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1.
Front Immunol ; 15: 1437961, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39170614

RESUMO

A patient with a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated metastatic non-small cell lung cancer (NSCLC) experienced a multisite radiological progression at 3 months after initiation of chemoimmunotherapy as first-line treatment for metastatic disease. After the radiological progression, while she was not undergoing treatment, the patient had spontaneous lesions shrinkage and further achieved a prolonged complete response. Genomic and transcriptomic data collected at baseline and at the time of pseudoprogression allowed us to biologically characterize this rare response pattern. We observed the presence of a tumor-specific T-cell response against tumor-specific neoantigens (TNAs). Endogenous retroviruses (ERVs) expression following chemoimmunotherapy was also observed, concurrent with biological features of an anti-viral-like innate immune response with type I IFN signaling and production of CXCR3-associated chemokines. This is the first biological characterization of a NSCLC pseudoprogression under chemoimmunotherapy followed by a prolonged complete response in a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated NSCLC. These clinical and biological data underline that even patients with multiple factors of resistance to immune checkpoint inhibitors could trigger a tumor-specific immune response to tumor neoantigen, leading to complete eradication of the tumor and probably a vaccinal immune response.


Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Progressão da Doença , Proteína 1 Associada a ECH Semelhante a Kelch , Neoplasias Pulmonares , Mutação , Humanos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Antígeno B7-H1/genética , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais
2.
Cancer Immunol Immunother ; 73(7): 133, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38753169

RESUMO

BACKGROUND: Glioblastoma (GBM) is a primary brain tumor with a dismal prognosis, often resistant to immunotherapy and associated with immune suppression. This study aimed to assess the impact of steroids and Stupp-regimen treatment on peripheral blood immune parameters in GBM patients and their association with outcomes. METHODS: Using cytometry panels and bioplex assays, we analyzed the immune phenotype and serum cytokines of 54 GBM patients and 21 healthy volunteers. RESULTS: GBM patients exhibited decreased lymphoid cell numbers (CD4, CD8 T cells, NKT cells) with heightened immune checkpoint expression and increased myeloid cell numbers (especially neutrophils), along with elevated pro-inflammatory cytokine levels. Steroid use decreased T and NK cell numbers, while radio-chemotherapy led to decreased lymphoid cell numbers, increased myeloid cell numbers, and heightened immune checkpoint expression. Certain immune cell subsets were identified as potential outcome predictors. CONCLUSION: Overall, these findings shed light on the peripheral immune landscape in GBM, emphasizing the immunosuppressive effects of treatment. Baseline immune parameters may serve as prognostic indicators for treatment response.


Assuntos
Neoplasias Encefálicas , Quimiorradioterapia , Glioblastoma , Humanos , Glioblastoma/imunologia , Glioblastoma/terapia , Glioblastoma/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Quimiorradioterapia/métodos , Adulto , Idoso , Prognóstico , Citocinas/metabolismo , Citocinas/sangue
3.
STAR Protoc ; 4(4): 102658, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37910510

RESUMO

Here, we present a protocol for the simultaneous analysis of peripheral and intratumoral lymphocyte function by flow cytometry. Using tumor and blood samples from patients with colorectal cancer, we describe steps for tumor digestion, pre-labeling of the tumor-infiltrating leukocytes (TILs), and activation and labeling of the total cells (TILs and whole blood cells). For complete details on the use and execution of this protocol, please refer to Thibaudin et al.1.


Assuntos
Leucócitos , Neoplasias , Humanos , Citometria de Fluxo , Linfócitos
4.
Nat Med ; 29(8): 2087-2098, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37563240

RESUMO

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia
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