Lung cancer causes the largest number of cancer-related deaths in the world. Most (85%) of lung cancers are classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). The two predominant NSCLC histological phenotypes are adenocarcinoma (ADC) and squamous cell carcinoma (LSQCC). ADCs display several recurrent genetic alterations, including: KRAS, BRAF and EGFR mutations; recurrent mutations and amplifications of several oncogenes, including ERBB2, MET, FGFR1 and FGFR2; fusion oncogenes involving ALK, ROS1, Neuregulin1 (NRG1) and RET. In LSQCC recurrent mutations of TP53, FGFR1, FGFR2, FGFR3, DDR2 and genes of the PI3K pathway have been detected, quantitative gene abnormalities of PTEN and CDKN2A. Developments in the characterization of lung cancer molecular abnormalities provided a strong rationale for new therapeutic options and for understanding the mechanisms of drug resistance. However, the complexity of lung cancer genomes is particularly high, as shown by deep-sequencing studies supporting the heterogeneity of lung tumors at cellular level, with sub-clones exhibiting different combinations of mutations. Molecular studies performed on lung tumors during treatment have shown the phenomenon of clonal evolution, thus supporting the occurrence of a temporal tumor heterogeneity.

Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells.

The present invention relates to antibodies and their fragments that are immunoreactive to the mammalian, and more particularly, the human B7-H3 receptor and to uses thereof, particularly in the treatment of cancer and inflammation. The invention thus particularly concerns humanized B7-H3-reactive antibodies and their immunoreactive fragments that are capable of mediating, and more preferably enhancing the activation of the immune system against cancer cells that are associated with a variety of human cancers.

Antibodies reactive with b7-h3, immunologically active fragments thereof and uses thereof

An increasing number of studies show that genetic markers can aid in refining prognostic information and predicting the benefit from systemic therapy. Our goal was to develop a high throughput, cost-effective and simple methodology for the detection of clinically relevant hot spot mutations in colon cancer. The Maldi-Tof mass spectrometry platform and OncoCarta panel from Sequenom were used to profile 239 colon cancers and 39 metastatic lymph nodes from NSABP clinical trial C-07 utilizing routinely processed FFPET (formalin-fixed paraffin-embedded tissue). Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples. Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta. Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible. Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database. The frequencies were 43.5% for KRAS, 20.1% for PIK3CA, and 12.1% for BRAF. In addition, infrequent mutations in NRAS, AKT1, ABL1, and MET were detected. Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant. All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only. This study describes a high throughput technology that can be used to interrogate DNAs isolated from routinely processed FFPET and identifies the specific mutations that are common to colon cancer. The development of this technology and the ColoCarta panel may provide a mechanism for rapid screening of mutations in clinically relevant genes like KRAS, PIK3CA, and BRAF. 
ClinicalTrials.gov: NSABP C-07: NCT00004931

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/103252/1/T201005904.pdf

A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes

The invention provides the identification and characterization of disease and cancer-associated antigen, TES7 The invention also provides a family of monoclonal antibodies that bind to antigen TES7, methods of diagnosing and treating various human cancers and diseases that express TES7

TES7 and antibodies that bind thereto

An antibody exhibiting antitumor activity that binds to B7-H3, a functional fragment of the antibody, a pharmaceutical composition that includes the antibody or the functional fragment, methods for making the antibody or the functional fragment, methods for treating a tumor using the antibody or the functional fragment, and polynucleotides encoding the antibody or the functional fragment

Anti-b7-h3 antibody

There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with <10% remaining double positive. We also demonstrated the potential of the CSLC to differentiate to multi-lineage structures with branching lung morphology expressing bronchial, alveolar and neuroendocrine markers in vitro. Taken together the properties of these ASC-derived CSLC suggests that ASC may arise from a primitive lung stem cell distinct from the bronchial-alveolar or basal stem cells.

Isolation of cancer stem like cells from human adenosquamous carcinoma of the lung supports a monoclonal origin from a multipotential tissue stem cell.

2555 B7-H3 is a member of the B7 super-family of immunoregulatory proteins and is the only member existing in two isoforms. A two-domain structure, as shared by all members of the family, has been detected in mice and hamsters, while a four-domain structure, known as B7-H3b or B7-H3-4Ig, was found exclusively in humans and monkeys. B7-H3-4Ig is believed to originate from gene duplication - both IgV-IgC domains share very high sequence similarity. Although its function is still unclear, both co-stimulatory and co-inhibitory responses have been reported for B7-H3, suggesting B7-H3 may interact with multiple receptors or have diverging activities depending on biological context. The monoclonal antibody TES7 was raised using Raven’s cancer therapy platform and recognizes the B7-H3-4Ig antigen, but not a B7-H3-2Ig variant. ELISA-based binding studies with recombinant B7-H3 indicate TES7 requires a specific cell surface presentation of B7-H3-4Ig and TES7 binding is sensitive to antigen density and possibly conformation. Immunohistochemistry studies showed that TES7 exhibits very little binding to normal human tissues, while it binds to select fetal tissues and multiple human tumors, including prostate, colon, breast and lung adenocarcinomas, consistent with B7-H3-4Ig being an oncofetal antigen. Contrary to other B7-H3 antibodies, TES7 showed only very restricted staining on normal tissue and strong anti-tumor activity in vivo experiments. In addition, TES7 recognizes an antigen expressed on a broad variety of Raven-derived cancer stem cell lines from solid tumor explants, including colon, pancreas, prostate, lung, and breast cancers. Thus TES7 may recognize an epitope on B7-H3-4Ig that is unique relative to other anti-B7-H3 antibodies. The anti-tumor activity of TES7 was assessed in subrenal capsule (SRC) and subcutenous (SC) xenograft models. Treatment of established Hs700T pancreatic adenocarcinoma SC xenografts with TES7 led to a significant reduction in tumor size up 50% after 4 weeks of treatment. Further, treatment of prostate tumor stem cell SRC xenografts, with TES7 at 50 mg/kg/dose twice weekly for 3 weeks, led to a ~60% reduction in tumor size. Since tumor progression and development are influenced by intrinsic and micro-environmental factors, we investigated the cytokine profile of cancer stem cells in response to TES7. Importantly, TES7 significantly reduced the secretion of VEGF up to 60% in a subset of the tumor stem cell lines examined. This is the first report of regulation of angiogenic factors by tumor stem cells with an antibody that we are aware of, and suggests that regulation of VEGF may contribute to the anti-tumor activity of TES7 observed in vivo.

The anti-B7-H3-4Ig antibody TES7 recognizes cancer stem cell lines, modulates angiogenic factor secretion, and exhibits potent anti-tumor activity in vivo

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Isolation of cancer stem like cells from human adenosquamous carcinoma of the lung supports a monoclonal origin from a multipotential tissue stem cell.

The anti-B7-H3-4Ig antibody TES7 recognizes cancer stem cell lines, modulates angiogenic factor secretion, and exhibits potent anti-tumor activity in vivo