title: T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness.
abstract: 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.
authors.affiliation: Laboratory of Tumor Immunology, Department Medical Oncology, Erasmus MC Cancer Institute , 3000 CA Rotterdam, The Netherlands .
authors.forename: Cor H J
authors.initials: CH
authors.lastname: Lamers
authors.forename: Sabine
authors.initials: S
authors.lastname: van Steenbergen-Langeveld
authors.forename: Mandy
authors.initials: M
authors.lastname: van Brakel
authors.forename: Corrien M
authors.initials: CM
authors.lastname: Groot-van Ruijven
authors.forename: Pascal M M L
authors.initials: PM
authors.lastname: van Elzakker
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Krimpen
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology; D016922:Cellular Senescence; D005822:Genetic Vectors / Q000235:genetics; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D059425:Interferon-gamma Release Tests; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation; D009363:Neoplasm Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D014161:Transduction, Genetic
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; D015789:HLA-A2 Antigen; D007378:Interleukins; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases