T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness
Human Gene Therapy Methods , Volume 25 - Issue 6 p. 345- 357
Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for carbonic anhydrase IX (CAIX), we observed toxicities that (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have redefined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene-modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or after gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8+, CD27+, CD62L+, CD45RA+T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors.
|Human Gene Therapy Methods|
|Organisation||Department of Immunology|
Lamers, C.H.J, van Steenbergen-Langeveld, S, van Brakel, M, Groot-van Ruijven, C.M, van Elzakker, P.M.M.L, van Krimpen, B.A, … Debets, J.E.M.A. (2014). T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. Human Gene Therapy Methods, 25(6), 345–357. doi:10.1089/hgtb.2014.051