Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling

@article{Wilkie2012DualTO,
  title={Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling},
  author={S. Wilkie and M. V. Schalkwyk and S. Hobbs and D. M. Davies and S. Stegen and A. P. Pereira and S. Burbridge and C. Box and S. Eccles and J. Maher},
  journal={Journal of Clinical Immunology},
  year={2012},
  volume={32},
  pages={1059-1070}
}
PurposeChimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor… Expand
CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation
TLDR
The findings demonstrate the feasibility of targeting breast cancer using transgenic T cells equipped to thrive in the suppressive tumor milieu and highlight the importance of providing transgenicT cells with signals that recapitulate physiologic TCR signaling – [activation, co-stimulation and cytokine support] to promote in vivo persistence and memory formation. Expand
Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment.
TLDR
This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site. Expand
Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma
TLDR
Together, T cells carrying two complementary CARs against GPC3 and ASGR1 may reduce the risk of on-target, off-tumor toxicity while maintaining relatively potent antitumor activities on G PC3+ASGR1+ HCC. Expand
CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies
TLDR
The engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors is engineered to enhance tumor-directed T-cell trafficking. Expand
Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells
TLDR
This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis, and recommends future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. Expand
Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer
TLDR
The results indicate that the co-expression of the TAG-72 CAR and the CD47-truncated monomer CAR on T cells could be an effective, dual CAR-T cell strategy for ovarian cancer, also applicable to other adenocarcinomas. Expand
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.
TLDR
A CAR is created that joins a HER2-binding scFv and an IL13Ra2- binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.z endodomains to improve the antitumor activity of T cells. Expand
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.
TLDR
TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape. Expand
Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model
TLDR
It is found that CAR T cell therapy of solid tumors, in which the targeted antigen is not expressed by the vast majority of tumor cells, will not likely be successful unless combination strategies to enhance bystander effects are used. Expand
CAR T-cell immunotherapy of MET-expressing malignant mesothelioma
TLDR
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. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 52 REFERENCES
Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4*
TLDR
This system allows rapid ex vivo expansion and enrichment of engineered T-cells from small blood volumes, under GMP-compliant conditions, and provides proof of principle for the development of IL-4-enhanced T-cell immunotherapy of cancer. Expand
Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains
TLDR
Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance in the context of poorly immunogenic tumors. Expand
CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.
TLDR
The results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies. Expand
Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor1
TLDR
Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells. Expand
Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors.
TLDR
The study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen. Expand
Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28‐OX40 signalling
TLDR
A thoroughly controlled side‐by‐side comparison of the most frequently used endodomains with respect to their impact on CD4+ and CD8+ T cell effector functions and combined the beneficial functions in a 3rd generation CD28‐OX40 CAR which substantially improved the antitumor response without loosing specificity. Expand
Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy.
TLDR
These studies provide the rationale for exploring the clinical utility of adoptive therapy with CD20-specific CTL as a component of immunotherapeutic targeting of CD20+ malignancy. Expand
Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
TLDR
It is speculated 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, consistent with a cytokine storm. Expand
CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack
TLDR
CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions, and is concluded that it could not be replaced by high-affinity CD3ζ CAR binding or high-density antigen engagement. Expand
CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells.
TLDR
In vivo, it is shown in vivo that adoptively transferred CD19RCD28(+) T cells show an improved persistence and antitumor effect compared with CD19R(+) T cells, implying that modifications to the CAR can result in improved therapeutic potential of CD19-specific T cells expressing this second-generation CAR. Expand
...
1
2
3
4
5
...