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Monoclonal antibodies play important roles in medical oncology. The antibodies were designed as specific molecular targeting drugs and supposed to have less toxicity to normal cells compared to classical cytotoxic agents. Indeed, they do not have severe bone marrow suppression, nausea, or vomiting unlike cytotoxic drugs. On the other hand, clinicians often undergo characteristic adverse events we have never experienced before the appearance of the molecular targeting drugs. To fully utilize these powerful yet particular medicines, we have to be well aware of their severe or fatal adverse events and comprehend how to manage those toxic events. In this manuscript, important adverse events including infusion reaction, gastrointestinal perforation, cardiotoxicity, venous thromboembolism, and interstitial lung disease are subjects for discussion.

Anti-tumor antibodies show significant anti-tumor activity against various tumor types especially by the combination with other cytotoxic drugs. Antibodies have been targeted against (1) Cell surface differentiation antigen, (2) Growth factor, (3) Growth factor receptor, (4) Signal transduction factors. By these antibodies significant increase in response rate, and prolongation of PFS/OS have been reported. Some antibodies have contributed to the establishment of new standard treatment. Patient selection has extensively been tried except for the treatment with bevacizumab. New problem appeared for the proof of principle study for immunotherapeutic antibody, ipilimumab because the mode of action of it seems to be non specific.

Cancer therapy utilizing cellular immunity has been developed using various reagents including stimulus for innate immunity, cytokines, vaccines, autologous cells and gene-vectors. Recently, mono-clonal antibodies have been added to the list as well. These reagents of modalities have been developed base on the findings in the basic research in cellular immunology which has been proven to have potent activities to suppress the tumor growth in either in vitro or in vivo. This review describes the characteristics of the reagents of modalities focusing on their mechanisms of action.

Monoclonal antibodies have become the most effective therapeutic modality for treating human cancer. Anti-cancer monoclonal antibodies can be targeted against cancer cells by several mechanisms. Even unconjugated antibodies show significant efficacy in the treatment of solid tumors and hematological malignancies. Immunoconjugates composed of antibodies conjugated to chemo-drugs, radioactive or toxins are powerful therapy for lymphomas and solid tumors. Moreover, immunomodulatory antibodies can promote the induction of anti-tumor immune responses by directly activating or inhibiting molecules of the immune system. Antibody structures now can be readily manipulated to facilitate selective interaction between the immune system and cancer cells, so that these reagents will become important components of the anti-neoplastic protocols of the future.

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, triggers a downstream signaling cascade through areas such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, survival and motility.Inhibiting EGFR activation has demonstrated significant promise as a molecular targeting therapy for various solid tumors. Two monoclonal antibodies (mAbs) targeting EGFR, cetuximab and panitumumab, are established to be new treatment options for metastatic colorectal cancer (mCRC). Among activating mutations in downstream of EGFR, the KRAS mutation, which is present in 40% of mCRC patients, has shown to be a predictive biomarker for resistance to anti-EGFR antibody therapy based on Caucasian studies. However, only a small proportion of patients achieved an objective response and benefit from anti-EGFR antibody, even among those with wild-type KRAS tumors. Other downstream factors in EGFR signaling are now being explored, such as the BRAF, PIK3CA, PTENgenes. Cetuximab, a chimeric immunoglobulin 1 (IgG1) monoclonal antibody, may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is influenced by FCrR1 a-H131R and FC7RIKa-V158F polymorphisms. Additional analysis of BRAF, PIK3CA, PTEN and FcqR genes in KRAS wild-type patients could narrow down the selection of patients who are most likely to benefit from anti-EGFR antibody therapy.

Cetuximab is a monoclonal antibody that inhibits human epidermal growth factor receptor, and was approved for metastatic advanced colorectal cancer (mCRC) in 2008 in Japan. Evidences confirming the efficacy of cetuximab have been accumulated in western countries. As the first- and second-line therapy, cetuximab plus chemotherapy showed longer survival compared with chemotherapy alone. As a third-line chemotherapy, among various anti-cancer agents for mCRC, only cetuximab could exhibit survival benefits in monotherapy or combination therapy with irinotecan. Recent studies suggest that the status of KRAS mutation is a predictive marker in colorectal cancer patients treated with cetuximab, and these findings lead to personalized cancer treatment.

The use of cetuximab, a mouse chimeric immunoglobulin G1 monoclonal antibody, is approved as anti-epidermal growth factor receptor(EGFR)therapy for the treatment of metastatic colorectal cancer in Japan. Further, panitumumab, matuzumab, nimotuzumab and zalutumumab which also target EGFR, are currently under clinical development. Cetuximab is the first that has been developed as an anti-EGFR antibody. Approximately 30% of the protein which constructs the mouse chimeric antibodies is from mouse, which yields the possibility that the mouse chimeric antibodies induce host immune-reaction. After cetuximab, the humanized monoclonal antibodies such as matuzumab and nimotuzumab, and fully humanized monoclonal antibodies such as panitumumab and zalutumumab, have been developed. In this article, we will introduce the current status of development of these four anti-EGFR antibodies, by focusing on the individual clinical trials using each anti-EGFR antibody.

EGFR constitute an attractive target for tumor therapy, because it is a transmembrane receptor tyrosine kinase which is critically involved in tumorigenesis by stimulating cell proliferation and inhibiting apoptosis or other biological functions. The anti-tumor effects of targeted therapy by anti-EGFR monoclonal antibodies are mainly based on direct inhibition of the EGFR signal transduction pathway. In addition, monoclonal antibody has the potential advantage of recruiting immune effect or mechanisms to kill tumor cells. The pre-clinical and clinical data indicated that antibody-dependent cellular cytotoxicity (ADCC) contributes to tumor cell lysis by anti-EGFR monoclonal antibodies. Some polymorphisms in Fc gamma receptor genes have been shown to be a predictive marker for the efficacy of anti-EGFR antibodies. Continued research on the immunotherapeutic mechanisms of monoclonal antibodies will improve the efficacy of antibody-based targeted therapy for cancer.

Cetuximab and panitumumab, both anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAb), have demonstrated clinical activity in patients with colorectal cancer. They are well tolerated, but they involve various adverse events that are rare among cytotoxic agents. Typical adverse events associated with anti-EGFR MAbs include infusion reaction, skin toxicity, lung toxicity, and hypomagnesemia. It is necessary to recognize and manage adverse events promptly to continue treatments without drug discontinuation. This report details the adverse events and their management with anti-EGFR MAbs use.

For the patient in whom the Kras gene variation appears, cancer cell grow and continue to multiply even if blocked by EGFR inhibitor. A topping the offered figure effect of cetuximab is not accepted. The addition of cetuximab for treatment of metastatic colorectal cancer with Kras wild-type tumors is effective.

The revised version of the Japanese colorectal cancer treatment guidelines by the Japanese Society for Cancer of the Colon and Rectum published in July 2009 showed remarkable changes in the field of systemic chemotherapy compared with the 2005 edition. Bevacizumab was approved in 2004 in United States, in 2005 in Europe, and in 2007 in Japan. On the other hand, cetuximab was approved in 2004 in Europe and United States, and in July 2008 in Japan. Besides, capecitabine was approved in September 2009 in Japan for not only adjuvant chemotherapy but also unresectable advanced colorectal cancer. Thus, we had one more treatment option of capecitabine with Oxaliplatin as CapeOx (XELOX). Therefore, most of the standard chemotherapy regimens in Western countries then became available in Japan. There has been no major difference in the drug treatment strategy except for the approval of panitumumab in Europe and the US, but this was not true in Japan. Now KRAS testing is recommended, and the indication for cetuximab is limited to KRAS wild type. Cetuximab can not be administered as the first-line treatment in Japan because KRAS testing is not covered by health insurance. This article deals with the difference in the anti EGFR antibody indication between the Japanese and overseas guidelines.

Anthracycline, taxane or trastuzumab play a central role in systemic chemotherapy for breast cancer. The standard of subsequent treatment is capecitabine, S-1, vinorelbine, irinotecan or gemcitabine. Ixabepilone or nanoparticle paclitaxel is effective for taxane-resistant breast cancer. Lapatinib proves effective for trastuzumab-resistant HER2-overexpressing breast cancer and also for brain metastasis. Trastuzumab-DM1, pertuzumab and neratinib are promising drugs. In terms of antiangiogenic agents, bevacizumab in combination with taxane demonstrates efficacy. Axitinib, sunitinib or pazopanib is under investigation. It is necessary to study the best manner of sequence and combination in these drugs.

The goal of therapy for recurrent cancer is to delay progression, relieve symptoms, and improve QOL. Cytotoxic agents combined with carboplatin for sensitive disease(TFIB6 months), and cytotoxic agents without cross-resistance to taxane/platinum against resistant diseases are required. There is a limit to improvement in efficacy by using cytotoxic agents, and a promising biological agent is expected to emerge while phase II studies of various biological agents continue. Regarding molecular-target drugs, only bevacizumab is confirmed to be effective at present, so it is used in monotherapy or combination therapy with anticancer drugs. In the GOG started a RCT of bevacizumab or placebo that was combined with TC regimen. Also in patients with chemo-sensitive disease, a RCT of TC regimen combined with or without bevacizumab started. In addition, EORTC and ICON trials of cediranib and erlotinib combined with platinum-based regimen are on-going.

For the current metastatic colorectal cancer, FOLFIRI or FOLFOX is chosen as first-line chemotherapy. Second-line irinotecan-based chemotherapy is commonly used after first-line oxaliplatin-based chemotherapy. Of course, FOLFOX becomes the second-line if FOLFIRI becomes primary therapy. It is important that these regimens combine molecular targetting agents such as Bevacizumab or Cetuximab. The addition of these new agents offers a chance to further enhance the activity of conventional chemotherapy.

The prognosis of advanced colorectal cancer has been improved by introduction of molecular targeting agents, such as bevacizumab and cetuximab. Several clinical trials revealed a median survival time of more than 2 years. However, the main purpose of chemotherapy for advanced colorectal cancer has not been cure but prolongation of life to date. One explanation of the difficulty of cure is the inherent and/or acquired resistance to chemotherapeutic agents and molecular targeting agents. A better understanding of the mechanisms of inherent resistance will make it possible to identify predictive markers of responder or non-responder to select the optimal patients for a certain drug. Additionally, knowledge of the acquired mechanism will provide for the rational development of therapies that circumvent or overcome resistance. Although the mechanisms of the resistance of molecular targeting agents for colorectal cancer are still unclear, the inherent resistance to cetuximab or panitumumab by why of expression of KRAS mutation is the first breakthrough in this field. Further basic research and biomarker analysis of large clinical study are necessary to clarify the resistance to molecular targeting agents.

The patient was a 73-year-old female with sigmoid colon cancer, who underwent resection of sigmoid colon cancer and liver metastasis. She was treated with 5-fluorouracil and levofolinate calcium(sLV5FU2)plus bevacizumab(BV) for advanced colorectal cancer. She was treated with angiotensin II receptor blocker(ARB)because hersystolic blood pressure was 200 mmHg and her diastolic blood pressure 100 mmHg after five courses of BV therapy. As a result, her blood pressure was controlled. It was possible to administer BV. Therefore, ARB may be the preferred antihypertensive agent in the management of BV-induced hypertension.

Monoclonal antibody treatment, which is one of the most promising molecular targeting cancer therapies, has recently become indispensable for the treatment of cancer due to its effectiveness and fewer side effects. Infusion reactions, which are similar to hypersensitivity or allergic reactions, are the generic term for the acute characteristic harmful reactions commonly associated with monoclonal antibody treatment. Those typically occur within the first 2 hours of the first infusion and are generally mild-to-moderate reactions which can be managed by either temporary interruption of infusion or administration of supportive care including corticosteroids, oxygen, or intravenous fluids. However, there are sometimes severe or life-threatening reactions, thus indicating the importance of closely observing the patient following the monoclonal antibody treatment. It is quite important that the entire medical staff understands the practical information regarding the timing and prevention or management of infusion reactions. In addition, it is also necessary to establish a system for prompt management of infusion reactions. Furthermore, sufficient information must be provided to the patient regarding infusion reactions.

Gemtuzumab Ozogamicin (GO) targets leukemia cells expressing CD33 by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. GO has been approved in Japan as monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (AML)since 2005. GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adult AML. Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimen. Although caution is advised when administering GO within 115 days of a stem cell transplantation (SCT) procedure because of veno-occlusive disease, recent clinical studies overseas suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic SCT in patients with relapsed AML. In order to reduce toxicity and improve efficacy, its optimal dose and schedule should be defined by large clinical trials.

The function of IgG antibody with regard to L-asparaginase (L-asp) was investigated in vivo. Blood samples were collected before, during and after IV administration of L-asp (6,000 U/sqm for 10 days) in 18 children with acute lymphoblastic leukemia (ALL) previously treated with L-asp. Using enzyme-linked immunosorbent assay (ELISA), serum levels of L-asp and anti-L-asp IgG antibody were measured simultaneously. In 11 cases, the level of anti-L-asp IgG antibody increased prior to, but decreased to within the normal range after drug administration whereas the level of serum L-asp increased after drug administration. In 5 cases, the level of anti-L-asp IgG antibody increased as the level of serum L-asp decreased after drug administration. In contrast, in the 13 cases with no increase in anti-L-asp IgG antibody during L-asp administration, the serum L-asp level was stable. These data indicate that anti-L-asp IgG antibodies play an important role in the immunoclearance of L-asp. We would like to continue to carefully follow patients showing high titers of anti-L-asp IgG antibody during the administration of L-asp.

In clinical practice, a number of tests are conducted to determine the immune reactivity of the patients. The principal cell in immunological surveillance against cancer has been thought to be the T cell. However, multiple immunological methods to evaluate the T cell function have failed to confirm a major role for the T cell in immunological surveillance. The role of other potential effector cells such as NK cells, K cells, macrophages and granulocytes needs more intensive investigation. In this report the effects of anticancer agents on immune effector cells were analyzed and the possibility about the development of a reliable monitoring procedure for determining a potent treatment protocol was discussed.