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Frontiers in Immunology 2023Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major...
BACKGROUND
Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC.
MATERIALS AND METHODS
A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[F]fluoro-D-glucose ([F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [Zr]-labeled anti-PD-1 antibody and measured as Zr tumor uptake.
RESULTS
Conventional [F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found ( = 0.8; = 0.001).
CONCLUSION
Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.
Topics: Humans; Mice; Animals; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Positron Emission Tomography Computed Tomography; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Fluorodeoxyglucose F18; B7-H1 Antigen
PubMed: 37841258
DOI: 10.3389/fimmu.2023.1272570 -
Translational Oncology Dec 2023The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they...
BACKGROUND
The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they could be used as potential predictors of response and immune-related adverse events (irAEs) for ICIs therapy.
METHODS
The levels of TGF-β, IFN-γ, IL-6, IL-8, IL-10 were measured in sera and plasma by ELISA method of 30 healthy controls (HC) and 32 BRAF wild type (wt) MM patients before and after every 12 weeks of Pembrolizumab, PD-1 inhibitor, until one year or disease progression (DP).
RESULTS
Higher pretherapy levels of circulating TGF-β, IFN-γ, IL-6, and IL-10 were shown in MM patients compared to HC. In patients with disease control, TGF-β and IL-6 first decreased during the therapy, while then they started to successively increase reaching the initial values by the end of the follow up. Furthermore, in this group of patients IFN-γ increased, while IL-8 and IL-10 decreased at final points of the follow up. In patients with DP IL-6 increased at the time of progression, while IL-8 decreased when the best response was achieved. In patients with pseudoprogression IL-6 and IL-10 significantly increased compared to the pretreatment values. Melanoma patients with irAEs had increased baseline values of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC. However, no significant changes in cytokines levels were found in these patients during therapy.
CONCLUSIONS
Inflammatory cytokines monitoring in circulation of BRAFwt MM patients could help in the selection of patients who will have the benefit from Pembrolizumab therapy.
PubMed: 37806113
DOI: 10.1016/j.tranon.2023.101799 -
Journal of Cancer Research and... 2023Systemic therapy in lung cancer is mainstay of treatment as most patients present in advanced stages, with rising importance of new immunotherapy agents.
BACKGROUND
Systemic therapy in lung cancer is mainstay of treatment as most patients present in advanced stages, with rising importance of new immunotherapy agents.
PURPOSE
To compare the RECIST 1.1 and the immunotherapy Response Evaluation Criteria in Solid Tumors (iRECISTs) criteria for response assessment in lung cancer patients on immunotherapy. To find the incidence of pseudoprogression and associated imaging patterns.
MATERIAL AND METHODS
Retrospective study in 28 patients treated with immunotherapy for advanced metastatic NSCLC. End points were progression-free survival (PFS) and overall survival (OS). Response assessments were separately tabulated according to RECIST 1.1 and iRECIST and classified into dichotomous groups of responders and nonresponders. Agreement in assessments between RECIST 1.0 and iRECIST examined using Cohen kappa (κ) coefficient with 95% confidence intervals. Kaplan-Meier survival analysis was done for PFS and OS. Differences between RECIST 1.1 and iRECIST for both responder and nonresponder were evaluated by the log rank test, Breslow (Generalized Wilcoxon) test, and Tarone-Ware test.
RESULTS
Incidence of pseudoprogression was 7% (2/28). The RECIST1.1 and iRECIST were in disagreement in two patients. The agreement between RECIST and iRECIST was almost perfect. The PFS and the OS are significantly longer in duration for responders in comparison to nonresponders for both RECIST and iRECIST and the difference between two assessment criteria is not significant.
CONCLUSION
Although iRECIST aims to monitor treatment more precisely than conventional response criteria, this must be weighed against how infrequent pseudoprogression is and the cost of this therapy, both financially and in the potential delay in changing to a more effective treatment.
Topics: Humans; Lung Neoplasms; Response Evaluation Criteria in Solid Tumors; Nivolumab; Retrospective Studies; Carcinoma, Non-Small-Cell Lung; Treatment Outcome
PubMed: 37787285
DOI: 10.4103/jcrt.jcrt_1456_21 -
Journal of Clinical Oncology : Official... Nov 2023The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of...
PURPOSE
The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria.
METHODS
Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0).
RESULTS
We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment.
CONCLUSION
The revised RANO 2.0 criteria refine response assessment in gliomas.
Topics: Humans; Adult; Brain Neoplasms; Reproducibility of Results; Neoplasm Recurrence, Local; Glioma; Magnetic Resonance Imaging
PubMed: 37774317
DOI: 10.1200/JCO.23.01059 -
Cancer Research Communications Sep 2023Immune checkpoint inhibitors (ICI) can induce atypical tumor responses including pseudoprogression in a subset of patients who may benefit from treatment beyond...
UNLABELLED
Immune checkpoint inhibitors (ICI) can induce atypical tumor responses including pseudoprogression in a subset of patients who may benefit from treatment beyond progression. While ICIs have emerged as frontline treatments for hepatocellular carcinoma (HCC) and are associated with clinical benefit in a minority of patients, it is unclear whether treatment beyond progression has utility in this disease type. In a multicenter cohort analysis, treatment beyond progression was associated with no new safety signals, objective responses in 5.8% of patients, and disease control in 44% of patients. Progression-free survival and overall survival were comparable between patients treated beyond progression and patients treated with subsequent therapies, demonstrating that treatment beyond progression was not detrimental to survival outcomes. Rather, treatment beyond progression may benefit select patients with HCC and could represent a viable strategy for maximizing treatment benefit in these patients.
SIGNIFICANCE
Treatment beyond progression with ICIs in patients with HCC is safe and may benefit a subset of patients due to later-onset tumor responses or disease stability. These findings may guide the design of trials testing ICIs in HCC and the use of treatment beyond progression in routine practice.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms
PubMed: 37772995
DOI: 10.1158/2767-9764.CRC-23-0025 -
Cancers Sep 2023Glioma and glioblastoma multiform (GBM) remain among the most debilitating and life-threatening brain tumors. Despite advances in diagnosing approaches, patient... (Review)
Review
Glioma and glioblastoma multiform (GBM) remain among the most debilitating and life-threatening brain tumors. Despite advances in diagnosing approaches, patient follow-up after treatment (surgery and chemoradiation) is still challenging for differentiation between tumor progression/recurrence, pseudoprogression, and radionecrosis. Radiomics emerges as a promising tool in initial diagnosis, grading, and survival prediction in patients with glioma and can help differentiate these post-treatment scenarios. Preliminary published studies are promising about the role of radiomics in post-treatment glioma/GBM. However, this field faces significant challenges, including a lack of evidence-based solid data, scattering publication, heterogeneity of studies, and small sample sizes. The present review explores radiomics's capabilities in following patients with glioma/GBM status post-treatment and to differentiate tumor progression, recurrence, pseudoprogression, and radionecrosis.
PubMed: 37760399
DOI: 10.3390/cancers15184429 -
Current Oncology (Toronto, Ont.) Aug 2023Gliomas are the most frequent intrinsic central nervous system tumors. The new 2021 WHO Classification of Central Nervous System Tumors brought significant changes into... (Review)
Review
Gliomas are the most frequent intrinsic central nervous system tumors. The new 2021 WHO Classification of Central Nervous System Tumors brought significant changes into the classification of gliomas, that underline the role of molecular diagnostics, with the adult-type diffuse glial tumors now identified primarily by their biomarkers rather than histology. The status of the isocitrate dehydrogenase (IDH) 1 or 2 describes tumors at their molecular level and together with the presence or absence of 1p/19q codeletion are the most important biomarkers used for the classification of adult-type diffuse glial tumors. In recent years terminology has also changed. IDH-mutant, as previously known, is diagnostically used as astrocytoma and IDH-wildtype is used as glioblastoma. A comprehensive understanding of these tumors not only gives patients a more proper treatment and better prognosis but also highlights new difficulties. MR imaging is of the utmost importance for diagnosing and supervising the response to treatment. By monitoring the tumor on followup exams better results can be achieved. Correlations are seen between tumor diagnostic and clinical manifestation and surgical administration, followup care, oncologic treatment, and outcomes. Minimal resection site use of functional imaging (fMRI) and diffusion tensor imaging (DTI) have become indispensable tools in invasive treatment. Perfusion imaging provides insightful information about the vascularity of the tumor, spectroscopy shows metabolic activity, and nuclear medicine imaging displays tumor metabolism. To accommodate better treatment the differentiation of pseudoprogression, pseudoresponse, or radiation necrosis is needed. In this report, we present a literature review of diagnostics of gliomas, the differences in their imaging features, and our radiology's departments accumulated experience concerning gliomas.
Topics: Humans; Adult; Brain Neoplasms; Diffusion Tensor Imaging; Mutation; Glioma; Biomarkers
PubMed: 37754483
DOI: 10.3390/curroncol30090568 -
Nature Medicine Oct 2023Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long...
Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4 T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M diffuse midline glioma.
Topics: Humans; Adult; Animals; Mice; Brain Neoplasms; Histones; Glioma; Mutation; Vaccines
PubMed: 37735561
DOI: 10.1038/s41591-023-02555-6 -
Journal of Neuro-oncology Sep 2023In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated...
PURPOSE
In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO).
METHODS
We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined.
RESULTS
Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm.
CONCLUSION
The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.
Topics: Humans; Dacarbazine; Brain Neoplasms; Temozolomide; Glioblastoma; Lomustine; Magnetic Resonance Imaging; Antineoplastic Agents, Alkylating
PubMed: 37728779
DOI: 10.1007/s11060-023-04444-x -
Cancer Cell Sep 2023In this issue of Cancer Cell, Topp et al. analyze data from 799 patients treated with pembrolizumab beyond progression by RECIST 1.1 across six trials. Although...
In this issue of Cancer Cell, Topp et al. analyze data from 799 patients treated with pembrolizumab beyond progression by RECIST 1.1 across six trials. Although 8.9%-24.4% of patients demonstrate a ≥30% reduction in target lesions, conversely 11%-18% of patients had a ≥20% increase. The benefits of treatment beyond progression must be carefully weighed against physical and financial toxicities.
Topics: Humans; Neoplasms; Disease Progression
PubMed: 37699332
DOI: 10.1016/j.ccell.2023.08.003