Italia Grenga

Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab

PurposeThe aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.MethodsForty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI)u2009+u2009Bev (male/femaleu2009=u200922:18, age (median)u2009=u200961xa0years). Eight VGPs within the promoter/5’UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.ResultsVGPs −2578, −1512, −1451, −1411, and −460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18xa0bp insertion-T-4G-C and Haplo2: C-18xa0bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4xa0months, respectively, pu2009=u20090.02; hazard ratio (HR), 2.64). Also, VGPs −152 (G/G vs. G/Au2009+u2009A/A) and −1154 (G/G vs. G/Au2009+u2009A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4xa0months, pu2009=u20090.007; HR, 3.53 and 9.8 vs. 16xa0months, pu2009=u20090.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP −1154 retained an independent predictive value for mPFS (G/G over G/Au2009+u2009A/Au2009=u2009HR, 4.43; pu2009=u20090.02). With regard to ORR, only VGP −634 was significantly associated with response (G/G vs. G/Cu2009+u2009C/Cu2009=u200964% vs. 14%, pu2009=u20090.03). No significant influence on OS and toxicity by the investigated VGPs was observed.ConclusionsAlthough these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.

The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells.

Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83+ conventional DCs, and a decrease in immature activated Tim3+ NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.

Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.” Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.

Peripheral CD45RO, PD-1, and TLR4 expression in metastatic colorectal cancer patients treated with bevacizumab, fluorouracil, and irinotecan (FOLFIRI-B)

Abstract CD45RO, PD-1, and TLR4 immune pathways have proven pivotal in regulating antitumor response and correlate with survival for localized colorectal cancer (CRC). We evaluated if their peripheral expression was associated with outcome in metastatic CRC (mCRC). Thirty-one mCRC patients were eligible for this prospective study (clinicaltrial.gov NCT01533740) and treated with first-line FOLFIRI-B. Blood was drawn before the first and third cycle and analyzed by flow cytometry for frequency (%) of CD4+, CD8+, CD45RO+, and PD1+ mononuclear cells and for TLR4 expression on neutrophils. Two cycles of chemotherapy determined changes in immune variables that were prognostically meaningful. Pre-third-cycle (ptc) CD45RO+CD8+cell% displayed a statistically significant association with progression-free survival (PFS) (median PFS 22.4 vs. 9.4xa0months for patients with CD45RO+CD8+cell%> vs. <the median value of 12xa0%, respectively, p 0.02) and overall survival (OS) (2-year OS rate 62 vs. 44xa0%, respectively, p 0.04). Surprisingly, ptc-PD1 overexpression was also associated with improved PFS of borderline statistical significance (HR 0.42, p 0.06). A Cox regression multivariate analysis for PFS including ptc-CD45RO+CD8+cell%, ptc-PD1+cell%, CEA, LDH, and Köhne risk class demonstrated CD45RO+CD8+cell% to be the only independent prognostic factor (HR 0.23, p 0.04). TLR4 and CD4 were not associated with the outcome. Peripheral CD8+CD45RO+ cells were confirmed to be of independent prognostic value in mCRC patients. Overexpression of the PD-1 immunosuppressor after two cycles of therapy may be a negative feedback mechanism, and therefore, an indirect sign of chemotherapy induced antitumor immune response with a favorable association with outcome. Enhancement of CD8+CD45RO+ cell response may be a fascinating therapeutic target to improve the efficacy of FOLFIRI-B.

An activated protein C-dependent thrombin generation assay predicts chemotherapy-associated venous thromboembolism in cancer patients.

An activated protein C-dependent thrombin generation assay predicts chemotherapy-associated venous thromboembolism in cancer patients -

Rehabilitation in neuro-oncology: a meta-analysis of published data and a mono-institutional experience

Background. Rehabilitation for cancer patients with central nervous system (CNS) involvement is rarely considered and data on its use are limited. The purpose of the present study is to collect all available published data on neuro-oncology rehabilitation and perform a meta-analysis where results were presented in a comparable manner. Moreover, the authors report results on cancer patients with neurological disabilities undergoing rehabilitation at their unit. Study design. A PubMed search was performed to identify studies regarding cancer patients with CNS involvement undergoing inpatient physical rehabilitation. Studies with a complete functional evaluation at admission and discharge were selected. As the most common evaluation scales were Functional Independence Measure (FIM) and Barthel Index (BI), only articles with complete FIM and/or BI data were selected for the meta-analysis. Moreover, 23 cancer patients suffering from diverse neurological disabilities underwent standard rehabilitation program between April 2005 and December 2007 at the San Raffaele Pisana Rehabilitation Center. Patient demographics and relevant clinical data were collected. Motricity Index, Trunk Control Test score, and BI were monitored during rehabilitation to assess patient progresses. BI results of patients in this study were included in the meta-analysis. Results. The meta-analysis included results of a total of 994 patients. A statistically significant (P < .05) improvement of both BI and FIM scores was demonstrated after rehabilitation (standardized mean difference = 0.60 and 0.75, respectively). Functional status determined by either FIM or BI improved on average by 36%. Conclusion. Published data demonstrate that patients with brain tumors undergoing inpatient rehabilitation appear to make functional gains in line with those seen in similar patients with nonneoplastic conditions.

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients—a pilot study

PurposeIdentifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification.MethodsA retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen.ResultsRetrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10–0.19; pu2009<u20090.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12–0.52, pu2009<u20090.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group.ConclusionsWe may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.

Abstract LB-059: Neoadjuvant immunotherapy with androgen deprivation therapy (ADT) prior to radiation in prostate cancer: Impact on multiparametric prostate MRI and immune responses

Background: There is increasing interest in using combination immunotherapy in the neoadjuvant setting in prostate cancer, however, endpoints for such studies remain elusive. We have conducted a clinical trial evaluating immunotherapy with ADT in patients with high risk prostate cancer. Patients were assessed for immune responses and changes in endorectal (er) MRI which can be used to assess intraprostatic tumors. Methods: Treatment-naive high-risk (Gleason 8-10, PSA>20, or stage T3) prostate cancer patients (pts) were randomized to standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25) in this trial (NCT01496131). ADT consisted of gonadotropin-releasing hormone therapy. Immunotherapy included low dose (300 mg/m2, maximum 600 mg) pre-treatment cyclophosphamide for regulatory T-cell depletion. erMRI was done at baseline and after 2 months of immunotherapy including multiparametric MRI evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments analyzed immune cell subsets using flow cytometry and intracellular cytokine (ICC) staining for MUC-1 specific responses. Results: 28 pts with high risk prostate cancer were enrolled (n=14/arm). As expected, PSA declined in all pts 2 months after ADT. erMRI after 2 months of treatment suggested greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI indicates increased intratumoral diffusion and has been associated with decreased tumor density. The improvements in ADC were seen when one dominant tumor per patient was evaluated (p=0.17) but were more pronounced when up to 3 lesions were evaluated per pt (n=44 lesions; p=0.031). Compared to baseline, there were trends to increases in CTLA4+ CD8+ T-cells consistent with immune activation and decreases in myeloid derived suppressor cells (MDSCs) in pts receiving immunotherapy+ADT coinciding with the erMRI changes. These immune findings were not seen in the ADT alone group. 3 of 14 pts had MUC1 specific immune response by ICC. 2 of these patients had the greatest changes in ADC noted on erMRI over a 2-year period. Conclusions: Based on assessments by erMRI, pts who received ADT+immunotherapy had greater improvements in ADC than pts receiving ADT alone. Given that ADC improvements are associated with decreased tumor density, this suggests a possible greater anti-tumor effect of the ADT-immunotherapy combination vs. ADT alone. These findings were associated with trends to increased activated CD8+ T-cells and decreased MDSCs in pts receiving immunotherapy+ADT, with 3/14 pts having MUC1 specific immune responses. Further studies are required to confirm the potential to use ADC on erMRI as a potential (bio)marker of anti-tumor effect of immune combinations including ADT. Citation Format: Ravi A. Madan, Baris Turkbey, Lauren M. Lepone, Renee N. Donahue, Italia Grenga, Samuel Samuel Borofsky, Peter A. Pinto, Deborah Citrin, Aradhana Kaushal, Andra Krauze, Sheri McMahon, Myrna Rauchhorst, Anna Couvillon, Martin H. Falk, S Peter Eggleton, Stephen C. Greco, Peter L. Choyke, William L. Dahut, Jeffrey Schlom, James L. Gulley. Neoadjuvant immunotherapy with androgen deprivation therapy (ADT) prior to radiation in prostate cancer: Impact on multiparametric prostate MRI and immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-059. doi:10.1158/1538-7445.AM2017-LB-059

Abstract 1403: Correlations between overall survival and patient regulatory T-cell levels at initiation of Folfiri therapy in colorectal cancer

Twenty-three patients with metastatic colon or rectal carcinoma were enrolled in a first-line study of Folfiri therapy consisting of irinotecan (180 mg/m 2 day 1), levo-leucovorin (200 mg/m 2 day 1), 5-FU (400 mg/m 2 bolus day 1 and 2400 mg/m 2 continuous infusion over 48h), and bevacizumab (5 mg/kg day 1). This treatment schedule was repeated every 2 weeks. Peripheral blood samples were collected prior to the start of cycle I, and after 30 days, and assayed by 4-color flow cytometry and regulatory T-cell (Treg) suppression assay. Cytofluorometric analysis of PBMCs of the entire group of patients revealed no statistical differences between the PBMCs collected at baseline and post 30 days of therapy in terms of PBMC amount, percent of CD4 + T cells, CD8 + T cells, or Tregs, or the ratios of CD4 + T cells or CD8 + T cells vs. Tregs. Lower levels of Tregs ( 2.5% Tregs at baseline PFS was 10.7 weeks (p = 0.037, n = 23). Furthermore, a forward step-wise regression analysis model demonstrated that lower Tregs at baseline (regression coefficient = 0.467, p = 0.004) and the decrease in Tregs (as% of PBMC) at 30 days of chemotherapy (regression coefficient = 0.454, p = 0.006) were both independent predictors of better OS, independent of age, gender, ALP, LDH, mucinous vs. non-mucinous phenotype, serum CEA, serum 19.9, and number of metastatic sites. Of the 23 patients on study, 14 demonstrated clinical responses by RECIST criteria and nine did not. Eight of the 14 (57%) responders by RECIST criteria displayed Treg levels 2 = 3.9 with Pearson test). In conclusion, we found lower frequencies of Tregs at baseline in responders than non-responders, which was associated with longer PFS. In addition, lower Tregs at baseline and a decrease in Treg frequency after 1 month of Folfiri therapy were both independent predictors of longer OS. Citation Format: Caroline Jochems, Vittore Cereda, Romaine I. Fernando, Jacob Richards, Italia Grenga, Patrizia Ferroni, Fiorella Guadagni, Jeffrey Schlom, Mario Roselli. Correlations between overall survival and patient regulatory T-cell levels at initiation of Folfiri therapy in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1403.