  Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[150]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. , 2006, The New England journal of medicine.

[151]  E. Small,et al.  Combination immunotherapy with prostatic acid phosphatase pulsed antigen‐presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy , 2006, Cancer.

[152]  M. Kurosumi,et al.  Combination docetaxel and trastuzumab treatment for patients with her-2-overexpressing metastatic breast cancer: A multicenter, phase-II study , 2006, Breast cancer.

[153]  A. Qattan,et al.  The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. , 2006, Neoplasia.

[154]  M. Saif,et al.  Management of skin toxicities of anti-EGFR agents in patients with pancreatic cancer and other GI tumors by using electronic communication: effective and convenient. , 2010, JOP : Journal of the pancreas.

[155]  H. Kantarjian,et al.  Phase II trial of HyperCVAD and Dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia , 2014, American journal of hematology.

[156]  J. Leonard,et al.  Radioimmunotherapy with tositumomab and iodine-131 tositumomab for non-Hodgkin’s lymphoma , 2007, Biologics : targets & therapy.

[157]  G. Feldmann,et al.  Everolimus for the treatment of pancreatic neuroendocrine tumors , 2012, Expert opinion on pharmacotherapy.

[158]  T. Okazaki,et al.  Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. , 2001, Science.

[159]  Loise M. Francisco,et al.  PD-L1 regulates the development, maintenance, and function of induced regulatory T cells , 2009, The Journal of experimental medicine.

[160]  G. Freeman,et al.  Tissue expression of PD-L1 mediates peripheral T cell tolerance , 2006, The Journal of experimental medicine.

[161]  J. Byrd,et al.  Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). , 2003, Blood.

[162]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[163]  G. Freeman,et al.  The Programmed Death-1 Ligand 1:B7-1 Pathway Restrains Diabetogenic Effector T Cells In Vivo , 2011, The Journal of Immunology.

[164]  Scott C. Williams,et al.  Radioimmunotherapy of Non-Hodgkin’s Lymphoma: From the ‘Magic Bullets’ to ‘Radioactive Magic Bullets’ , 2011, The Yale journal of biology and medicine.

[165]  P. Grivas,et al.  Monoclonal antibodies in the management of solid tumors. , 2006, Current topics in medicinal chemistry.

[166]  M. Nishimura,et al.  B7-H1 Expression on Non-Small Cell Lung Cancer Cells and Its Relationship with Tumor-Infiltrating Lymphocytes and Their PD-1 Expression , 2004, Clinical Cancer Research.

[167]  Lucio Crinò,et al.  Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[168]  Drew A. Torigian,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011, Science.

[169]  D. Stearns,et al.  Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma , 2010 .

[170]  E. Small,et al.  Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[171]  S. Anand,et al.  B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. , 2010, Blood.

[172]  N. Agarwal,et al.  Sequencing Systemic Therapies for Metastatic Kidney Cancer , 2015, Current Treatment Options in Oncology.