Chimeric antigen receptors (CARs) are hybrid proteins consisting of the portion of an antibody that recognizes a tumor-associated antigen (TAA) fused to protein domains that signal to activate the CAR-expressing cell. Human cells that express CARs, most notably T cells, can recognize specific tumor antigens in an MHC-unrestricted manner with high reactivity. CARs are able to mediate an immune response that promotes robust tumor killing in targeted cells.

Scientists at the National Institutes of Health (NIH) have developed CARs with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR2) (also known as kinase domain region (KDR) in humans and fetal liver kinase-1 (Flk-1) in mice) to utilize as an antiangiogenic tumor therapy. VEGFR2 is expressed on non-cancerous vascular endothelia cells, but is overexpressed on tumor endothelial cells in a variety of cancers, especially solid tumors. VEGFR2 overexpression promotes tumor vasculature, growth, and metastasis. The VEGFR2-specific CARs feature the antigen binding domain of the KDR-1121 or DC101 antibody, which recognize portions of the human and mouse VEGFR2, respectively. This antibody component is fused to the transmembrane and intracellular signaling domains of a T cell receptor (TCR). These CARs combine high affinity recognition of VEGFR2 provided by the antibody portion with the target cell killing activity of a cell expressing an activated TCR. Infusion of these VEGFR2-specific CARs into patients could prove to be a powerful new immunotherapeutic tool for blocking angiogenic cancer metastasis by killing VEGFR2+ tumor cells.

Advantages:

This discovery is widely applicable to many different cancers: VEGFR2 is overexpressed in many metastatic cancers that utilize angiogenesis to spread from their initial site of development. An immunotherapy protocol using anti-VEGFR2 CAR could treat a variety of cancer types.

Antiangiogenic tumor therapy is anticipated to generate fewer side-effects compared to other treatment approaches: These CARs can be delivered directly to the bloodstream to gain easy access to the targeted tumor vascular endothelial cells with minimal effects to normal tissues. Furthermore, destroying tumor blood vessels could accelerate tumor cell death so that the therapy can be administered for a shorter period of time. A reduced therapeutic timeframe and minimal access to normal tissues should contribute to reduced side-effects and lowered toxicity for this treatment.

The technology is anticipated to be highly effective in killing metastatic cells: Most angiogenic tumor epithelial cells are believed to overexpress VEGFR2 to a similar degree. Administering a therapeutically effective amount of anti-VEGFR2 CARs to patients may leave no or little tumor cells remaining with an opportunity to metastasize. Many current angiogenesis therapies do not kill tumors, but rather stabilize the tumor, so they require long periods of administration.

Development Status: This technology could soon be ready for clinical development since the inventors plan to initiate clinical trials using CAR engineered lymphocytes for adoptive immunotherapy of cancer.

Market:

The Food and Drug Administration (FDA) has approved eight therapies with antiangiogenic properties, including Avastin®, Erbitux®, Vectibix®, Herceptin®, Tarceva®, Nexavar®, Sutent®, ToriselTM, Velcade®, and Thalomid®. The majority of these drugs produced worldwide sales exceeding an estimated $500 million in 2007. The fight against cancer and its spread will continue to benefit from the development of new therapeutics aimed at treating individual patients.

Cancer continues to be a medical and financial burden on US public health. Statistically, in the U.S. cancer is the second leading cause of death with over 565,000 deaths reported in 2008 and almost 1.5 million new cases were reported (excluding some skin cancers) in 2008, many with the potential to metastasize. In 2007, the NIH estimated that the overall cost of cancer was $219.2 billion dollars and $89 billion went to direct medical costs.

A possible prophylactic therapy to prevent the spread of cancer in patients whose cancer is predicted to metastasize.

A drug component of a combination immunotherapy regimen aimed at targeting the specific tumor-associated antigens expressed by cancer cells within individual patients.

Collaborative Research Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.