CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma

Raj, Deepak; Kotopoulea-Nikolaidi, Maria; Garces, Irene; Lorizio, Daniela; Castro, Natalia M.; Caiafa, Sabrina G.; Moore, Kate M.; Brown, Nicholas F.; Kocher, Hemant M.; Duan, Xinrui; Nelson, Brad H.; Lemoine, Nick R.; Marshall, John F.

doi:10.1158/1078-0432.ccr-19-2163

Cited by 45 publications

(42 citation statements)

References 44 publications

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“…However, down-regulation of CEACAM7 in hyperplastic polyps and early adenomas represent some of the earliest observable molecular events leading to colorectal tumors ( Scholzel et al, 2000 ). Though CEACAM7 expression was thought to be restricted to the epithelial cells of the colon and pancreas, according to the Human Protein Atlas, grandular cells of the breast have moderate CEACAM7 protein expression ( Uhlen et al, 2015 ; Raj et al, 2021 ). How CEACAM7 plays a role in breast cancer is currently unknown, but the link could even be indirect and due to expression in non-breast tissue ( Ferreira et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk – A Comparative Oncology Approach to Discovery

2021

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IntroductionRecent studies comparing canine mammary tumors (CMTs) and human breast cancers have revealed remarkable tumor similarities, identifying shared expression profiles and acquired mutations. CMTs can also provide a model of inherited breast cancer susceptibility in humans; thus, we investigated breed-specific whole genome sequencing (WGS) data in search for novel CMT risk factors that could subsequently explain inherited breast cancer risk in humans.MethodsWGS was carried out on five CMT-affected Gold Retrievers from a large pedigree of 18 CMT-affected dogs. Protein truncating variants (PTVs) detected in all five samples (within human orthlogs) were validated and then genotyped in the 13 remaining CMT-affected Golden Retrievers. Allele frequencies were compared to canine controls. Subsequently, human blood-derived exomes from The Cancer Genome Atlas breast cancer cases were analyzed and allele frequencies were compared to Exome Variant Server ethnic-matched controls.ResultsCarcinoembryonic Antigen-related Cell Adhesion Molecule 24 (CEACAM24) c.247dupG;p.(Val83Glyfs∗48) was the only validated variant and had a frequency of 66.7% amongst the 18 Golden Retrievers with CMT. This was significant compared to the European Variation Archive (p-value 1.52 × 10–8) and non-Golden Retriever American Kennel Club breeds (p-value 2.48 × 10–5). With no direct ortholog of CEACAM24 in humans but high homology to all CEACAM gene family proteins, all human CEACAM genes were investigated for PTVs. A total of six and sixteen rare PTVs were identified in African and European American breast cancer cases, respectively. Single variant assessment revealed five PTVs associated with breast cancer risk. Gene-based aggregation analyses revealed that rare PTVs in CEACAM6, CEACAM7, and CEACAM8 are associated with European American breast cancer risk, and rare PTVs in CEACAM7 are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire CEACAM gene family are associated with breast cancer risk in both European and African Americans with respective p-values of 1.75 × 10–13 and 1.87 × 10–04.ConclusionThis study reports the first association of inherited CEACAM mutations and breast cancer risk, and potentially implicates the whole gene family in genetic risk. Precisely how these mutations contribute to breast cancer needs to be determined; especially considering our current knowledge on the role that the CEACAM gene family plays in tumor development, progression, and metastasis.

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Section: Discussionmentioning

confidence: 99%

CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk – A Comparative Oncology Approach to Discovery

2021

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“…The well-known PDAC tumor-associated antigens, such as CEA, EGFR, Her2, MUC1, and mesothelin, are targeted for CAR-T development [ 156 ]. Recently, a team led by John F. Marshall developed and demonstrated the clinical potential of the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7)—a novel target for CAR-T development for PDAC treatment with promising outcomes [ 157 ]. Pre-conditioning strategies, such as optimizing the TH2-TH1 ratio, depletion of Tregs, and increasing macrophage activation for enhancing CAR-T cell therapy, have also been investigated [ 156 ].…”

Section: Pdac Therapeutics and Tumor Microenvironmentmentioning

confidence: 99%

Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

Truong

Pauklin

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.

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“…Thus, it was concluded that bi-specific CAR-NK cells may prove a promising immunotherapeutic when combined with 125 I seed therapy in treatment of pancreatic cancer. Identification of novel antigens for therapy are useful strategies for cell-based therapy[ 83 , 84 ].…”

Section: Nk Cells As Therapy In Pdacmentioning

confidence: 99%

Natural killer cells in pancreatic cancer stroma

Fincham¹,

Delvecchio²,

Goulart³

et al. 2021

WJG

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Pancreatic cancer remains one of medicine’s largest areas of unmet need. With five-year survival rates of < 8%, little improvement has been made in the last 50 years. Typically presenting with advance stage disease, treatment options are limited. To date, surgery remains the only potentially curative option, however, with such late disease presentation, the majority of patients are unresectable. Thus, new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients. Natural killer (NK) cells are crucial effector units in cancer immunosurveillance. Often used as a prognostic biomarker in a range of malignancies, NK cells have received much attention as an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. Despite this interest, the role of NK cells in pancreatic cancer remains poorly defined. Nevertheless, increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light. Here, we review the role of NK cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.

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CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma

Cited by 45 publications

References 44 publications

CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk – A Comparative Oncology Approach to Discovery

CEACAM Gene Family Mutations Associated With Inherited Breast Cancer Risk – A Comparative Oncology Approach to Discovery

Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

Natural killer cells in pancreatic cancer stroma

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