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IFN-? and CD38 in Hyperprogressive Cancer Development.

ABSTRACT: Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-? is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-? may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.

SUBMITTER: Angelicola S

PROVIDER: S-EPMC7830527 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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IFN-γ and CD38 in Hyperprogressive Cancer Development.

Angelicola Stefania S Ruzzi Francesca F Landuzzi Lorena L Scalambra Laura L Gelsomino Francesco F Ardizzoni Andrea A Nanni Patrizia P Lollini Pier-Luigi PL Palladini Arianna A

Cancers 20210115 2

Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated ...[more]

PMID: 33467713

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Project description:PurposeCluster of differentiation 38 (CD38) is a promising therapeutic target in multiple myeloma (MM) patients and has resulted in the development of several CD38 immunotherapies. Current methods to evaluate CD38 expression in the preclinical setting include ex vivo flow cytometry and immunohistochemistry, which can be cumbersome and do not give whole-body information. In vivo imaging technologies such as positron emission tomography rely on decay of radioisotopes, limiting the number of molecular interactions observed at any given time point. Here, we demonstrate the use of near-infrared (NIR) fluorescence imaging for spatiotemporal monitoring of CD38 expression in preclinical MM using the anti-CD38 daratumumab (DARA) conjugated to the NIR fluorophore IRDye800CW (DARA-IRDye800).ProceduresStability studies with human serum and binding assays with human myeloma cells were performed with DARA-IRDye800. Immunocompromised mice with intra- and extramedullary tumors (n = 5/group) were administered with DARA-IRDye800 for in vivo imaging up to 7 days after injection. Ex vivo biodistribution and flow cytometry studies were performed to validate in vivo imaging results. A separate therapy study was performed in mice with intramedullary tumors that were treated and not treated with DARA at a therapeutic dose (n = 7/group). DARA-IRDye800 was administered for subsequent in vivo and ex vivo imaging in both cohorts of mice.ResultsDARA-IRDye800 maintained stability and had high affinity for CD38 (KD = 3.5 ± 0.05 nM). DARA-IRDye800 demonstrated a 5- and 18-fold increase in contrast in tumor-bearing regions of mice with extra- and intramedullary MM. Finally, mice treated with therapeutic doses of DARA and imaged with DARA-IRDye800 showed an 11-fold decrease in fluorescence intensities in vivo compared with untreated controls.ConclusionsOur studies establish DARA-IRDye800 as a promising contrast agent for preclinical evaluation of CD38 expression and for further investigating myeloma engraftment and kinetics in relation to anti-CD38 therapies.

Project description:ImportanceHyperprogressive disease (HPD) is an aggressive pattern of progression reported for patients treated with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) inhibitors as a single agent in several studies. However, the use of different definitions of HPD introduces the risk of describing different tumoral behaviors.ObjectiveTo assess the accuracy of each HPD definition to identify the frequency of HPD and the association with poorer outcomes of immune-checkpoint inhibitor (ICI) treatment in patients with advanced non-small cell lung cancer (NSCLC) and to provide an optimized and homogenized definition based on all previous criteria for identifying HPD.Design, setting, and participantsThis retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from November 1, 2012, to April 5, 2017, in 8 French institutions. Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least 2 computed tomographic scans before the initiation of ICI therapy and 1 computed tomographic scan during treatment. Data were analyzed from November 1, 2012, to August 1, 2019.ExposuresAdvanced NSCLC and treatment with PD-1/PD-L1 inhibitors.Main outcomes and measuresAssociation of the definition with the related incidence and the HPD subset constitution and the association between each HPD definition and overall survival. All dynamic indexes used in the previous proposed definitions, such as the tumor growth rate (TGR) or tumor growth kinetics (TGK), were calculated before and during treatment.ResultsAmong the 406 patients with NSCLC included in the analysis (259 male [63.8%]; median age at start of ICI treatment, 64 [range, 30-91] years), the different definitions resulted in incidences of the HPD phenomenon varying from 5.4% (n = 22; definition based on a progression pace >2-fold and a time to treatment failure of <2 months) to 18.5% (n = 75; definition based on the TGR ratio). The concordance between these different definitions (using the Jaccard similarity index) varied from 33.3% to 69.3%. For every definition, HPD was associated with poorer survival (range of median overall survival, 3.4 [95% CI, 1.9-8.4] to 6.0 [95% CI, 3.7-9.4] months). The difference between TGR before and during therapy (ΔTGR) was the most correlated with poor overall survival with an initial plateau for a larger number of patients and a slower increase, and it had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD. In addition, an optimal threshold of ΔTGR of greater than 100 was identified for this distinction.Conclusions and relevanceThe findings of this retrospective cohort study of patients with NSCLC suggest that the previous 5 definitions of HPD were not associated with the same tumor behavior. A new definition, based on ΔTGR of greater than 100, appeared to be associated with the characteristics expected with HPD (increase of the tumor kinetics and poor survival). Additional studies on larger groups of patients are necessary to confirm the accuracy and validate this proposed definition.

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IFN-? and CD38 in Hyperprogressive Cancer Development.

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IFN-γ and CD38 in Hyperprogressive Cancer Development.

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