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IFN? PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy.

ABSTRACT: IFN? is an attractive target for imaging active antitumor immunity due to its function in the T-cell signaling axis. Here, we test an IFN? immuno-PET (immunoPET) probe for its capacity to identify adaptive immunotherapy response after HER2/neu vaccination in both spontaneous salivary and orthotopic neu+ mouse mammary tumors. IFN? immunoPET detected elevated cytokine levels in situ after vaccination, which inversely correlated with tumor growth rate, an indicator of response to therapy. In a model of induced T-cell anergy where CD8 T cells infiltrate the tumor, but upregulate PD-1, IFN? tracer uptake was equivalent to isotype control, illustrating a lack of antitumor T-cell activity. The IFN? immunoPET tracer detected IFN? protein sequestered on the surface of tumor cells, likely in complex with the IFN? receptor, which may explain imaging localization of this soluble factor in vivo Collectively, we find that the activation status of cytotoxic T cells is annotated by IFN? immunoPET, with reduced off-target binding to secondary lymphoid tissues compared with imaging total CD3+ tumor-infiltrating lymphocytes. Targeting of soluble cytokines such as IFN? by PET imaging may provide valuable noninvasive insight into the function of immune cells in situ Significance: This study presents a novel approach to monitor therapeutic outcomes via IFN?-targeted positron emission tomography. Cancer Res; 78(19); 5706-17. ©2018 AACR.

SUBMITTER: Gibson HM

PROVIDER: S-EPMC6443251 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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IFNγ PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy.

Gibson Heather M HM McKnight Brooke N BN Malysa Agnes A Dyson Greg G Wiesend Wendy N WN McCarthy Claire E CE Reyes Joyce J Wei Wei-Zen WZ Viola-Villegas Nerissa T NT

Cancer research 20180816 19

IFNγ is an attractive target for imaging active antitumor immunity due to its function in the T-cell signaling axis. Here, we test an IFNγ immuno-PET (immunoPET) probe for its capacity to identify adaptive immunotherapy response after HER2/neu vaccination in both spontaneous salivary and orthotopic neu<sup>+</sup> mouse mammary tumors. IFNγ immunoPET detected elevated cytokine levels <i>in situ</i> after vaccination, which inversely correlated with tumor growth rate, an indicator of response to ...[more]

PMID: 30115693

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Project description:BackgroundAs the immune-related response evaluation criteria in solid tumors (irRECIST) by imaging greatly underestimated the objective response to immunotherapy, we established the response evaluation criteria in solid tumors based on tumor markers (RecistTM) to explore whether RecistTM can compensate for the deficiencies of the irRECIST criteria.MethodsThis was an observational study, which consisted of two parts. The first part (Group A) was a retrospective study including the patients with malignant solid tumors. The second part (Group B) was a prospective study, which were EGFR-negative and ALK-negative patients with stage IIIB-IV non-small cell lung cancer receiving first-line treatment. From January 2017 to September 2020, one hundred and ten patients with a three-time increase in tumor markers receiving immunotherapy were recruited. The treatment response to immunotherapy was evaluated by irRECIST and RecistTM. Efficacy, overall survival (OS), first evaluation time and earliest response time under the different evaluation criteria were compared by statistics.FindingsThe treatment response evaluated by the RecistTM criteria was not consistent with that evaluated by the irRECIST criteria (Kappa = 0.386, p < 0.001). RecistTM had a higher completed response (CR) rate compared to irRECIST criteria (20.9% vs 1.8%, p < 0.001). The earliest response time under the RecistTM criteria was 3.42 weeks earlier than that under the irRECIST criteria (u = -5.233, p < 0.001). There were significant differences in median OS between tumor marker-related complete response (tmCR) and tumor marker-related partial response (tmPR), as well as between tmPR and tumor marker-related stable disease (tmSD) (χ2 = 15.572, p < 0.001; χ2 = 7.720, p = 0.005), but not between tmSD and tumor marker-related progressive disease (tmPD) (χ2 = 1.596, p = 0.206). When applying both criteria together, for patients with immune-related CR / immune-related PR (irCR/irPR) (n = 54) under irRECIST criteria, there was a significant difference in median OS between achieving tmCR (n = 22) and tmPR (n = 32) (χ2 = 14.011, p < 0.001). RecistTM criteria can predict 1-year and 2-year OS more accurately than irRECIST criteria (AUCs:0.862 vs 0.552, 0.649 vs 0.521, respectively;both p < 0.001). In RecistTM, 4 patients had been observed with pseudoprogression in tumor markers.InterpretationThe RecistTM criteria could effectively distinguish CR, PR, and SD, which may help resolve the shortcomings of the RECIST criteria in evaluating the treatment response to immunotherapy, especially in assessing whether patients can achieve deep or even complete response as soon as possible.FundingThis work was supported by the Key projects of Chongqing Health and Family Planning Commission (to Xueqin Yang, 2019ZDXM011).

Project description:In recent years, various systemic immunotherapies have been developed for cancer treatment, such as monoclonal antibodies (mABs) directed against immune checkpoints (immune checkpoint inhibitors, ICIs), oncolytic viruses, cytokines, cancer vaccines, and adoptive cell transfer. While being estimated to be eligible in 38.5% of patients with metastatic solid or hematological tumors, ICIs, in particular, demonstrate durable disease control across many oncologic diseases (e.g., in melanoma, lung, bladder, renal, head, and neck cancers) and overall survival benefits. Due to their unique mechanisms of action based on T-cell activation, response to immunotherapies is characterized by different patterns, such as progression prior to treatment response (pseudoprogression), hyperprogression, and dissociated responses following treatment. Because these features are not encountered in the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which is the standard for response assessment in oncology, new criteria were defined for immunotherapies. The most important changes in these new morphologic criteria are, firstly, the requirement for confirmatory imaging examinations in case of progression, and secondly, the appearance of new lesions is not necessarily considered a progressive disease. Until today, five morphologic (immune-related response criteria (irRC), immune-related RECIST (irRECIST), immune RECIST (iRECIST), immune-modified RECIST (imRECIST), and intra-tumoral RECIST (itRECIST)) criteria have been developed to accurately assess changes in target lesion sizes, taking into account the specific response patterns after immunotherapy. In addition to morphologic response criteria, 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is a promising option for metabolic response assessment and four metabolic criteria are used (PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT), immunotherapy-modified PET Response Criteria in Solid Tumors (imPERCIST5), and immune PERCIST (iPERCIST)). Besides, there is evidence that parameters on 18F-FDG-PET/CT, such as the standardized uptake value (SUV)max and several radiotracers, e.g., directed against PD-L1, may be potential imaging biomarkers of response. Moreover, the emerge of human intratumoral immunotherapy (HIT-IT), characterized by the direct injection of immunostimulatory agents into a tumor lesion, has given new importance to imaging assessment. This article reviews the specific imaging patterns of tumor response and progression and available imaging response criteria following immunotherapy.

Project description:PurposeTumor voxel dose-response matrix (DRM) can be quantified using feedback from serial FDG-PET/CT imaging acquired during radiotherapy. This study investigated the dynamic characteristics and the predictive capability of DRM.MethodsFDG-PET/CT images were acquired before and weekly during standard chemoradiotherapy with the treatment dose 2 Gy × 35 from 31 head and neck cancer patients. For each patient, deformable image registration was performed between the pretreatment/baseline PET/CT image and each weekly PET/CT image. Tumor voxel DRM was derived using linear regression on the logarithm of the weekly standard uptake value (SUV) ratios for each tumor voxel, such as SUV measured at a dose level normalized to the baseline SUV0. The dynamic characteristics were evaluated by comparing the DRMi estimated using a single feedback image acquired at the ith treatment week (i = 1, 2, 3, or 4) to the DRM estimated using the last feedback image for each patient. The predictive capability of the DRM estimated using 1 or 2 feedback images was evaluated using the receiver operating characteristic test with respect to the treatment outcome of tumor local-regional control or failure.ResultsThe mean ± SD of tumor voxel SUV measured at the pretreatment and the 1st, 2nd, 3rd, 4th, and last treatment weeks was 6.76 ± 3.69, 5.72 ± 3.43, 3.85 ± 2.22, 3.27 ± 2.25, 2.5 ± 1.79, and 2.23 ± 1.27, respectively. The deviations between the DRMi estimated using the single feedback image obtained at the ith week and the last feedback image were 0.86 ± 4.87, -0.06 ± 0.3, -0.09 ± 0.17, and -0.09 ± 0.12 for DRM1, DRM2, DRM3, and DRM4, respectively. The predictive capability of DRM3 and DRM4 was significant (p < 0.001). The area under the curve (AUC) was increased with the increase in treatment dose level. The DRMs constructed using the single feedback image achieved an AUC of 0.86~1. The AUC was slightly improved to 0.94~1 for the DRMs estimated using 2 feedback images.ConclusionTumor voxel metabolic activity measured using FDG-PET/CT fluctuated noticeably during the first 2 treatment weeks and obtained a stabilized reduction rate thereafter. Tumor voxel DRM constructed using a single FDG-PET/CT feedback image after the 2nd treatment week (>20 Gy) has a good predictive capability. The predictive capability improved continuously using a later feedback image and marginally improved when two feedback images were applied.

Project description:ObjectiveCancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective biomarkers. This study aimed to identify effective biomarkers for immunotherapy treatment by characterizing the tumor microenvironment.MethodsWe retrieved the RNA-seq data from gastric cancer patients treated with the programmed death 1 (PD-1) blockade pembrolizumab. Differentially expressed genes associated with clinical outcomes were identified and further analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Gene signature scores were calculated by single sample Gene Set Enrichment Analysis (ssGSEA). The infiltration levels of immune cells were quantified using the xCell website. Cell type enrichment analysis was performed to compare treatment response and non-response groups, and regression analysis was used to investigate the relationship between interferon gamma (IFNγ) immune response and immune cell infiltration. Biomarkers were identified using least absolute shrinkage and selection operator (LASSO) analysis.ResultsCompared to normal tissues, cytokine activity and interleukin-6 production were highly activated in gastric tumors. Responders to pembrolizumab showed significantly up-regulated expression of IFNγ response-related genes. Cell type enrichment analysis revealed that Th1 cells were significantly enriched in the tumor microenvironment of responders. Regression analysis indicated that Th1 cells induced IFNγ response more efficiently than other cell types. Using signatures of Th1 cells, stromal cells and IFNγ response, a set of eight genes were identified that effectively predicted the efficacy of immunotherapy treatment and patient prognosis.ConclusionsTh1 cells promote therapeutic efficacy of PD-1 blockade by promoting IFNγ immune response in gastric cancer. The identified biomarkers have the potential to improve the effectiveness of immunotherapy treatment for gastric cancer patients.

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IFN? PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy.

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IFNγ PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy.

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