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This review focuses on the recent advances in clinical data regarding antibody-based therapy in the management of solid tumors. We also discuss perspectives on antibody-based therapy in the future. Thorough understanding of the complex interactions between components of the immunological response has led to interest in the concept of immune-mediated therapy for solid tumors. Over the last few years, several humanized and chimeric monoclonal antibodies (MAbs) targeting human epidermal receptor 2 (HER2), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) have been employed in treating solid tumors, including breast, colorectal, lung, head and neck, and gynecologic cancers. Trastuzumab, bevacizumab, cetuximab, and panitumumab are MAbs that are most widely used in clinical practice with acceptable rates of adverse events. Combination of MAbs with small-molecule inhibitors of the same pathway could potentially increase the efficacy and specificity of antibody-based treatment. Immune-mediated effects may be further exploited with the use of bivalent molecules.
Mol Med
PMID:Recent advances relating to the clinical application of naked monoclonal antibodies in solid tumors. 1930 91

Ten years after the first clinical application of Rituximab, an anti-CD20 recombinant monoclonal antibody, immunotherapy has become common practice in oncology wards. Thanks to the great diversity of the immune system and the powerful methodology of genetic engineering, the pharmacologic potential of antibody-based therapy is far from exhaustion. The recent application of Trastuzumab, an antibody to a receptor tyrosine kinase, in adjuvant breast cancer therapy marks the beginning of a new phase in cancer treatment. Here we discuss molecular mechanisms of antibody-based therapy, the emerging ability to target minimal disease and the therapeutic potential of combining antibodies with other modalities.
Mol Oncol 2007 Jun
PMID:Cancer therapeutic antibodies come of age: targeting minimal residual disease. 1938 86

Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Because the malignant phenotype of tumours is the culmination of multiple mutations that occur in several genes eventually leading to aberrant signalling pathways, oncolytic viruses, either natural or engineered, specifically target tumour cells, taking advantage of this cellular deviant signalling for their replication. Reovirus is one such naturally occurring double-stranded RNA (dsRNA) virus that exploits altered Ras signalling pathways in a myriad of cancers. The ability of reovirus to infect and lyse tumours both solid and haematological, under in vitro, in vivo, and ex vivo conditions, is discussed in this chapter. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis. In addition, the synergistic anti-tumour effects of reovirus in combination with radiation or chemotherapy has also been demonstrated for reovirus-resistant and moderately sensitive tumours. In most of the clinical trials undertaken to date, an anti-reovirus immune response has been seen likely circumventing efficacy. Investigation into the use of reovirus as an immune adjuvant is currently underway to try and re-direct this immune response to tumour. Reovirus phase I clinical trials have shown indications of efficacy and several phase I/II trials are ongoing at present. The extensive pre-clinical efficacy, replication competency, and low toxicity profile in humans has placed the reovirus as an attractive anti-cancer therapeutic for ongoing clinical testing.
Methods Mol Biol 2009
PMID:Oncolytic viral therapy using reovirus. 1956 24

Breast cancer is one of the most common and leading causes of cancer death in women. Early diagnosis, selection of appropriate therapeutic strategies, and efficient follow-up play an important role in reducing mortality. Recently, HER-2/neu in breast cancer has been routinely used to guide treatment of using Trastuzumab in less than 25-30% of patients. More new biomarkers will be still expected in the future to tailor treatments. However, there are still many obstacles in developing clinically useful biomarker tests for clinical practice. A lack of specificity of tumor markers and lack of sensitivity of testing systems have been noticed, which limit their clinical use. Finding biomarkers for breast cancer could allow physicians to identify individuals who are susceptible to certain types and stages of cancer to tailor preventive and therapeutic modalities based on the genotype and phenotype information. These biomarkers should be cancer specific, and sensitively detectable in a wide range of specimen(s) containing cancer-derived materials, including body fluids (plasma, serum, urine, saliva, etc.), tissues, and cell lines. This review highlights the new trends and approaches in breast cancer biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches, and follow-up of patients.
Genet Test Mol Biomarkers 2009 Oct
PMID:New trends in molecular biomarker discovery for breast cancer. 1981 13

Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of IL-12 when given in combination with trastuzumab and paclitaxel to patients with metastatic HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m(2) every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic HER2-positive tumors (breast, 7; colon, 6; esophagus, 4; stomach, 2; pancreas, 1; thyroid, 1). The IL-12 component was dose-escalated in cohorts of three patients. The dose-limiting toxicity was grade 3 fatigue at the 300 ng/kg dose level in two patients. The recommended phase II dose was 200 ng/kg administered s.c. There was one complete response in a patient with breast cancer, partial responses in 4 patients (breast, 2; esophageal, 2), and stabilization of disease lasting 3 months or greater (SD) in 6 other patients. All but one response occurred in patients with HER2 3+ disease. Two SD patients completed 1 year of therapy. Ten patients had progressive disease. There was increased activation of extracellular signal-regulated kinase in peripheral blood mononuclear cells and increased levels of IFN-gamma and several chemokines in patients with clinical benefit (complete response, partial response, or SD), but not in patients with progressive disease. IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers.
Mol Cancer Ther 2009 Nov
PMID:A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies. 1988 43

HER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations.
Mol Cancer Ther 2009 Nov
PMID:Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents. 1988 55

Humanized antibodies vary and have certain effects, but they are expensive and require repeated administration. We developed cells which constantly express a humanized antibody, and we performed anticancer humanized antibody therapy involving cell transplantation. Genes with the same amino acid sequence as that of the variable region of trastuzumab (Herceptin) as the humanized anti-HER2 monoclonal antibody were produced by overlap-PCR and were connected to the anti-human CD16 antibody [anti-HER2+anti-CD16 single-chain antibody (anti-HER2+CD16 scAb)]. For transplantation, stem cell-like cells that are immunologically tolerant and do not transform into cancer [mouse embryo fibroblast cell line C3H10T1/2 (10T1/2)] were used. The antibody was incorporated into 10T1/2 (antibody-expressing cells) using the pMX-IRES-EGFP retroviral vector. Cell supernatants and human monocytes were exposed to the human breast cancer strain HTB131 expressing HER2, and the in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) effects were evaluated. After the transplantation of antibody-expressing and HTB131 cells into SCID mice, human monocytes were intermittently administered, and the in vivo ADCC effects were evaluated. We found that the ex vivo dead cell rate was 15.4% for Herceptin, 5.6% for anti-HER2+CD16 scAb, 1.5% for anti-CD16 scAb, and 2.1% for the control, demonstrating the antitumor effects of anti-HER2+CD16 scAb. In an antibody-expressing cell transplantation model, the inhibitory effects of this antibody on HTB131 cell establishment were observed. In conclusion, the establishment of breast cancer cells in the peritoneum was inhibited by the transplantation of antibody-expressing cells. Since this method requires cell transplantation only once, the drug cost may be reduced.
Int J Mol Med 2010 Feb
PMID:Bispecific anti-HER2 and CD16 single-chain antibody production prolongs the use of stem cell-like cell transplantation against HER2-overexpressing cancer. 2004 29

In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.
Mol Ther 2010 Apr
PMID:Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. 2035 76

Trastuzumab and lapatinib provide clinical benefit to women with human epidermal growth factor receptor 2 (HER)-positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. Consequently, there is an urgent need to identify new predictive factors for these agents. The aim of this study was to investigate the role of receptor tyrosine kinase signaling and phosphoinositide 3-kinase (PI3K)/AKT pathway activation in conferring resistance to trastuzumab and lapatinib. To address this question, we evaluated response to trastuzumab and lapatinib in a panel of 18 HER2-amplified cell lines, using both two- and three-dimensional culture. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1, and MDA-453 cell lines were found to be innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202, and UACC-893 cells are innately lapatinib resistant. Lapatinib was active in de novo (SUM-225, HCC-1419, and HCC-1954) and in a BT-474 cell line with acquired resistance to trastuzumab. In these cells, trastuzumab had little effect on AKT phosphorylation, whereas lapatinib retained activity through the dephosphorylation of AKT. Increased phosphorylation of HER2, epidermal growth factor receptor, HER3, and insulin-like growth factor IR correlated with response to lapatinib but not trastuzumab. Loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab, but lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway correlates with resistance to trastuzumab, which can be overcome by lapatinib. In conclusion, pharmacologic targeting of the PI3K/AKT pathway may provide benefit to HER2-positive breast cancer patients who are resistant to trastuzumab therapy.
Mol Cancer Ther 2010 Jun
PMID:Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. 2070 Aug 98

Roche Holding AG, and its subsidiaries Genentech Inc and Chugai Pharmaceutical Co Ltd, are developing trastuzumab emtansine (trastuzumab-DM1) for the treatment of HER2+ metastatic breast cancer. Trastuzumab emtansine is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc's cytotoxic and antimitotic maytansine derivative DM1. The maytansinoids bind microtubules in a manner similar to the vinca alkaloids; however, maytansinoids have been recognized to be 20- to 100-fold more potent at blocking mitosis. Nevertheless, the use of these compounds as single agents is limited by toxicity. By conjugating DM1 with trastuzumab, the delivery of the cytotoxic agent to target cells is more specific and reduces the safety concerns. In preclinical studies, the conjugation was effective in breast cancer cell lines resistant to trastuzumab, and demonstrated complete tumor regression in SCID mice bearing KPL4 breast cancer xenografts. Clinically, trastuzumab emtansine exhibited efficacy in patients with HER2+ metastatic breast cancer who had progressed on previous chemotherapy regimens or with trastuzumab therapy. Furthermore, preclinical studies have reported that trastuzumab emtansine potentiates the effect of a number of chemotherapeutic agents (including carboplatin, 5-fluorouracil and docetaxel), other antibodies, receptor tyrosine kinase inhibitors and PI3K inhibitors, and many of these combinations are set to be tested in humans. Trastuzumab emtansine offers an exciting new option for the treatment of patients with refractory, metastatic breast cancer.
Curr Opin Mol Ther 2010 Jun
PMID:Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer. 2052 Dec 24


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