Navigation Links
Engineered T cells kill tumors but spare normal tissue in an animal model
Date:4/7/2013

PHILADELPHIA The need to distinguish between normal cells and tumor cells is a feature that has been long sought for most types of cancer drugs. Tumor antigens, unique proteins on the surface of a tumor, are potential targets for a normal immune response against cancer. Identifying which antigens a patient's tumor cells express is the cornerstone of designing cancer therapy for that individual. But some of these tumor antigens are also expressed on normal cells, inching personalized therapy back to the original problem.

T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell's function.

Importantly, CARs allow patients' T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients' own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen.

To address this issue, Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, and director of the Cellular Therapy Tissue Facility, developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity -- mesothelin and a-folate receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer.

Powell likens this dual CAR approach to having two different gas pedals, one for starting the immune system and a second for revving it up. Dual CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue.

Dual CAR T cells showed weak cytokine production against target cells expressing only one tumor-associated antigen in lab assays, similar to first-generation CAR T cells bearing the CD3 activation domain only, but demonstrated enhanced cytokine production upon encountering natural or engineered tumor cells expressing both antigens, equivalent to second-generation CAR T cells with dual, but unseparated signaling.

In a mouse model of human ovarian cancer, T cells with the dual-signaling CARs persisted at high numbers in the blood, accumulated in tumors, and showed potent anti-cancer activity against human tumors. Dual CAR T cells were equivalent to second-generation CAR T cells in activity against tumors bearing two antigens. However, the dual-signaling CAR T cells did not react vigorously with normal tissue expressing one antigen while second- generation CAR T cells did.

"This new dual-specificity CAR approach can enhance the therapeutic efficacy of CAR T cells against cancer while minimizing reactivity against normal tissues," says Powell.

Their findings have been published in the inaugural issue of Cancer Immunology Research, the newest journal from the American Association for Cancer Research.


'/>"/>

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-459-0544
University of Pennsylvania School of Medicine
Source:Eurekalert

Related medicine news :

1. Nanoparticles engineered at Notre Dame promise to improve blood cancer treatment
2. Lab-engineered muscle implants restore function in animals
3. Genetically-engineered preclinical models predict pharmacodynamic response
4. Hardwoods4less Introduces New Line of Engineered Hardwood Flooring
5. Immune cells engineered in lab to resist HIV infection, Stanford study shows
6. Selexis SA Announces Publication in Metabolic Engineering of Data Demonstrating Improvement of Therapeutic Protein Secretion with Engineered CHO Cells
7. Almost Nuts! Supports Whole Foods Decision on Banning Gentically Modified Salmon and Continues to Support the Movement Against Genetically Engineered Foods
8. New drug prevents spread of human prostate cancer cells
9. Tiny hitchhikers attack cancer cells
10. To prevent leukemias dreaded return, go for the stem cells
11. Scientists identify major source of cells defense against oxidative stress
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/24/2017)... York, New York (PRWEB) , ... January 24, 2017 , ... ... for Brazilian butt lifts is on the rise. According to the American Society ... augmentations since 2000. On average, these procedures are performed every 30 minutes of every ...
(Date:1/24/2017)... (PRWEB) , ... January 24, 2017 , ... ... solution provider of enterprise software products, today announced a strategic partnership with ... Blue users to access and analyze their Fusion platform for building powerful enterprise ...
(Date:1/24/2017)... Calverton, MD (PRWEB) , ... January 24, 2017 , ... ... Year by MSC Cruises as part of the line’s 4th Annual MSC True ... Cruises’ top performing North American travel partners for the year based on overall business ...
(Date:1/24/2017)... ... January 24, 2017 , ... West’s Health Advocate Solutions, ... Series of webinars will start January 31 with a session about understanding healthcare ... health and benefits topics, including employee engagement, pricing transparency, population health and wellness, ...
(Date:1/24/2017)... ... January 24, 2017 , ... Center for Hispanic ... leadership, has named Hector M. Chavez, Manager, Employee & Labor Relations at City ... as its Hispanic Leader of the Month. City of Hope is committed to stay ...
Breaking Medicine News(10 mins):
(Date:1/24/2017)... 2017  BioSpecifics Technologies Corp. (NASDAQ: ... originated and continues to develop collagenase based-therapies ... collagenase clostridium histolyticum, or CCH, marketed as ... ®  in Europe, today announced that BioSpecifics, President, Tom ... the upcoming NobleCon13 - Noble Capital Markets, ...
(Date:1/24/2017)... MOINES, Iowa , Jan. 24, 2017 When tragedy ... who the victim is, what conditions they have, and who back ... was created—to keep loved ones informed about the safety of their ... information they need about victims in times of crisis. ... If you find yourself or ...
(Date:1/24/2017)... PORTLAND, Oregon and PUNE, India ... A new report published by Allied Market Research, titled, ... Vegetables, Bakery & Confectionary, Dairy & Frozen Dessert, Meat, ... Industries): Global Opportunity Analysis and Industry Forecasts, 2014-2022," projects ... to garner $426,275 million by 2022, growing at a ...
Breaking Medicine Technology: