Engineered T cells kill tumors but spare normal tissue in an animal model

April 7, 2013

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 , 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 and kill certain . 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 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 . 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 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.

Explore further: New universal platform for cancer immunotherapy developed

Related Stories

New universal platform for cancer immunotherapy developed

March 5, 2012
(Medical Xpress) -- Researchers from the Perelman School of Medicine at the University of Pennsylvania report this month in Cancer Research a universal approach to personalized cancer therapy based on T cells. It is the first ...

Adoptive cell transfer: New technique could make cell-based immune therapies for cancer safer, more effective

December 16, 2012
A team led by Michel Sadelain, MD, PhD, Director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center, has shown for the first time the effectiveness of a new technique that could allow the development ...

Study finds more effective approach against ovarian cancer

August 8, 2011
In a recent issue of Cancer Research, Daniel J. Powell, Jr., PhD, a research assistant professor of Pathology and Laboratory Medicine and Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, ...

New anti-tumor cell therapy strategies are more effective

October 25, 2012
Targeted T-cells can seek out and destroy tumor cells that carry specific antigen markers. Two novel anti-tumor therapies that take advantage of this T-cell response are described in articles published in Human Gene Therapy, ...

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.