Metastasis, the growth and spread of cancer from a localized tumor to other sites in the body, is promoted by the formation of new blood vessels through angiogenesis to "feed" the tumor. There is an urgent need to develop new therapeutic strategies that combine fewer side-effects and more specific anti-tumor activity in order to block cancer metastasis in patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including the spread of cancer.
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 Cancer Institute (NCI) 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.
• Immunotherapeutics to treat and/or prevent the reoccurrence of a variety of human cancers that overexpress human VEGFR2 by introducing anti-VEGFR2 CAR expressing T cells into patients with metastatic cancer.
• 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.
• 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.
Steven Rosenberg (NCI), Dhanalakshmi Chinnasamy (NCI)
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- Foreign Filed: Foreign Filed - Patent Application PCT/US2010/048701, Filed 14 Sep 2010
- U.S. Patent Issued: U.S. Patent Number 9522955, Issued 20 Dec 2016
- U.S. Patent Issued: U.S. Patent Number 8822196, Issued 09 Sep 2014
- U.S. Patent Filed: U.S. Patent Application Number 13/499,349, Filed 30 Mar 2012
- Foreign Filed: Australia - Patent Application 2010301042, Filed 27 Mar 2012
- Foreign Filed: Japan - Patent Application 532100/2012, Filed 21 Mar 2012