Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease

Diem, Stefan; Ali, Omar Hasan; Ackermann, Christoph; Bomze, David; Koelzer, Viktor H.; Jochum, Wolfram; Speiser, Daniel E.; Mertz, Kirsten D.; Flatz, Lukas

doi:10.1007/s00262-017-2061-4

Cited by 36 publications

(29 citation statements)

References 24 publications

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“…The success of melanoma immunotherapy is highly dependent on the type of tumor microenvironment [33]. The objective of this study was to test whether combined FUS40 can modify key immune-suppressive pathways and stimulate immune effector pathways in melanoma tumors to promote local and systemic immunity.…”

Section: Discussionmentioning

confidence: 99%

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma

Singh

Sethuraman

Ritchey

et al. 2019

International Journal of Hyperthermia

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The success of melanoma immunotherapy is dependent on the presence of activated and functional T-cells in tumors. The objective of this study was to investigate the impact of local-focused ultrasound (FUS) heating ($42-45 C) and in-situ anti-CD-40 agonistic antibody in enhancing T-cell function for melanoma immunotherapy. We compared the following groups of mice with bilateral flank B16 F10 melanoma: (1) Control, (2) FUS, (3) CD-40, and (4) CD-40 þ FUS (FUS40). FUS heating was applied for $15 min in right flank tumor, and intratumoral injections of CD-40 were performed sequentially within 4 h. A total of 3 FUS and 4 anti-CD-40 treatments were administered unilaterally 3 days apart. Mice were sacrificed 30 days post-inoculation, and the treated tumor and spleen tissues were profiled for T-cell function and macrophage polarization. Compared to all other groups, histology and flow cytometry showed that FUS40 increased the population of tumor-specific CD-4þ and CD-8þ T cells rich in Granzyme Bþ, interleukin-2 (IL-2) and IFN-c production and poor in PD-1 expression. In addition, FUS40 promoted the infiltration of tumor-suppressing M1 phenotype macrophages in the treated mice. The resultant immune-enhancing effects of FUS40 suppressed B16 melanoma growth at the treated site by 2-3-folds compared to control, FUS, and CD-40, and also achieved significant abscopal effects in untreated tumors relative to CD40 alone. Additionally, the local FUS40 prevented adverse liver toxicities in the treated mice. Our study suggests that combined FUS and CD-40 can enhance T-cell and macrophage functions to aid effective melanoma immunotherapy.

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Section: Discussionmentioning

confidence: 99%

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma

Singh

Sethuraman

Ritchey

et al. 2019

International Journal of Hyperthermia

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“…6), tumor-infiltrating lymphocytes (TIL; ref. 7), and immune-regulatory mRNA expression signatures (8) are potentially applicable to the clinical selection of patients for ICBs, but each has limited utility.…”

Section: Introductionmentioning

confidence: 99%

Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade

Wang

Zhao²,

Wang³

et al. 2018

Cancer Research

188

216

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Biomarkers such as programmed death receptor 1 ligand (PD-L1) expression, tumor mutational burden (TMB), and high microsatellite instability are potentially applicable to predict the efficacy of immune checkpoint blockade (ICB). However, several challenges such as defining the cut-off value, test platform uniformity, and low frequencies limit their broad clinical application. Here we identify comutations in the DNA damage response (DDR) pathways of homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER; defined as co-mut) that are associated with increased TMB and neoantigen load and increased levels of immune gene expression signatures. In four public clinical cohorts, co-mut patients presented a higher objective response rate and a longer progression-free survival or overall survival than co-mut patients. Overall, identification of DDR comutations in HRR-MMR or HRR-BER as predictors of response to ICB provides a potentially convenient approach for future clinical practice. Identification of comutations in specific DDR pathways as predictors of superior survival outcomes in response to immune checkpoint blockade provide a clinically convenient approach for estimation of tumor mutational burden and delivery of ICB therapy. .

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“…1,2 However, only~20% of patients with lung cancer respond to ICBs. 3 Several biomarkers, such as tumor-infiltrating lymphocytes (TILs), 4,5 PD-L1 expression, 6,7 gene expression profile (GEP), 8 tumor mutational burden (TMB), 9 high microsatellite instability (MSI-H), and neoantigen counts, 10,11 have been proposed to predict the response of patients to ICBs. However, these predictors have some deficiencies.…”

Section: Introductionmentioning

confidence: 99%

Deep neural network classification based on somatic mutations potentially predicts clinical benefit of immune checkpoint blockade in lung adenocarcinoma

et al. 2020

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Although several biomarkers have been proposed to predict the response of patients with lung adenocarcinoma (LUAD) to immune checkpoint blockade (ICB) therapy, existing challenges such as test platform uniformity, cutoff value definition, and low frequencies restrict their effective clinical application. Here, we attempted to use deep neural networks (DNNs) based on somatic mutations to predict the clinical benefit of ICB to LUAD patients undergoing immunotherapy. We used DNNs to train and validate the predictive model in three cohorts. Kaplan-Meier estimates determined the overall survival (OS) and progression-free survival (PFS) between specific subgroups. Then, we performed a relevant analysis on the multiple-dimension data types including immune cell infiltration, programmed death receptor 1 ligand (PD-L1) expression, and tumor mutational burden (TMB) from cohorts of LUAD public database and immunotherapeutic patients. Two classification groups (C1 and C2) in the training and two validation sets were identified for the efficacy of ICB via the DNN algorithm. Patients in C1 showed remarkably long OS and PFS to programmed death 1 (PD-1) inhibitors. The C1 group was significantly associated with increased expression of immune cell infiltration, immune checkpoints, activated T-effectors, and interferon gamma signature. C1 group also exhibited significantly higher TMB, neoantigens, transversion, or transition than the C2 group. This work provides novel insights that classification of DNNs using somatic mutations in LUAD could serve as a potentially predictive approach in developing a strategy for anti-PD-1/PD-L1 immunotherapy.

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Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease

Cited by 36 publications

References 24 publications

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma

Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade

Deep neural network classification based on somatic mutations potentially predicts clinical benefit of immune checkpoint blockade in lung adenocarcinoma

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