RESUMO
Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in-depth characterization of acute responses to TDBs in tumor-bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM-1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.
Assuntos
Anticorpos Biespecíficos , Neoplasias , Camundongos , Animais , Linfócitos T , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Neoplasias/tratamento farmacológico , Comunicação Celular , Células EndoteliaisRESUMO
Fibromatoses encompass a broad group of histopathologically similar fibroblastic/myofibroblastic proliferations with divergent clinical manifestations and behavior. Deep (desmoid-type) fibromatoses are typically large, rapidly growing, and locally aggressive tumors that occur in the abdominal wall, mesentery, and extra-abdominal soft tissue, principally the musculature of the trunk and extremities. Most sporadic cases of desmoid fibromatosis harbor inactivating mutations in CTNNB1, the gene encoding beta-catenin. Tumors occurring in the context of familial adenomatous polyposis and Gardner syndrome bear inactivating mutations in APC. By contrast, mutations in CTNNB1 or APC have not been identified in cases of superficial fibromatosis. Cutaneous involvement by desmoid fibromatosis is exceedingly rare. Here we present a 78-year-old male with desmoid-type fibromatosis arising in the dermis of the right medial calf with a pathogenic mutation in CTNNB1 and a variant of unknown significance in APC.
Assuntos
Polipose Adenomatosa do Colo/patologia , Derme/patologia , Fibromatose Agressiva/diagnóstico , Síndrome de Gardner/patologia , Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo , Idoso , Diagnóstico Diferencial , Fibromatose Agressiva/genética , Fibromatose Agressiva/cirurgia , Síndrome de Gardner/genética , Humanos , Masculino , Mutação , Resultado do Tratamento , beta Catenina/metabolismoRESUMO
BACKGROUND AND AIMS: Endoscopic resection (ER) is a safe and effective treatment for nonmalignant complex colorectal polyps (complex polyps). Surgical resection (SR) remains prevalent despite limited outcomes data. We aimed to evaluate SR outcomes for complex polyps and compare SR outcomes to those of ER. METHODS: We performed a single-center, retrospective, cohort study of all patients undergoing SR (2003-2013) and ER (2011-2013) for complex polyps. We excluded patients with invasive carcinoma from the SR cohort. Primary outcomes were 12-month adverse event (AE) rate, length of stay (LOS), and costs. SR outcomes over a 3-year period (2011-2013) were compared with the overlapping ER cohort. RESULTS: Over the 11-year period, 359 patients (mean [± SD] age 64 ± 11 years) underwent SR (58% laparoscopic) for complex polyps. In total, 17% experienced an AE, and 3% required additional surgery; 12-month mortality was 1%. Including readmissions, median LOS was 5 days (IQR 4-7 days), and costs were $14,528. When an AE occurred, costs ($25,557 vs $14,029; P < .0001) and LOS (11 vs 5 days; P < .0001) significantly increased. From 2011 to 2013, 198 patients were referred for ER, and 73 underwent primary SR (70% laparoscopic). There was a lower AE rate for ER versus primary SR (10% vs 18%; P = .09). ER costs (including rescue SR, when required) were lower than those of primary SR ($2152 vs $15,264; P < .0001). CONCLUSIONS: AEs occur in approximately one-sixth of patients after SR for complex polyps. ER-accounting for rescue SR caused by malignancy, AEs, or incomplete resection-is associated with markedly lower costs than SR. These data should be used when counseling patients about treatment options for complex polyps.
Assuntos
Adenoma/cirurgia , Colectomia , Pólipos do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais/cirurgia , Ressecção Endoscópica de Mucosa , Custos de Cuidados de Saúde , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Idoso , Feminino , Humanos , Tempo de Internação/economia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/economia , Estudos Retrospectivos , Estados UnidosRESUMO
Hemangiomas are common lesions, best known for their appearance in the liver. Their appearance in less common locations, such as the gastrointestinal and genitourinary tracts, is less well known. We will review the typical and atypical appearance of hemangiomas in these locations on sonography, CT, and MRI.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Hemangioma/diagnóstico , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Ultrassonografia , Neoplasias Urogenitais/diagnóstico , Humanos , Neoplasias HepáticasRESUMO
Liver predominant small cell carcinoma is rare but often presents as hyperacute liver failure with unknown primary and is a medical emergency. We present 2 autopsy and 7 biopsy cases of liver predominant small cell carcinoma and demonstrate that these patients present with liver failure and identifiable hepatomegaly but lack discrete lesions on imaging as well as no mass lesions identified in other organs including lung. Compared with the multiple nodules of metastatic small cell carcinoma in the liver, unique morphologic feature of liver predominant/primary small cell carcinoma in autopsy and biopsy specimens was a diffuse infiltration of small blue neoplastic cells predominantly in the sinusoidal space in the liver parenchyma. Before diagnosing liver predominant/primary small cell carcinoma, other infiltrating small blue cell neoplasms including lymphoma and peripheral neuroectodermal tumor need to be ruled out through immunohistochemistry. We, therefore, demonstrate that liver biopsy together with a rapid panel of immunostains is necessary to firmly establish a diagnosis of liver predominant small cell carcinoma and allow clinicians to immediately implement potentially lifesaving chemotherapy.
Assuntos
Carcinoma de Células Pequenas/patologia , Hepatomegalia/patologia , Falência Hepática Aguda/patologia , Neoplasias Hepáticas/patologia , Autopsia , Biópsia , Carcinoma de Células Pequenas/diagnóstico por imagem , Bases de Dados Factuais , Hepatomegalia/diagnóstico por imagem , Humanos , Falência Hepática Aguda/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)-amplified and/or -overexpressed and/or -mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Adulto , Humanos , Trastuzumab/efeitos adversos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The consensus molecular subtypes (CMS) of colorectal cancer (CRC) is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signals, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our study illustrates the potential of ST to resolve CRC molecular heterogeneity and thereby help advance personalized therapy.
RESUMO
Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in approximately 10% of cases and is thought to represent more advanced disease. The intravascular nature of VTT suggests that it may serve as a source for hematogenous metastases. RCC with VTT and distant metastasis provides unique opportunities to examine the origins and emergence timing of these distinct tumor lesions, and to identify molecular correlates with disease state. We performed multi-region exome and RNA-sequencing analysis of 16 patients with RCC with VTT, with eight patients also having sequenced metastasis, to identify genomic alterations, biological pathways, and evolutionary processes contributing to VTT and metastasis, and to ask whether metastasis arises directly from or independent of VTT. No specific genomic alterations were associated with VTT. Hallmark copy-number alterations (deletions of 14q, 8p, and 4q) were associated with metastasis and disease recurrence, and secondary driver alterations tended to accumulate in metastatic lineages. Mismatch repair mutational signatures co-occurred across most tumors, suggesting a role for intracellular DNA damage in RCC. Robust phylogenetic timing analysis indicated that metastasis typically emerged before VTT, rather than deriving from it, with the earliest metastases predicted to emerge years before diagnosis. As a result, VTT in metastatic cases frequently derived from a metastatic lineage. Relative to the primary tumor, VTT upregulated immediate-early genes and transcriptional targets of the TNFα/NF-κB pathway, whereas metastases upregulated MTOR and transcriptional targets downstream of mTORC1 activation. IMPLICATIONS: These results suggest that VTT and metastasis formation occur independently, VTT presence alone does not necessarily imply more advanced disease with inevitably poor prognosis.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Trombose , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Recidiva Local de Neoplasia , FilogeniaRESUMO
New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.
Assuntos
Anticorpos Biespecíficos , Neoplasias Colorretais , Imunoglobulinas , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoglobulinas/imunologia , Camundongos , Instabilidade de Microssatélites , Linfócitos T/imunologiaRESUMO
BACKGROUND: Individualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types. METHODS: We combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting. RESULTS: Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases. CONCLUSIONS: We show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.
Assuntos
Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/metabolismo , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias/genéticaRESUMO
Tumor enrichment in low tumor content tissues, those below 20% tumor content depending on the method, is required to generate quality data reproducibly with many downstream assays such as next generation sequencing. Automated tissue dissection is a new methodology that automates and improves tumor enrichment in these common, low tumor content tissues by decreasing the user-dependent imprecision of traditional macro-dissection and time, cost, and expertise limitations of laser capture microdissection by using digital image annotation overlay onto unstained slides. Here, digital hematoxylin and eosin (H&E) annotations are used to target small tumor areas using a blade that is 250 µm2 in diameter in unstained formalin fixed paraffin embedded (FFPE) or fresh frozen sections up to 20 µm in thickness for automated tumor enrichment prior to nucleic acid extraction and whole exome sequencing (WES). Automated dissection can harvest annotated regions in low tumor content tissues from single or multiple sections for nucleic acid extraction. It also allows for capture of extensive pre- and post-harvest collection metrics while improving accuracy, reproducibility, and increasing throughput with utilization of fewer slides. The described protocol enables digital annotation with automated dissection on animal and/or human FFPE or fresh frozen tissues with low tumor content and could also be used for any region of interest enrichment to boost adequacy for downstream sequencing applications in clinical or research workflows.
Assuntos
Dissecação/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/cirurgia , Animais , HumanosRESUMO
Formalin-fixed, paraffin-embedded (FFPE) tissue is the most commonly used material for tumor molecular profiling, therapy selection, and prognostication. Tumor tissue enrichment by tissue dissection is highly recommended to generate quality data reproducibly for use in downstream assays, such as real-time PCR and next-generation sequencing. The aim of this study was to evaluate the performance of the automated tissue dissection tool AVENIO Millisect System compared with a manual dissection method using 18 FFPE tissue specimens. The study assessed performance of these two methods with paraffinized and deparaffinized sections at 5- and 10-µm thickness as well as at low (5% to 10%) and high (>50%) tumor content. In addition, compatibility with various nucleic acid and protein extraction methods was assessed. Overall, dissection by Millisect resulted in statistically significantly higher yields of nucleic acids and protein compared with manual dissection (P = 0.00524). In downstream analysis on a statistically nonpowered sample set, EGFR mutation testing by PCR led to highly concordant results, and next-generation sequencing testing yielded significantly higher allelic frequencies when tissue was dissected by Millisect compared with manual scraping, demonstrating noninferiority of the automated method. In summary, the AVENIO Millisect System may replace manual labor and support automation of FFPE tumor tissue workflows in clinical molecular laboratories with high testing volumes with adequate validation.
Assuntos
Dissecação/métodos , Fixadores/química , Formaldeído/química , Técnicas de Diagnóstico Molecular/métodos , Neoplasias/diagnóstico , Inclusão em Parafina/métodos , Fixação de Tecidos/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Confiabilidade dos Dados , Receptores ErbB/genética , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncologia/métodos , Mutação , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos TestesRESUMO
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
Assuntos
Biomarcadores Tumorais/genética , Fibroblastos/imunologia , Neoplasias Ovarianas/imunologia , Análise de Célula Única/métodos , Células Estromais/imunologia , Linfócitos T/imunologia , Microambiente Tumoral , Biomarcadores Tumorais/imunologia , Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Quimiocina CXCL16/genética , Quimiocina CXCL16/imunologia , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA-Seq , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
Ovarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with â¼70% prevalence in the serous cancer subset. Bispecific antibodies targeting CD3 on T cells and a tumor antigen on cancer cells have demonstrated significant clinical activity in hematologic cancers. We have developed an anti-LYPD1/CD3 T-cell-dependent bispecific antibody (TDB) to redirect T-cell responses to LYPD1 expressing ovarian cancer. Here we characterize the nonclinical pharmacology of anti-LYPD1/CD3 TDB and show induction of a robust polyclonal T-cell activation and target dependent killing of LYPD1 expressing ovarian cancer cells resulting in efficient in vivo antitumor responses in PBMC reconstituted immune-deficient mice and human CD3 transgenic mouse models. Anti-LYPD1/CD3 TDB is generally well tolerated at high-dose levels in mice, a pharmacologically relevant species, and showed no evidence of toxicity or damage to LYPD1 expressing tissues.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Complexo CD3/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Sequência de Aminoácidos , Animais , Anticorpos Biespecíficos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Ovarianas/patologiaRESUMO
Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ε expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. Mol Cancer Ther; 17(4); 776-85. ©2018 AACR.
Assuntos
Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/farmacocinética , Complexo CD3/imunologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Receptor ErbB-2/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Afinidade de Anticorpos , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/patologia , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab-immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell-directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.
Assuntos
Afinidade de Anticorpos/imunologia , Complexo CD3/imunologia , Citotoxicidade Imunológica , Receptor ErbB-2/imunologia , Anticorpos Biespecíficos/imunologia , Linhagem Celular Tumoral , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Ativação Linfocitária/imunologia , Ligação ProteicaRESUMO
Composite tumors are formed when there is intermingling between two components of separate tumors seen histologically. Cases demonstrating composite tubular adenoma with other types of tumors in the colon are rare. Composite tubular adenomas with nonlymphoid tumors including carcinoids, microcarcinoids, and small cell undifferentiated carcinoma have been reported in the literature. The occurrence of composite lymphoma and tubular adenoma within the colorectal tract is extremely rare. Only three cases have been reported and include one case of mantle cell lymphoma and two cases of diffuse large B-cell lymphoma arising in composite tubular adenomas. We present the first case of composite Epstein-Barr virus-associated B-cell lymphoproliferative disorder and tubular adenoma in a rectal polyp with a benign endoscopic appearance.
Assuntos
Adenoma/patologia , Linfócitos B/patologia , Infecções por Vírus Epstein-Barr/patologia , Transtornos Linfoproliferativos/patologia , Pólipos/patologia , Neoplasias Retais/patologia , Adenoma/complicações , Idoso , Infecções por Vírus Epstein-Barr/complicações , Humanos , Transtornos Linfoproliferativos/complicações , Masculino , Pólipos/complicações , Neoplasias Retais/complicaçõesRESUMO
Malignant melanoma has a variety of morphologic patterns and can metastasize and mimic any type of neoplastic process creating significant diagnostic difficulty. When metastasis to the gastrointestinal system is identified, it is most commonly associated with widely metastatic disease. We report a rare case of isolated gallbladder intramucosal metastatic melanoma with features mimicking lymphoepithelial carcinoma in an adult patient who presented with cholecystitis. Additionally, we report the imaging and morphologic features and discuss the importance of these findings along with a clear clinical history and immunohistochemical profile to make a definitive diagnosis.
Assuntos
Neoplasias da Vesícula Biliar/secundário , Melanoma/secundário , Neoplasias Cutâneas/patologia , Colecistografia , Diagnóstico Diferencial , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/diagnóstico , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Mucosa/patologia , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
It has been recently recognized that adenovirus is a pathogen with high morbidity and mortality among immunocompromised patients, particularly after solid organ or stem cell transplant. Confluent necrotizing hepatitis secondary to adenovirus infection alone or together with other organ involvement is extremely rare. There are only 32 cases of confluent necrotizing hepatitis reported in adults since 1960 and most occur after iatrogenic immunosuppression for bone marrow or solid organ transplantation or in other states of immunosuppression, including acquired immunodeficiency syndrome or chemotherapy treatment. We present the first case of concurrent adenovirus-induced necrotizing hepatitis and enterocolitis in an adult patient after double cord stem cell transplant for refractory Crohn's disease. Additionally, we report the imaging and morphologic findings and discuss the potential significance of morphology and immunohistochemistry as a practical approach for identifying adenovirus.