2:06 PM
May 16, 2018
 |  BC Extra  |  Preclinical News

Nanoparticle pretreatment could boost solid tumor CAR T therapy

Research from the University of Washington and the Fred Hutchinson Cancer Research Center suggests preconditioning cancer patients with immunomodulatory nanoparticles could increase the efficacy of CAR T therapies to treat solid tumors.

The main hypothesis as to why CAR Ts have not shown efficacy in solid tumors is because they are overwhelmed by immunosuppressive factors in the tumor microenvironment (see BioCentury Innovations, May 3).

In the paper published in Cancer Research, the researchers engineered a liposomal nanoparticle to carry two agents: a small molecule tool inhibitor of phosphoinositide 3-kinase (PI3K) catalytic subunit delta polypeptide (PI3KCD; p110delta) and an analog of alpha-galactosylceramide, a natural killer T cell agonist.

The researchers selected the two molecules because in a mouse model of breast cancer, the combination reduced the levels of immunosuppressive cells in the tumor microenvironment and increased the number of antitumor effector cells.

To target tumors, the nanoparticles were coated with iRGD peptides, which bind to integrin alpha(V) (CD51) highly expressed on tumor cells and have been shown in studies to penetrate tumors.

The researchers first engineered a CAR T specific for receptor tyrosine kinase-like orphan receptor 1 (ROR1). In the breast cancer mouse model, three weeks of nanoparticle preconditioning increased CAR T levels in tumors twenty-twofold compared with mice that received no preconditioning. Additionally, nanoparticle treatment before CAR T infusion decreased tumor size and increased survival compared with nanoparticles administered concurrent with CAR T therapy, or after.

To test the nanoparticles in a xenograft mouse model of glioblastoma, the researchers developed a CAR T targeting epidermal growth factor receptor variant III (EGFRvIII). CAR T cells infused after nanoparticle preconditioning underwent increased proliferation at the tumor site. The combination reduced tumor growth and more than doubled survival of treated mice compared with CAR T cell therapy alone.

The authors noted that the time required for manufacturing and infusion of autologous CAR Ts -- about two to three weeks -- would provide a time period to precondition patients with the nanoparticles, which can be stored long-term for off-the-shelf use.

Gilead Sciences Inc. (NASDAQ:GILD) has EGFRvIII CAR, a CAR T cell therapy against EGFRvIII, in Phase I/II testing to treat brain cancer. CARsgen Therapeutics Co. Ltd. (Shanghai, China) and Novartis AG (NYSE:NVS; SIX:NOVN) each have CAR T therapies against the target in Phase I testing for the indication.

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