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16 pages, 3687 KiB

Open AccessArticle

Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients

by Ken Kudura, Florentia Dimitriou, Lucas Basler, Robert Förster, Daniela Mihic-Probst, Tim Kutzker, Reinhard Dummer, Joanna Mangana, Irene A. Burger and Michael C. Kreissl

Cancers 2021, 13(15), 3830; https://doi.org/10.3390/cancers13153830 - 29 Jul 2021

Cited by 13 | Viewed by 2584 | Correction

Abstract

We aimed to investigate, whether ¹⁸F-2-fluoro-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans performed at baseline (time point 0; TP 0) and three months after initiation of immunotherapy (time point 1; TP 1) can be used on a metastasis- and patient-level [...] Read more.

We aimed to investigate, whether ¹⁸F-2-fluoro-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans performed at baseline (time point 0; TP 0) and three months after initiation of immunotherapy (time point 1; TP 1) can be used on a metastasis- and patient-level to predict the response to immune-checkpoint inhibition using FDG-PET/CT six months after treatment start (time point 2; TP 2) in metastatic melanoma patients. This single-center retrospective study considered metastatic melanoma patients treated with immune checkpoint inhibition from TP 0 to TP 2. An analysis on a metastasis- and patient-level was carried out. Tumor volume, standardized uptake values SUV (mean, maximum, and peak), metabolic tumor volume MTV and total lesion glycolysis TLG of each included metastasis were recorded at each time point, respectively TP 0, TP 1 and TP 2. Total tumor volume, total metabolic tumor volume and total lesion glycolysis per patient were also calculated at TP 0, TP 1 and TP 2. Treatment response was assessed at metastasis- and patient-level based on FDG-PET/CT scans at TP 2. 612 melanoma metastases in 111 patients were included. The analysis on a metastasis-level showed that metastatic SUVpeak at TP 1 and volume variation between TP 0 and TP 1 were the strongest negative predictive biomarkers for response. However, at TP 0, metastatic SUVmean and SUVpeak indicated a low negative prediction power, whereas initial metastatic volume was not a predictive biomarker. Also, melanoma metastases located in bone structures had a negative influence on the outcome at TP 2, particularly in women. The analysis on a patient-level showed, that total tumor volume, total metastatic tumor volume and total lesion glycolysis of all metastases three months after treatment initiation were strong negative predictive biomarkers for response to immunotherapy six months after initiation. Age and female sex were also found to be negative predictive biomarkers with lower predictive power. Interestingly, total tumor volume at TP 0 and number of metastases at TP 0 as well as the occurrence of early immune-related adverse events between TP 0 and TP 2 did not have any predictive value for early treatment response. FDG-PET/CT performed for treatment response assessment three months after initiation of immune checkpoint inhibition in metastatic melanoma patients can also be used to predict early response to treatment. On a metastasis-level SUV peak and volume variation of metastases are strong outcome predictive biomarkers. On a patient-level total tumor volume and semiquantitative parameters such as total metabolic tumor volume MTV and total lesion glycolysis TLG of all metastases are promising outcome predictive biomarkers. Also, early complete response on a metastasis- and patient-level seems to be predictive for lasting complete response. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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17 pages, 2886 KiB

Open AccessArticle

Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma

by Stephan Spahn, Daniel Roessler, Radu Pompilia, Gisela Gabernet, Beryl Primrose Gladstone, Marius Horger, Saskia Biskup, Magdalena Feldhahn, Sven Nahnsen, Franz J. Hilke, Bernhard Scheiner, Jean-François Dufour, Enrico N. De Toni, Matthias Pinter, Nisar P. Malek and Michael Bitzer

Cancers 2020, 12(12), 3830; https://doi.org/10.3390/cancers12123830 - 18 Dec 2020

Cited by 45 | Viewed by 3832

Abstract

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall [...] Read more.

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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11 pages, 1540 KiB

Open AccessArticle

Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression

by Lydia Warburton, Leslie Calapre, Michelle R. Pereira, Anna Reid, Cleo Robinson, Benhur Amanuel, Mel Ziman, Michael Millward and Elin Gray

Cancers 2020, 12(11), 3486; https://doi.org/10.3390/cancers12113486 - 23 Nov 2020

Cited by 10 | Viewed by 2817

Abstract

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in [...] Read more.

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2–70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher’s exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645–0.930) and 0.80 (95% CI 0.284–0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p < 0.001, HR: 0.008, 95% CI: 0.001–0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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Review

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28 pages, 3409 KiB

Open AccessReview

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

by Hansol Lee, Inês Pires Da Silva, Umaimainthan Palendira, Richard A. Scolyer, Georgina V. Long and James S. Wilmott

Cancers 2021, 13(6), 1363; https://doi.org/10.3390/cancers13061363 - 17 Mar 2021

Cited by 32 | Viewed by 5057

Abstract

Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and [...] Read more.

Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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28 pages, 1528 KiB

Open AccessReview

The Peripheral Immune Landscape of Breast Cancer: Clinical Findings and In Vitro Models for Biomarker Discovery

by Sofia Batalha, Sofia Ferreira and Catarina Brito

Cancers 2021, 13(6), 1305; https://doi.org/10.3390/cancers13061305 - 15 Mar 2021

Cited by 21 | Viewed by 3520

Abstract

Breast cancer is the deadliest female malignancy worldwide and, while much is known about phenotype and function of infiltrating immune cells, the same attention has not been paid to the peripheral immune compartment of breast cancer patients. To obtain faster, cheaper, and more [...] Read more.

Breast cancer is the deadliest female malignancy worldwide and, while much is known about phenotype and function of infiltrating immune cells, the same attention has not been paid to the peripheral immune compartment of breast cancer patients. To obtain faster, cheaper, and more precise monitoring of patients’ status, it is crucial to define and analyze circulating immune profiles. This review compiles and summarizes the disperse knowledge on the peripheral immune profile of breast cancer patients, how it departs from healthy individuals and how it changes with disease progression. We propose this data to be used as a starting point for validation of clinically relevant biomarkers of disease progression and therapy response, which warrants more thorough investigation in patient cohorts of specific breast cancer subtypes. Relevant clinical findings may also be explored experimentally using advanced 3D cellular models of human cancer–immune system interactions, which are under intensive development. We review the latest findings and discuss the strengths and limitations of such models, as well as the future perspectives. Together, the scientific advancement of peripheral biomarker discovery and cancer–immune crosstalk in breast cancer will be instrumental to uncover molecular mechanisms and putative biomarkers and drug targets in an all-human setting. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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19 pages, 357 KiB

Open AccessEditor’s ChoiceReview

The Multiple Potential Biomarkers for Predicting Immunotherapy Response—Finding the Needle in the Haystack

by Tamiem Adam, Therese M. Becker, Wei Chua, Victoria Bray and Tara L. Roberts

Cancers 2021, 13(2), 277; https://doi.org/10.3390/cancers13020277 - 13 Jan 2021

Cited by 17 | Viewed by 5123

Abstract

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is [...] Read more.

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is therefore critical to personalise treatments and improve outcomes. A number of biomarkers have shown promising results, including from tumour (programmed cell death ligand 1 (PD-L1), tumour mutational burden (TMB), stimulator of interferon genes (STING) and apoptosis-associated speck-like protein containing a CARD (ASC)), from blood (peripheral blood mononuclear cells (PBMCs), circulating tumour DNA (ctDNA), exosomes, cytokines and metal chelators) and finally the microbiome. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

Other

Jump to: Research, Review

2 pages, 172 KiB

Open AccessCorrection

Correction: Kudura et al. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients. Cancers 2021, 13, 3830

by Ken Kudura, Florentia Dimitriou, Lucas Basler, Robert Förster, Daniela Mihic-Probst, Tim Kutzker, Reinhard Dummer, Joanna Mangana, Irene A. Burger and Michael C. Kreissl

Cancers 2022, 14(13), 3268; https://doi.org/10.3390/cancers14133268 - 4 Jul 2022

Cited by 2 | Viewed by 1389

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

11 pages, 1231 KiB

Open AccessCommentary

TGF-β Mediated Immune Evasion in Cancer—Spotlight on Cancer-Associated Fibroblasts

by Parisa Ghahremanifard, Ayan Chanda, Shirin Bonni and Pinaki Bose

Cancers 2020, 12(12), 3650; https://doi.org/10.3390/cancers12123650 - 5 Dec 2020

Cited by 47 | Viewed by 4075

Abstract

Various components of the tumor microenvironment (TME) play a critical role in promoting tumorigenesis, progression, and metastasis. One of the primary functions of the TME is to stimulate an immunosuppressive environment around the tumor through multiple mechanisms including the activation of the transforming [...] Read more.

Various components of the tumor microenvironment (TME) play a critical role in promoting tumorigenesis, progression, and metastasis. One of the primary functions of the TME is to stimulate an immunosuppressive environment around the tumor through multiple mechanisms including the activation of the transforming growth factor-beta (TGF-β) signaling pathway. Cancer-associated fibroblasts (CAFs) are key cells in the TME that regulate the secretion of extracellular matrix (ECM) components under the influence of TGF-β. Recent reports from our group and others have described an ECM-related and CAF-associated novel gene signature that can predict resistance to immune checkpoint blockade (ICB). Importantly, studies have begun to test whether targeting some of these CAF-associated components can be used as a combinatorial approach with ICB. This perspective summarizes recent advances in our understanding of CAF and TGF-β-regulated immunosuppressive mechanisms and ways to target such signaling in cancer. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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13 pages, 2099 KiB

Open AccessBrief Report

Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma

by Elena Shklovskaya, Jenny H Lee, Su Yin Lim, Ashleigh Stewart, Bernadette Pedersen, Peter Ferguson, Robyn PM Saw, John F Thompson, Brindha Shivalingam, Matteo S Carlino, Richard A Scolyer, Alexander M Menzies, Georgina V Long, Richard F Kefford and Helen Rizos

Cancers 2020, 12(11), 3374; https://doi.org/10.3390/cancers12113374 - 14 Nov 2020

Cited by 27 | Viewed by 4000

Abstract

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the [...] Read more.

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma. Full article

(This article belongs to the Special Issue Biomarkers of Immune Checkpoint Therapy Response and Resistance)

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