Hyperprogressive disease (HPD) is a new phenomenon developing in the era of immune checkpoint inhibitor (ICI) therapy. HPD is characterized by an unexpected and fast progression in tumor volume and poor survival. There is no standardized definition for HPD and clinicopathological variables associated with HPD are unclear. Herein, we assessed incidence, treatment outcomes and factors predictive of HPD in patients treated with ICIs.We retrospectively analyzed patients with advanced cancer treated with ICI at one academic center between 2014 and 2021. We used the Lo Russo's adopted criteria combined with clinical and radiologic parameters for the definition of HPD. All patients who underwent their first tumor evaluation according to RECIST1.1 were included.Of 155 patients, 147 were eligible for analysis. The median age was 61 and 83% were male. The cancer types were; lung 67.3%, bladder 12.9%, gastric 9.5%, 5, colon 5.4% and renal cell carcinoma 4.8%. 59.9% of patients were treatment-naive and others had one or more lines of chemotherapy. 19 (12.9%) patients had HPD. In patients who had HPD, progression-free survival (PFS) was significantly shorter (1.5 vs 9.8 months, (HR 9.56; 95% CI (5.51-16.57), p < 0.001). The median overall survival (OS) was also shorter for HPD patients than non-HPD (3.0 vs 23.1 months, respectively, HR 12.03, 95% CI (6.64-21.81), p < 0.001). Gastric cancer, larger sum of target lesion diameters at baseline, liver metastases, higher LDH level and higher neutrophil-lymphocyte ratio (NLR) were significantly associated with HPD.Our findings demonstrated that HPD was a rapid phenomenon with significantly poor survival rates. Several clinicopathological factors and tumor characteristics might indicate HPD.© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).

While evidence of hyperprogressive disease (HPD) continues to grow, the lack of a consensual definition obscures a proper characterization of HPD incidence. We examined how HPD incidence varies by the tumor type or the type of definition used.

Immune checkpoint inhibitors (ICIs) may be associated with hyperprogressive disease (HPD). However, there is currently no standardized definition of HPD, with its risk factors and clinical implications remaining unclear. We investigated HPD in lung cancer patients undergoing immunotherapy, aiming to redefine HPD, identify risk factors, and assess its impact on survival.Clinical and radiologic data from 121 non-small cell lung cancer (NSCLC) patients with 136 immunotherapy cases were reviewed retrospectively. Three HPD definitions (Champiat et al., HPDc; Saâda-Bouzid et al., HPDs; and Ferrara et al., HPDf) were employed. Additionally, all new measurable lesions on the post-treatment CT scan were incorporated in measuring the sum of longest diameters (SLD) to define modified HPD (mHPD).Among the 121 patients, 4 (3.3%) had HPDc, 11 (9.1%) had HPDs, and none had HPDf. Adding all new measurable lesions increased HPD incidence by 5%-10% across definitions. Multivariate analysis revealed significantly lower progression-free survival (PFS) and overall survival (OS) for patients with HPDc (HR 5.25, P =.001; HR 3.75, P =.015) and HPDs (HR 3.74, P <.001; HR 3.46, P <.001) compared to those without. Patients with mHPD showed similarly poor survival outcomes as HPD patients. Liver metastasis at diagnosis was associated with HPDs, and a high tumor burden correlated with HPDc.The incidence and risk factors of HPD varied with different definitions, but mHPD identified more cases with poor outcomes. This comprehensive approach may enhance the identification of at-risk patients and lead to a better understanding of HPD in lung cancer during immunotherapy.Copyright © 2024 Elsevier Inc. All rights reserved.

Hyper progressive disease (HPD) describes the phenomenon that patients can't benefit from immunotherapy but cause rapid tumor progression. HPD is a particular phenomenon in immunotherapy but lacks prediction methods. Our study aims to screen the factors that may forecast HPD and provide a predictive model for risky stratifying.We retrospectively reviewed advanced-stage tumor patients who received immune checkpoint inhibitors (ICI) in the General PLA Hospital. Subsequently, we calculated the tumor growth kinetics ratio (TGKr) and identified typical HPD patients. Differences analysis of clinical characteristics was performed, and a predictive binary classification model was constructed.867 patients with complete image information were screened from more than 3000 patients who received ICI between January 2015 and January 2020. Among them, 36 patients were identified as HPD for TGKr > 2. After the propensity score matched, confounding factors were limited. Survival analysis revealed that the clinical outcome of HPD patients was significantly worse than non-HPD patients. Besides, we found that Body Mass Index (BMI), anemia, lymph node metastasis in non-draining areas, pancreatic metastasis, and whether combined with anti-angiogenesis or chemotherapy therapy were closely connected with the HPD incidence. Based on these risk factors, we constructed a visualised predicted nomogram model, and the Area Under Curve (AUC) is 0.850 in the train dataset, whereas 0.812 in the test dataset.We carried out a retrospective study for HPD based on real-world patients and constructed a clinically feasible and practical model for predicting HPD incidence, which could help oncologists to stratify risky patients and select treatment strategies.© 2023. BioMed Central Ltd., part of Springer Nature.

Hyperprogressive disease (HPD) is a phenomenon defined as extremely rapid tumor progression within a short time following immunotherapy. To date, distinguishing which subgroups may be eligible for anti-PD-1/PD-L1 treatment has presented a clinical challenge. Moreover, no sufficiently convincing biomarkers of HPD have been identified. Herein, we present two cases of cancer patients who suffered from liver metastasis before immunotherapy. A 63-year-old man presented with cough and pain in right collarbone. He was finally diagnosed as suffering from right upper lobe adenocarcinoma with cTxN3M1c and stage IVB. First-line carboplatin plus pemetrexed chemotherapy combined with sintilimab anti-PD-1 was initiated after a multi-disciplinary discussion. In the second case, a 46-year-old female was diagnosed as moderately differentiated cervical squamous cell carcinoma. Widespread recurrence 2 years after extensive total hysterectomy for early cervical carcinoma. After six cycles of first-line chemotherapy and radiotherapy, the disease progressed and new-onset liver metastasis was detected. Pembrolizumab plus abraxane was administered as second-line therapy. After the first cycle of anti-PD-1 therapy, in both cases, an extremely rapid radiological progression was observed in the liver metastases with obvious symptoms, while the primary tumor site and other metastatic lesions remained stable or shrunken. These aberrations were confirmed as HPD. The risk of HPD appears to be higher in patients with liver metastases. We believe that further research will pave the way for the discovery of more significant biomarkers of HPD.2020 Annals of Translational Medicine. All rights reserved.

Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy. Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (= 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace. Amongst 155 patients, TTF <2 months was seen in all six individuals with amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, and alterations correlated with TTF <2 months. Two of 10 patients with alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). Some patients with family amplification or aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed..©2017 American Association for Cancer Research.

Delayed responses observed with immune checkpoint blockade (ICB) present a challenge for patients with peritoneal malignancies, who risk early symptomatic disease progression requiring treatment discontinuation. While efforts are ongoing to define the biomarkers of response, it is equally important to identify patients at risk for early discontinuation. We sought to investigate the timing of disease progression in epithelial ovarian cancer (EOC) patients treated with ICB and to identify pre-treatment clinical parameters associated with early discontinuation.Retrospective analysis was performed on EOC patients treated with ICB at MSKCC from January 2013 to May 2017. Cutoffs for early and very early discontinuation due to disease progression were defined at 12 and 8 weeks, respectively. Univariate and multivariate logistic regression models were built based on pre-treatment clinical variables.Of 108 identified patients, 89 were included in the analysis. Forty-six (51.7%) patients discontinued therapy early, 30 of which (33.7%) discontinued therapy very early. Eight patients (9.0%) died within 12 weeks of ICB initiation from disease progression. In multivariate analyses, bulky peritoneal disease (p = 0.009, OR: 4.94) and liver parenchymal metastases (p = 0.001, OR: 8.08) were associated with early discontinuation. Liver parenchymal metastases (p = 0.001, OR 6.64), and high neutrophil-to-lymphocyte ratio (p = 0.021, OR: 3.54), were associated with very early discontinuation.Over 50% of EOC patients suffer disease progression requiring early discontinuation of ICB. Pre-treatment prognostic clinical characteristics may identify patients at highest risk for early discontinuation due to disease progression and warrant caution in using these agents in late line patients with advanced disease.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

\n The programmed cell death 1 (PD-1), exhibits limited efficacy in high-grade serous ovarian cancer (HGSOC), with an average response rate of 10 to 15%. Furthermore, hyper-progression disease (HPD), which mostly occurs under immune checkpoint blockade (ICB) therapy, is a potentially deleterious side effect of ICB therapy that accelerates disease progression in HGSOC patients. Our study aims to identify the approach to improve the efficacy of anti-PD-1 treatment on HGSOC in preclinical settings. The prominent TIM-3 upregulation in CD8\n +\n tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating dendritic cells (TIDCs) and the phenomenon of HPD were observed in ID8\n VEGF\n -bearing mice after anti-PD-1 treatment. TIM-3 and PD-1 co-blockades prevented the occurrence of HPD in pre-clinical models and prolonged their survival. Meanwhile, TIM-3 and PD-1 co-blockades effectively enhanced the function and proliferation of CD8\n +\n TILs and TIDCs from ID8\n VEGF\n -bearing mice. Notably, TIM-3 and PD-1 inhibitors effectively enhanced the anti-tumor immunity of CD8\n +\n TILs and CD11c\n +\n myeloid cells from HGSOC patients. Our study uncovers the significance of TIM-3 inhibition in preventing the occurrence of HPD and enhancing the efficacy of anti-PD-1 therapy in HGSOC.\n

Hyperprogressive disease (HPD) is a novel pattern of paradoxically rapid tumor progression, which often leads to early death, mostly in the first 2 months of treatment with immune checkpoint inhibitors (ICIs). Currently, there is no validated biomarker to assess patients at risk of HPD.

The view of neutrophils has shifted from simple phagocytic cells, whose main function is to kill pathogens, to very complex cells that are also involved in immune regulation and tissue repair. These cells are essential for maintaining and regaining tissue homeostasis. Neutrophils can be viewed as double-edged swords in a range of situations. The potent killing machinery necessary for immune responses to pathogens can easily lead to collateral damage to host tissues when inappropriately controlled. Furthermore, some subtypes of neutrophils are potent pathogen killers, whereas others are immunosuppressive or can aid in tissue healing. Finally, in tumor immunology, many examples of both protumorigenic and antitumorigenic properties of neutrophils have been described. This has important consequences for cancer therapy, as targeting neutrophils can lead to either suppressed or stimulated antitumor responses. This review will discuss the current knowledge regarding the pro- and antitumorigenic roles of neutrophils, leading to the concept of a confused state of neutrophil-driven pro-/antitumor responses.© 2024. The Author(s).

Immune checkpoint inhibitors (ICIs) have demonstrated promising results in a variety of advanced cancer types. The phenomenon of hyperprogressive disease (HPD) has only been documented in recent years, however, there have been no reports of HPD in hepatocellular carcinoma. We present a case series of six patients with advanced hepatocellular carcinoma treated with ICIs who demonstrated rapid radiological progression, this was confirmed by comparing tumor growth rates before and during treatment with HPD defined as tumor growth rate ≥2. Although ICIs have demonstrated profound efficacy in advanced cancer, they might also be responsible for HPD in a small subset of patients. The ability to predict treatment response to ICI is thus of importance in protecting patients from the deleterious effects of HPD.

Indications of immunotherapy in oncology are continuously expanding, and unconventional types of response have been observed with these new treatments. These include transient progressive disease followed by a partial response, described as pseudoprogression, that raises the question of treatment beyond progression; and rapid disease progression associated with clinical decline, reported as hyperprogression. However, there are currently no consensual definitions of these phenomena and their impact on daily practice remains unclear. We reviewed existing data on pseudoprogression and hyperprogression with a focus on the definitions, incidence, predictive factors, potential biological mechanisms, and methods published to help distinguish pseudoprogression from progression and hyperprogression. The incidence of pseudoprogression ranged from 0 to 15%, with some authors also including disease stabilization after a first progression. For hyperprogression, incidence ranged from 4 to 29% with various definitions, and several authors reported a correlation with worse survival. Both phenomena were observed in a large panel of cancer types. Several radiological and biological methods have been reported to help distinguish pseudoprogression from progression and hyperprogression, such as analysis of radiomics, and circulating-tumor DNA or cell-free DNA, but these need to be confirmed in larger prospective cohorts. In conclusion, pseudoprogression and hyperprogression are both frequent types of responses under immunotherapy, and there is a need to better characterize these to improve the management of cancer patients. Treatment beyond progression should always be considered with caution and necessitates close clinical monitoring. In case of suspected hyperprogression, immunotherapy should be stopped early.

Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGK (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGK≥2. TGK calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy.

Hyperprogressive disease (HPD) is a paradoxically rapid disease progression during or shortly after antitumor treatment, especially immune checkpoint inhibitors (ICIs). Various diagnosis criteria of HPD cause heterogeneous incidence rates in different clinical research, and there is no consensus on potential risk factors associated with HPD occurrence. Hence, we aimed to summarize incidence of HPD in ICI treatment for solid tumors. Clinicopathological factors associated with HPD are also analyzed.

Predictive factors of nivolumab treatment response in patients with gastric cancer (GC) remain unclear.

Programmed cell death 1 (PD-1) blockade therapy can result in dramatic responses in some cancer patients. However, about 15% of patients receiving PD-1 blockade therapy experience rapid tumor progression, a phenomenon termed "hyperprogressive disease" (HPD). The mechanism(s) underlying HPD has been difficult to uncover because HPD is challenging to reproduce in animal models. Near-infrared photoimmunotherapy (NIR-PIT) is a method by which specific cells in the tumor microenvironment (TME) can be selectively depleted without disturbing other cells in the TME. In this study, we partially depleted CD8+ T cells with NIR-PIT by targeting the CD8β antigen thereby temporarily changing the balance of T-cell subsets in two different syngeneic tumor models. PD-1 blockade in these models led to rapid tumor progression compared to controls. CD3ε+CD8α+/CD3ε+CD4+FoxP3+ (Teff/Treg) ratios in the PD-1 and NIR-PIT groups were lower than in controls. Moreover, in a bilateral tumor model, low dose CD8β-targeted NIR-PIT with anti-PD-1 blockade showed rapid tumor progression only in the tumor exposed to NIR light. In this experiment CD8β-targeted NIR-PIT in the exposed tumor reduced local CD8+ T cells resulting in a regulatory T cell (Treg)-dominant TME. In conclusion, this reports an animal model to simulate the Treg-dominant TME, and the data generated using the model suggest that HPD after PD-1 blockade therapy can be attributed, at least in part, to imbalances between effector T cells and Tregs in the TME.

Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8 T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.Copyright © 2022 Elsevier Inc. All rights reserved.

Little is known about molecular biomarkers that predict the response and prognosis in unresectable hepatocellular carcinoma (HCC) treated with programmed death (PD)-1 inhibitors.

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status of tumors is a distinct predictive biomarker of immune checkpoint inhibitors (ICIs) for colorectal and non-colorectal cancer populations. The overall response rate (ORR) varies from approximately 40% to 60%, indicating that nearly half of MSI-H tumors do not respond to ICIs. The mechanism of response heterogeneity in MSI-H/dMMR cancers is unclear. Some patients who have been treated with ICIs have developed a novel pattern of progression called hyperprogression, which is defined as unexpected accelerated tumor growth. No case of MSI-H/dMMR immunotherapy-associated hyperprogression has been reported in the literature. Here, we present the case of a patient with dMMR gastrointestinal cancer who suffered hyperprogressive disease (HPD) after treatment with nivolumab. We explored the potential mechanisms of HPD by clinical, immune, and genomic characteristics. Extremely high levels of serum LDH, low TMB and TILs, and the disruption of TGFβ signaling, may be related to hyperprogression.

Chimeric antigen receptor T-cell therapy (CAR-T) has been widely applied in the clinical practice of relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) due to its promising effects. Hyperprogressive disease (HPD) has gained attention for rapid tumor progression and has become a therapeutic and prognostic challenge. Here, we present a patient who had suffered from several recurrences previously and controlled well with a very small tumor lesion left was infused with CD19/CD22 bispecific CAR-T, with no immune effector cell-associated neurotoxicity syndrome, or cytokine release syndrome observed. However, rapid deterioration, subsequent imaging examination, circulating tumor DNA, and serum biomarkers detection identified HPD. The patient did not respond to salvage treatment and died 40 days after infusion. To our knowledge, only one case of HPD in DLBCL after CAR-T therapy has been reported. This fatal case alarmed the risk of HPD and the ctDNA profile monitoring we used was performed as a non-invasive method to diagnose HPD, providing far-reaching practical instruction for CAR-T therapy.

Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, = 0.003), MIKI67 mutation (HR = 114.11, = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.Copyright © 2020 Chen, Li, Liu, Chen, Xu, Song and Wang.

Objective. Immunotherapy has proven effective in treating advanced gastric cancer (AGC), yet its benefits are limited to a subset of patients. Our aim is to swiftly identify prognostic biomarkers using cytokines to improve the precision of clinical guidance and decision‐making for PD‐1 inhibitor‐based cancer immunotherapy in AGC. Materials and Methods. The retrospective study compared 36 patients with AGC who received combined anti‐PD‐1 immunotherapy and chemotherapy (immunochemotherapy) with a control group of 20 patients who received chemotherapy alone. The concentrations of TNF‐α, IL‐1β, IL‐2R, IL‐6, IL‐8, IL‐10, and IL‐17 in the serum were assessed using chemiluminescence immunoassay at three distinct time intervals following the commencement of immunochemotherapy. Results. When compared to controls, patients undergoing immunochemotherapy demonstrated a generalized rise in cytokine levels after the start of treatment. However, patients who benefited from immunochemotherapy showed a decrease in IL‐6 or IL‐8 concentrations throughout treatment (with varied trends observed for IL‐1β, IL‐2R, IL‐10, IL‐17, and TNF‐α) was evident in patients benefiting from immunochemotherapy but not in those who did not benefit. Among these markers, the combination of IL‐6, IL‐8, and CEA showed optimal predictive performance for short‐term efficacy of immunochemotherapy in AGC patients. Conclusion. Reductions in IL‐6/IL‐8 levels observed during immunochemotherapy correlated with increased responsiveness to treatment effectiveness. These easily accessible blood‐based biomarkers are predictive and rapid and may play a crucial role in identifying individuals likely to derive benefits from PD‐1 blockade immunotherapy.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.© 2018 UICC.

We assessed the predictive potential of positron emission tomography (PET)/CT-based radiomics, lesion volume, and routine blood markers for early differentiation of pseudoprogression from true progression at 3 months.112 patients with metastatic melanoma treated with immune checkpoint inhibition were included in our study. Median follow-up duration was 22 months. 716 metastases were segmented individually on CT and 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET imaging at three timepoints: baseline (TP0), 3 months (TP1), and 6 months (TP2). Response was defined on a lesion-individual level (RECIST 1.1) and retrospectively correlated with FDG-PET/CT radiomic features and the blood markers LDH/S100. Seven multivariate prediction model classes were generated.Two-year (median) overall survival, progression-free survival, and immune progression-free survival were 69% (not reached), 24% (6 months), and 42% (16 months), respectively. At 3 months, 106 (16%) lesions had progressed, of which 30 (5%) were identified as pseudoprogression at 6 months. Patients with pseudoprogressive lesions and without true progressive lesions had a similar outcome to responding patients and a significantly better 2-year overall survival of 100% (30 months), compared with 15% (10 months) in patients with true progressions/without pseudoprogression (= 0.002). Patients with mixed progressive/pseudoprogressive lesions were in between at 53% (25 months). The blood prediction model (LDH+S100) achieved an AUC = 0.71. Higher LDH/S100 values indicated a low chance of pseudoprogression. Volume-based models: AUC = 0.72 (TP1) and AUC = 0.80 (delta-volume between TP0/TP1). Radiomics models (including/excluding volume-related features): AUC = 0.79/0.78. Combined blood/volume model: AUC = 0.79. Combined blood/radiomics model (including volume-related features): AUC = 0.78. The combined blood/radiomics model (excluding volume-related features) performed best: AUC = 0.82.Noninvasive PET/CT-based radiomics, especially in combination with blood parameters, are promising biomarkers for early differentiation of pseudoprogression, potentially avoiding added toxicity or delayed treatment switch.©2020 American Association for Cancer Research.

\n 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-[\n 18\n F]fluoro-D-glucose positron emission tomography/computed tomography (\n 18\n F-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\n 18\n F-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.\n

Checkpoint blockade therapy has shown significant therapeutic benefits and resulted in durable responses in patients with various tumors. However, accumulating evidence has demonstrated that 4‐29% of all patients with cancers with various histologies may suffer from tumor flare following such therapy. This novel tumor response pattern, termed hyperprogression, is a potentially deleterious side effect of checkpoint blockade therapy that accelerates disease progression in a subset of patients. In this review, we describe possible immune checkpoint blockade biomarkers and the epidemiology, different definitions, and predictors of hyperprogression based on the research findings and further present the available evidence supporting pathophysiological hypotheses that might explain hyperprogression during checkpoint blockade therapy. We also compare hyperprogression and pseudoprogression. Finally, we discuss areas requiring further study.

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.Copyright © 2024 by The Author(s).