CO 001: TOWARDS CLINICAL TRANSLATION OF T-CELL RECEPTOR GENE EDITING TO MEDIATE ADOPTIVE ANTITUMOR IMMUNOTHERAPY

J Pharm Pharmacogn Res 2(Suppl. 1): S2, 2014

Special supplement with the abstract book of LATINFARMA 2013

Oral Communication

CO 001: TOWARDS CLINICAL TRANSLATION OF T-CELL RECEPTOR GENE EDITING TO MEDIATE ADOPTIVE ANTITUMOR IMMUNOTHERAPY

Ciceri F, Mastaglio S, Bonini C.

Experimental Hematology Unit, San Raffaele Scientific Institute, Milan, Italy.
Abstract

Introduction: The genetic addition of a tumor specific receptor into T cells yielded already substantial clinical results in patients affected by hematological malignancies.

Methods: To completely substitute T cell specificity, we recently developed the TCR gene editing approach, based on the combination of: i. Somatic knockout of the endogenous TCR genes (achieved by transient exposure to β- and α-chain specific Zinc Finger NucleasesZFN), and ii. Introduction of a tumor-specific TCR by lentiviral vectors (LV). By avoiding competition for surface expression between exogenous and endogenous TCR β- and α-chains, and by abrogating the risk of inappropriate TCR pairing, the TCR editing approach permanently overcomes the major limitations of TCR gene transfer (Provasi, Genovese et al., Nat. Med. 2012).

Results: To promote an effective and persistent therapeutic effect, and to facilitate its clinical application, we established a scalable protocol of TCR single editing, applicable within a single round of T cell stimulation. This approach completely and permanently abrogates expression of the endogenous TCR repertoire of donor T cells, which is responsible of GvHD. In addition, we validated the TCR editing approach on NY-ESO-1, expressed by solid tumors and hematological malignancies. We observed similar high levels of TCR expression, measured by NY-ESO-1 specific dextramer binding, in single edited and transferred T cells (RFI 73 vs. 66). Single edited cells efficiently recognized and killed NY-ESO-1+ myeloma cell lines, without aberrant response to NY-ESO-1- targets, and displayed improved tumor specificity than unedited TCR-transferred cells in co-culture assays (99% of elimination of target cells in both single edited and transferred cells; 0% vs. 45.9% of elimination of unspecific targets, respectively).

Conclusions: These results suggest that the TCR gene editing approach can mediate Graft versus Tumor and overcome the risk of GvHD in patients with hematological malignancies undergoing allo-HSCT.