Enter Your Search:
Results 1-2 (2)
Go to page number:
Select a Filter Below
Clinical and Developmental Immunology (1)
Human Gene Therapy Methods (1)
Debets, Reno (2)
van Brakel, Mandy (2)
Broertjes, Marieke (1)
Bruggen, Pierre van Der (1)
Coulie, Pierre G. (1)
Drexhage, Joost (1)
Groot-van Ruijven, Corrien M. (1)
Hegmans, Joost (1)
Lambrecht, Bart N. (1)
Lamers, Cor (1)
Lamers, Cor H.J. (1)
Sleijfer, Stefan (1)
Straetemans, Trudy (1)
van Elzakker, Pascal M.M.L. (1)
van Krimpen, Brigitte (1)
van Steenbergen, Sabine (1)
van Steenbergen-Langeveld, Sabine (1)
Year of Publication
T Cell Receptor-Engineered T Cells to Treat Solid Tumors: T Cell Processing Toward Optimal T Cell Fitness
Lamers, Cor H.J.
van Steenbergen-Langeveld, Sabine
Groot-van Ruijven, Corrien M.
van Elzakker, Pascal M.M.L.
van Krimpen, Brigitte
Human Gene Therapy Methods
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.
TCR Gene Transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 Epitopes as Melanoma-Specific Immune Targets
van Steenbergen, Sabine
Lambrecht, Bart N.
Bruggen, Pierre van Der
Coulie, Pierre G.
Clinical and Developmental Immunology
Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent “on-target” reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2336-344/HLA-A2 (MC2/A2) and MAGE-A3243-258/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial.
Results 1-2 (2)
Go to page number:
Remove citation from clipboard
Add citation to clipboard
This will clear all selections from your clipboard. Do you wish proceed?
Clipboard is full! Please remove an item and try again.
PubMed Central Canada is a service of the
Canadian Institutes of Health Research
(CIHR) working in partnership with the National Research Council's
national science library
in cooperation with the
National Center for Biotechnology Information
U.S. National Library of Medicine
(NCBI/NLM). It includes content provided to the
PubMed Central International archive
by participating publishers.