Comparative assessment of different radiological criteria to identify paradoxical hyperprogression (HPD) to IO drugs.

e15229 Background: HPD is a new pattern of response consisting of accelerated tumor growth due to immunotherapy (5%-20% of pts on IO drugs). The tumor growth rate (TGR, Champiat et al.) estimates the differential increase in tumor volume over time, pre- and on IO drugs, to assess for HPD, but it is not easily calculated in practice. A comparison of the different methods to identify HPD is missing. Methods: Retrospective study of 182 consecutive pts treated in Phase 1 studies of IO drugs at START Madrid-CIOCC in 2017-8, comparing 3 HPD measurement criteria (Champiat, Matos -which does not use pre-baseline CT scans-, and Saâda-Bouzid). Cohen’s Kappa index was calculated as a measure of the agreement between the 3 methods, being those values closer to 1 the more concordant ones. Overall survival (OS) rates were calculated by Kaplan-Meier (p < 0.05 to be significant). Results: 99 (54%) of 182 pts had progressive disease at cycle 1 of treatment and in 62 (34%) pre-baseline CT scans were available to calculate TGR. The Champiat method identified 18 (9.9%) pts with HPD. Of 61 cases validated to comparison, the Matos criteria labeled 27 pts (14.8% of 182) with HPD, of whom only 10 pts coincided with those identified by Champiat with a low agreement (Kappa: 0.140, p:0.251). No significant differences in OS between pts with non-HPD vs HPD by Matos criteria were seen (p = 0.16). With Saâda-Bouzid method, of 59 cases validated to comparison, 17 pts (9.3% of 182) were labeled with HPD and 13 of them coincided with those identified by Champiat method with a high agreement (Kappa:0.706, p:0.000). Differences in OS between non-HPD vs HPD pts were statistically significant (p = 0.038). Conclusions: HPD might have a detrimental effect to 10% of pts on IO drugs, also in our series. Every effort should be done to obtain pre-baseline CT scans to identify HPD response to IO drugs, based on differential TGR. The use of Saâda-Bouzid method is preferred due to its practical application and its correlation with survival. [Table: see text]

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A model-based approach to optimize detection of treatment effects in early oncology trials.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13508 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13508-e13508

Author(s):

Sylvie Retout ◽

Alex Phipps ◽

David Geho ◽

Jean Tessier ◽

Gwen L. Nichols ◽

...

Keyword(s):

Growth Rate ◽

Tumor Growth ◽

Measurement Errors ◽

Phase 1 ◽

Tumor Burden ◽

Simulated Patients ◽

Tumor Growth Rate ◽

Size Change ◽

Tumor Growth Model ◽

Investigational Agents

e13508 Background: Tumor size change from baseline (RECIST) is often used to assess antitumor activity of investigational agents in phase 1 trials, but this measure does not take into account the tumor growth rate (TGR) prior to treatment. TGR could be highly variable in a phase 1 ‘all-comers’ patient population, with a high TGR potentially masking a meaningful treatment effect (TE). Assessing the change in TGR (Mehrara et al, BJC 2011) using historical tumor burden assessments (Gomez-Roca et al, Eur J Cancer 2011) may provide higher sensitivity to true TE (TTE). The objectives of the current study are to formalize a Growth Rate Based Method (GRBM) and to compare, using simulated patients, the ability of GRBM and RECIST assessments to detect and quantify TTE. Methods: The exponential tumor growth model (Claret et al, J Clin Oncol. 2009) was used to simulate the sum of the longest diameters (SLD) individual time courses of 2000 virtual patients under different TGR scenarios: slow, medium, fast and ‘all comers’ (highly variable TGR as often encountered in phase 1). Different sampling designs were simulated wherein tumor assessments with measurement errors were obtained, ranging from 16 to 4 weeks prior to treatment initiation (TI), immediately before TI, and 8 and 16 weeks after TI. TTE was defined as the difference between the simulated SLDs at 16 weeks with and without treatment. GRBM response was defined as the model-predicted difference between the SLDs with and without treatment, as estimated from the simulated samples. Sensitivity (Se) of RECIST or GRBM was defined as the probability of classifying a patient as a RECIST or GRBM >30% reduction when the TTE >30%, and specificity (Sp) as the probability of RECIST or GRBM reduction <30% when TTE <30%. Results: RECIST Se was consistently inferior to GRBM, notably in the all-comers TGR (37% vs 74-89%) scenario. GRBM maintained Se (71-89%) irrespective of TGR whereas RECIST Se degraded significantly with increasing TGR. RECIST Sp was high (97-100%) while GRBM Sp was lower (55-80%) depending on sampling design and TGR. Conclusions: Incorporation of an additional pretreatment tumor assessment by GRBM may augment RECIST by increasing sensitivity to TTE, particularly in a heterogeneous TGR phase 1 setting.

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Evaluation of repeated [18F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas

EJNMMI Research ◽

10.1186/s13550-014-0065-z ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 4

Author(s):

Antti Silvoniemi ◽

Jonna Silén ◽

Sarita Forsback ◽

Eliisa Löyttyniemi ◽

Aleksi R Schrey ◽

...

Keyword(s):

Growth Rate ◽

Tumor Growth ◽

Head And Neck ◽

Ct Scans ◽

Tumor Growth Rate ◽

Head And Neck Carcinomas ◽

Pet Ct

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627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0627 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A663-A663

Author(s):

Keegan Cooke ◽

Juan Estrada ◽

Jinghui Zhan ◽

Jonathan Werner ◽

Fei Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Mouse Models ◽

T Cell Activation ◽

Phase 1 ◽

Phase 1 Study ◽

Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa154 ◽

2020 ◽

Author(s):

Gary L Gallia ◽

Matthias Holdhoff ◽

Henry Brem ◽

Avadhut D Joshi ◽

Christine L Hann ◽

...

Keyword(s):

Dose Escalation ◽

Plasma Levels ◽

Phase 1 ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

High Grade ◽

Newly Diagnosed ◽

Kaplan Meier ◽

High Grade Gliomas ◽

Expansion Cohort

Abstract Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

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Hyperprogressive Disease: Main Features and Key Controversies

International Journal of Molecular Sciences ◽

10.3390/ijms22073736 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3736

Author(s):

Hugo Arasanz ◽

Miren Zuazo ◽

Ana Bocanegra ◽

Luisa Chocarro ◽

Ester Blanco ◽

...

Keyword(s):

Tumor Growth ◽

Associated Factors ◽

Molecular Mechanisms ◽

Natural Course ◽

Preferential Treatment ◽

Radiological Criteria ◽

Tumor Histology ◽

Fast Progression ◽

Cancer Types ◽

Hyperprogressive Disease

Along with the positioning of immunotherapy as a preferential treatment for a wide variety of neoplasms, a new pattern of response consisting in a sudden acceleration of tumor growth has been described. This phenomenon has received the name of “hyperprogressive disease”, and several definitions have been proposed for its identification, most of them relying on radiological criteria. However, due to the fact that the cellular and molecular mechanisms have not been elucidated yet, there is still some debate regarding whether this fast progression is induced by immunotherapy or only reflects the natural course of some highly aggressive neoplasms. Moreover, contradictory results of trials including patients with different cancer types suggest that both the incidence, the associated factors and the implications regarding prognosis might differ depending on tumor histology. This article intends to review the main publications regarding this matter and critically approach the most controversial aspects.

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245 Human TLR8 knock-in mice potentiate immunotherapy responses of MC38 syngeneic tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0245 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A264-A264

Author(s):

Shanshan Qi ◽

Hongjuan Zhang ◽

Ruilin Sun ◽

Annie An ◽

Henry Li ◽

...

Keyword(s):

T Cells ◽

Tumor Growth ◽

Cancer Immunotherapy ◽

Tumor Regression ◽

Tumor Growth Rate ◽

Tumor Growth Inhibition ◽

List Type ◽

Rna Recognition ◽

Ethical Guidelines ◽

Ifn Γ

BackgroundToll-like receptors (TLRs) serve critical roles in mediating innate immune responses against many pathogens. However, they may also bind to endogenous ligands and lead to the pathogenesis of autoimmunity. Although TLR8 belongs to the same TLR family as TLR7, its role in inflammation and tumor progression is not yet fully understood due to the lack of suitable animal models. In humans, both TLR7 and TLR8 recognize single-stranded self-RNA, viral RNA, and synthetic small molecule agonists.1, 2 However, mouse Tlr8 is non-functional due to the absence of 5 amino acids necessary for RNA recognition. In order to create a mouse model with functional TLR8, we replaced exon 3 of mouse Tlr8 with human TLR8, therefore developing a hTLR8 knock-in (KI) model. Both heterozygous and homozygous hTLR8 KI mice are viable with inflammatory phenotypes, i.e. enlarged spleens and livers, and significantly higher IL-12 p40 levels under TLR8 agonist treatment. In this study, we evaluated the potential use of hTLR8 mice for cancer immunotherapy studies.MethodshTLR8 mice, together with naïve C57BL/6 mice, were inoculated with MC38 syngeneic tumor cells. Tumor bearing mice were grouped at a mean tumor volume of approximately 100 mm3 for treatment with PBS or 10 mg/kg anti-PD-1 (RMP1-14) antibody. At the efficacy endpoint, spleens and tumors were collected for flow cytometry profiling.ResultsAnti-PD-1 treatment of MC38 tumors in naïve C57BL/6 led to moderate tumor growth inhibition (TGI = 54%). Interestingly, anti-PD-1 treatment showed improved efficacy in hTLR8 mice (TGI = 79%), including 2/10 tumors with complete tumor regression. In comparison, non-treated MC38 tumor growth rate was slower in hTLR8 mice than in naïve mice. Anti-PD-1 treated hTLR8 mice also had significantly increased IFN-γ and TNF-a positive CD4+ T cells in the spleen, along with higher numbers of differentiated effector T cells. In addition, hTLR8 mice have activated dendritic cells and macrophages, acting as critical steps in initiation of the inflammatory process, with higher levels of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-a, and IL-1β, which may promote Th1 priming and differentiation of T cells into IFN-γ or TNF-a producing cells.ConclusionshTLR8 mice offer a great tool to model cancer immunotherapy in an inflammatory/autoimmunity prone background. Moreover, hTLR8 mice can be effectively used to shift a ‘cold’ tumor phenotype to ‘hot’ tumors in a syngeneic setting.Ethics ApprovalAnimal experiments were conducted in accordance with animal welfare law, approved by local authorities, and in accordance with the ethical guidelines of CrownBio (Taicang).ReferencesKugelberg E. Making mice more human the TLR8 way. Nat Rev Immunol 2014;14:6.Guiducci C, Gong M, Cepika A-M, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med 2013;210:2903–2919.

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Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽

10.1210/en.2012-2263 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1701-1710 ◽

Cited By ~ 21

Author(s):

Ran Rostoker ◽

Keren Bitton-Worms ◽

Avishay Caspi ◽

Zila Shen-Orr ◽

Derek LeRoith

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Breast Tumor ◽

Experimental Studies ◽

Tumor Development ◽

Treated Group ◽

Tumor Growth Rate ◽

Breast Cancer Patients ◽

Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

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Increased Tumor Growth in Mice with Diet-Induced Obesity: Impact of Ovarian Hormones

Endocrinology ◽

10.1210/en.2006-0311 ◽

2006 ◽

Vol 147 (12) ◽

pp. 5826-5834 ◽

Cited By ~ 95

Author(s):

Shoshana Yakar ◽

Nomeli P. Nunez ◽

Patricia Pennisi ◽

Pnina Brodt ◽

Hui Sun ◽

...

Keyword(s):

Insulin Resistance ◽

Tumor Growth ◽

Glucose Intolerance ◽

Tumor Development ◽

Tumor Growth Rate ◽

Obese Mice ◽

Female Mice ◽

Diet Induced Obesity ◽

Body Adiposity ◽

Obese Female

Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.

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Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Blood ◽

10.1182/blood-2011-11-390120 ◽

2012 ◽

Vol 119 (15) ◽

pp. 3403-3412 ◽

Cited By ~ 191

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Carlo Gambacorti-Passerini ◽

Michele Baccarani ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Phase 1 ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Abl Tyrosine Kinase ◽

Kaplan Meier

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

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Tumor growth characteristics of the Walker 256 AR tumor, a regressive variant of the rat Walker 256 A tumor

Brazilian Archives of Biology and Technology ◽

10.1590/s1516-89132010000500014 ◽

2010 ◽

Vol 53 (5) ◽

pp. 1101-1108 ◽

Cited By ~ 2

Author(s):

Fernando Guimarães ◽

Alessandra Soares Schanoski ◽

Tereza Cristina Samico Cavalcanti ◽

Priscila Bianchi Juliano ◽

Ana Neuza Viera-Matos ◽

...

Keyword(s):

Growth Rate ◽

Tumor Growth ◽

Wistar Rats ◽

Tumor Regression ◽

Growth Characteristics ◽

Tumor Growth Rate ◽

Continuous Growth ◽

Tumor Bearing ◽

Walker 256 ◽

Complete Tumor

The present study aimed at characterizing the subcutaneous development of the Walker 256 (W256) AR tumor, a regressive variant of the rat W256 A tumor. Wistar rats were injected subcutaneously with 4x10(6) W256 A or W256 AR tumor cells. The development of tumors was evaluated daily by percutaneous measurements. None of the W256 A tumors (n=20) regressed, but 62% of the W256 AR tumor-bearing rats (n=21) underwent complete tumor regression within 35 days. Continuous growth of AR tumors was characterized by an increase of the tumor growth rate from day 12, which reached values above 1.0 g/day, and were significantly higher (p<0.05) than those of the regressive AR tumors. Immunosuppression by irradiation before subcutaneous injection of AR cells completely abrogated tumor regression and was associated with severe metastatic dissemination. Daily evaluation of the tumor growth rate enabled the discrimination, in advance, between continuously growing tumors and those that regressed later on.

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