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1.
Cytotherapy ; 23(4): 320-328, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33262074

RESUMO

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34+) and normal (CD3+) cells isolated from the patients' blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4+ response and 11 (34%) induced a CD8+ response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients.


Assuntos
Síndromes Mielodisplásicas , Neoplasias , Antígenos de Neoplasias/genética , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Linfócitos T
2.
Cytotherapy ; 23(3): 236-241, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33279399

RESUMO

BACKGROUND: Myelodysplastic syndromes (MDS) represent the most common type of acquired bone marrow failure in adults and is characterized by ineffective maturation of myeloid precursor cells and peripheral cytopenias associated with higher rates of infection, bleeding and transfusion dependence. In higher-risk patients with MDS who relapse or do not respond after standard hypomethylating agent (HMA) therapy, the 2-year survival rate is 15%. METHODS: Here the authors report the feasibility and safety of a novel experimental T-cell therapy called personalized adoptive cell therapy, which selects, immunizes and expands T cells against MDS-specific mutations and is targeted to patient-specific tumor cell neoantigens. Somatic mutations serve as the pathogenic drivers of cancer, including MDS, as these transformative genetic mutations may generate novel immunogenic proteins (i.e., neopeptides and possible neoantigens) that may be targeted therapeutically. RESULTS: The authors demonstrate that the adaptive immune system can be trained ex vivo to recognize neopeptides as neoantigens and that the infusion of culture-expanded, neoantigen-immunized autologous T cells has been feasible and safe in the three patients treated to date. DISCUSSION: The authors report on early results from their first-in-human phase 1 clinical trial that aims to assess the safety and tolerability of this novel form of adoptive T-cell immunotherapy for HMA-refractory patients with higher-risk MDS.


Assuntos
Síndromes Mielodisplásicas , Recidiva Local de Neoplasia , Idoso , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva , Síndromes Mielodisplásicas/terapia , Linfócitos T
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