Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells

Whilding, Lynsey M.; Parente-Pereira, Ana C.; Zabinski, Tomasz; Davies, Daniel; Petrovic, Roseanna M.; Kao, Y. Vincent; Saxena, S.C.; Romain, Alex; Costa-Guerra, Jose A.; Violette, Shelia M.; Itamochi, Hiroaki; Ghaem‐Maghami, Sadaf; Vallath, Sabari; Marshall, John F.; Maher, John

doi:10.1016/j.ymthe.2016.10.012

Cited by 73 publications

(84 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B). 31 The resultant CARs, named 1-28z, M-28z and cM-28z respectively, were expressed in human Tcells by retroviral-mediated gene transfer. Comparison was made with a pan-ErbB targeted CAR (T-28z, targeted with a promiscuous ErbB ligand named T1E) 32 and a negative control in which the targeting moiety consisted of a scrambled 20mer peptide sequence (C-28z).…”

Section: Engineering Of Candidate Met-specific Chimeric Antigen Recepmentioning

confidence: 99%

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

et al. 2017

Self Cite

View full text Add to dashboard Cite

Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype. The presence of MET did not influence patient survival. Candidate MET-specific CARs were engineered in which a CD28+CD3ζ endodomain was fused to one of 3 peptides derived from the N and K1 domains of hepatocyte growth factor (HGF), which represents the minimum MET binding element present in this growth factor. Using an NIH3T3-based artificial antigen-presenting cell system, we found that all 3 candidate CARs demonstrated high specificity for MET. By contrast, these CARs did not mediate T-cell activation upon engagement of other HGF binding partners, namely CD44v6 or heparan sulfate proteoglycans, including Syndecan-1. NK1-targeted CARs demonstrated broadly similar potency, indicated by destruction of MET-expressing mesothelioma cell lines, accompanied by cytokine release. anti-tumor activity was demonstrated following intraperitoneal delivery to mice with an established mesothelioma xenograft. Progressive tumor regression occurred without weight loss or other clinical indicators of toxicity. These data confirm the frequent expression of MET in malignant pleural mesothelioma and demonstrate that this can be targeted effectively and safely using a CAR T-cell immunotherapeutic strategy.

show abstract

Section: Engineering Of Candidate Met-specific Chimeric Antigen Recepmentioning

confidence: 99%

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Chimeric cytokine receptors -engineered chemokine receptors with modified functions -can be used to achieve selective expansion of T cells by an administered cytokine 126 Once the T cell reaches the tumour microenvironment (TME), specific proteases liberate the decoy peptide and unmask the CAR for targeting 93 . b, Oxygen-sensing CARs are selectively degraded under normoxia, yet stably expressed in hypoxic conditions.…”

Section: Homing and Traffickingmentioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

View full text Add to dashboard Cite

T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

show abstract

“…A second generation anti-MUC1 CAR harboring TAB004 Ab scFv was synthesized by subcloning the scFv from TAB004 [26] into the SFG-based retroviral backbone plasmid encoding the transmembrane and intracellular domains of CD28 and CD3 (synthesized by Dr. John Maher's group [36]). This CAR contains a myc tag for detection.…”

Section: Car Constructs and Cloningmentioning

confidence: 99%

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Yazdanifar

Zhou

Grover

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Chimeric antigen receptor engineered T cells (CAR T cells) have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease. ductal adenocarcinoma (PDA), pancreatic cancer, and tumor associated MUC1 (tMUC1). T cell cytotoxicityTo test T cell cytotoxicity against target cells, 5,000-10,000 cancer cells or normal cells were plated in triplicate in 96 well plates one day prior to co-culture. Mock or CAR T cells were counted and added to cancer cells at the indicated target to effector (T:E) ratio. Cell viability was evaluated by MTT assay (MTT 500 ug/ml, Sigma) 24, 48, and 72 hrs after co-culture according to the product instructions. The OD value at 540 nm was read and percentage survival was calculated as 100-[(mock T OD -CAR T OD)/mock T OD Apoptosis assayMock and CAR T cells were stained with Annexin V/propidium iodide (PI) dyes according to the Dead Cell Apoptosis Kit protocol (Life Technology V13242) before and after co-culture with cancer cells for 24, 48, and 72 hrs. The percentage of positive cells was assessed using flowcytometry.

show abstract

Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells

Cited by 73 publications

References 45 publications

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

Programming CAR-T cells to kill cancer

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Contact Info

Product

Resources

About