new immunoapproach using modification of patient's own Tcells (experiment used her2+)

[Lani]

her2+ER- cell line modified to increase MUC-1 which is found in the majority of breast cancers


New treatment to detect and fight breast cancer
[King's College London]
Research led by Dr John Maher, Senior Research Fellow in the Division of Cancer Studies, School of Medicine at King's, has developed a new way for the body to detect and fight breast cancer.
The study published in the Journal of Immunology has shown that the body's own immune system could soon be used as a powerful new treatment to detect and fight breast cancer, according to the peer reviewed study published in the Journal of Immunology.
Project leader, Dr John Maher says: 'This three year study demonstrates that we can make it possible for white blood cells to kill breast cancer cells. We hope to follow this study with a clinical trial in patients with incurable breast cancer'.
Breast cancer is the most common cancer in the UK and accounts for nearly one in three of all cancers in women. Every year in the UK over 44,000 women and 300 men are diagnosed with breast cancer, and around 12,500 women and 100 men will die from the disease. The research for this study has been funded by Breast Cancer Campaign.
White blood cells play an important role in recognising and fighting infection, such as a cold or flu, by spotting proteins in the bacteria which cause the infection that are different from normal cells. But they are currently unable to recognise cancer cells.
New method
Dr Scott Wilkie, working with Dr Maher on the study, has developed a method to alter white blood cells so they are able to identify and kill breast cancer cells.
Dr Wilkie is confident that this treatment could work in humans by extracting the patient's white blood cells from a blood sample, modifying them in the laboratory and then introducing them back into the patient, similar to a blood transfusion.
ABSTRACT: Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor
[Journal of Immunology]
MUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in >80% of human cancers. To exploit this, we have constructed a panel of chimeric Ag receptors (CAR) that bind selectively to tumor-associated MUC1. Two parameters proved crucial in optimizing the CAR ectodomain. First, we observed that the binding of CAR-grafted T cells to anchored MUC1 is subject to steric hindrance, independent of glycosylation status. This was overcome by insertion of the flexible and elongated hinge found in immunoglobulins of the IgD isotype. Second, CAR function was highly dependent upon strong binding capacity across a broad range of tumor-associated MUC1 glycoforms. This was realized by using an Ab-derived single-chain variable fragment (scFv) cloned from the HMFG2 hybridoma. To optimize CAR signaling, tripartite endodomains were constructed. Ultimately, this iterative design process yielded a potent receptor termed HOX that contains a fused CD28/OX40/CD3ζ endodomain. HOX-expressing T cells proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines (IFN-γ and IL-17), and elicit brisk killing of MUC1+ tumor cells. To test function in vivo, a tumor xenograft model was derived using MDA-MB-435 cells engineered to coexpress MUC1 and luciferase. Mice bearing an established tumor were treated i.p. with a single dose of engineered T cells. Compared with control mice, this treatment resulted in a significant delay in tumor growth as measured by serial bioluminescence imaging. Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells.