A Retroviral Replicating Vector Encoding Cytosine Deaminase and 5-FC Induces Immune Memory in Metastatic Colorectal Cancer Models.

Autor:	Yagiz K; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Rodriguez-Aguirre ME; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Lopez Espinoza F; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Montellano TT; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Mendoza D; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Mitchell LA; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Ibanez CE; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Kasahara N; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA., Gruber HE; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Jolly DJ; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA., Robbins JM; Tocagen Inc., 3030 Bunker Hill St., Suite 230, San Diego, CA 92109, USA.; DNAtrix, Inc., 2450 Holcombe Boulevard, Suite X+ 200, Houston, TX 77021, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy oncolytics [Mol Ther Oncolytics] 2017 Dec 05; Vol. 8, pp. 14-26. Date of Electronic Publication: 2017 Dec 05 (Print Publication: 2018).
DOI:	10.1016/j.omto.2017.12.001
Abstrakt:	Treatment of tumors with Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, followed by 5-fluorocytosine (5-FC) kills tumors by local production of 5-fluorouracil (5-FU). In brain tumor models, this treatment induces systemic anti-tumor immune responses and long-term immune-mediated survival. Phase 1 Toca 511 and Toca FC (extended-release 5-FC) clinical trials in patients with recurrent high-grade glioma show durable complete responses and promising survival data compared to historic controls. The work described herein served to expand on our earlier findings in two models of metastatic colorectal carcinoma (mCRC). Intravenous (i.v.) delivery of Toca 511 resulted in substantial tumor-selective uptake of vector into metastatic lesions. Subsequent treatment with 5-FC resulted in tumor shrinkage, improved survival, and immune memory against future rechallenge with the same CT26 CRC cell line. Similar results were seen in a brain metastasis model of mCRC. Of note, 5-FC treatment resulted in a significant decrease in myeloid-derived suppressor cells (MDSCs) in mCRC tumors in both the liver and brain. These results support the development of Toca 511 and Toca FC as a novel immunotherapeutic approach for patients with mCRC. A phase 1 study of i.v. Toca 511 and Toca FC in solid tumors, including mCRC, is currently underway (NCT02576665).
Databáze:	MEDLINE
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