Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Abstract

Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I-and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLAidentical siblings. CD4 þ clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-g in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferong after melanoma stimulation. No CD4 þ clones responded to stimulation with recipient haemopoietic cells. The majority of CD8 þ clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4 þ clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.

Aberrant expression of BCL2A1-restricted minor histocompatibility antigens in melanoma cells: application for allogeneic transplantation

“…To date, peptide vaccination has resulted in a limited or marginal efficacy [19] while adoptive T lymphocyte infusion including Ag-specific CTL clones or TILs, especially after a lymphodepleted conditioning regimen, demonstrated promising results [20][21][22]. After allogeneic HSCT for patients with melanoma, there have been some reports indicating that CTLs against melanoma cells do exist and that these melanoma-reactive CTLs can be expanded in vitro [23,24]. These observations suggest that allogeneic HSCT after a nonmyeloablative conditioning regimen might be a promising therapeutic strategy for patients with refractory metastatic melanoma.…”

Ex vivo enrichment of PRAME antigen‐specific T cells for adoptive immunotherapy using CD137 activation marker selection

“…Adoptive T-cell therapies are under investigation for the treatment of a variety of malignancies. These include ex vivo expanded tumor-infiltrating lymphocytes (TILs), 1,2 ex vivo expanded circulating tumor antigen-specific T lymphocytes 3,4 and genetically modified products such as chimeric antigen receptor (CAR) 5,6 and transgenic T-cell receptor (TCR)-modified T cells. 7,8 Naturally occurring T cells that recognise intracellular or extracellular tumor-associated antigens or neoantigens formed by malignant genetic alterations can be ex vivo expanded and used therapeutically.…”