Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

The Role and Therapeutic Targeting of CCR5 in Breast Cancer.

The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells. The function of CCR5 on breast cancer epithelial cells includes the induction of aberrant cell survival signaling and tropism towards chemo attractants. As CCR5 is not expressed on normal epithelium, the receptor provides a potential useful target for therapy. Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors.

Impact of 68Ga-FAPI PET/CT on Staging and Oncologic Management in a Cohort of 226 Patients with Various Cancers.

Since the development of fibroblast activation protein-targeted radiopharmaceuticals, 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT has been found to be suitable for detecting primary and metastatic lesions in many types of tumors. However, there is currently a lack of reliable data regarding the clinical impact of this family of probes. To address this gap, the present study aimed to analyze the clinical impact of 68Ga-FAPI PET/CT by examining a large cohort of patients with various tumors. Methods: In total, 226 patients (137 male and 89 female) were included in this retrospective analysis. Pancreatic cancer and head and neck cancers were the most common tumor types in this cohort. TNM stage and oncologic management were initially determined with gold standard imaging, and these results were compared with 68Ga-FAPI PET/CT. Changes were classified as major and minor. Results: For 42% of all patients, TNM stage was changed by 68Ga-FAPI PET/CT results. Most of these changes resulted in upstaging. A change in clinical management occurred in 117 of 226 patients. Although a major change in management occurred in only 12% of patients, there was a significant improvement in the ability to accurately plan radiation therapy. In general, the highest clinical impact of 68Ga-FAPI PET/CT imaging was found in patients with lung cancer, pancreatic cancer, and head and neck tumors. Conclusion: 68Ga-FAPI PET/CT is a promising imaging probe that has a significant impact on TNM stage and clinical management. 68Ga-FAPI PET/CT promises to be a crucial new technology that will improve on conventional radiologic imaging methods such as contrast-enhanced CT and contrast-enhanced MRI typically acquired for cancer staging.

Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment.

PURPOSE: Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. METHODS: Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. RESULTS: Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (< 6 months) had an inferior overall survival (OS 6.3 vs. 13.8 months, p < 0.001) after relapse than those with a late relapse (> 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p < 0.0001). Multivariate analysis confirmed the prognostic benefit of the MSI status and a local intervention. CONCLUSION: Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer - The PICCASSO phase I trial.

BACKGROUND: PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC. METHODS: Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu. RESULTS: The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was >70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS. CONCLUSIONS: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.

JunB is a key regulator of multiple myeloma bone marrow angiogenesis.

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.

Predicting the Risk of Metastases by PSMA-PET/CT-Evaluation of 335 Men with Treatment-Naïve Prostate Carcinoma.

Men diagnosed with aggressive prostate cancer are at high risk of local relapse or systemic progression after definitive treatment. Treatment intensification is highly needed for that patient cohort; however, no relevant stratification tool has been implemented into the clinical work routine so far. Therefore, the aim of the current study was to analyze the role of initial PSMA-PET/CT as a prediction tool for metastases. In total, 335 men with biopsy-proven prostate carcinoma and PSMA-PET/CT for primary staging were enrolled in the present, retrospective study. The number and site of metastases were analyzed and correlated with the maximum standardized uptake value (SUVmax) of the intraprostatic, malignant lesion. Receiver operating characteristic (ROC) curves were used to determine sensitivity and specificity and a model was created using multiple logistic regression. PSMA-PET/CT detected 171 metastases with PSMA-uptake in 82 patients. A statistically significant higher SUVmax was found for men with metastatic disease than for the cohort without distant metastases (median 16.1 vs. 11.2; p < 0.001). The area under the curve (AUC) in regard to predicting the presence of any metastases was 0.65. Choosing a cut-off value of 11.9 for SUVmax, a sensitivity and specificity (factor 1:1) of 76.0% and 58.4% was obtained. The current study confirms, that initial PSMA-PET/CT is able to detect a relatively high number of treatment-naïve men with metastatic prostate carcinoma. Intraprostatic SUVmax seems to be a promising parameter for the prediction of distant disease and could be used for treatment stratification-aspects which should be verified within prospective trials.

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience.

OBJECTIVES: A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled. MATERIAL AND METHODS: Patients with resectable NSCLC stage II/IIIA were included. Two cycles of pembrolizumab (200 mg intravenously once every 3 weeks) were administered prior to surgery. The primary objectives were to assess the feasibility and safety of neoadjuvant pembrolizumab therapy and to evaluate antitumor activity. We analyzed the clinical parameters as well as pathological and radiological tumor response data. RESULTS: The NSCLC histology was adenocarcinoma for 13 patients and squamous cell carcinoma for 2 patients. All patients but two underwent 2 cycles of pembrolizumab prior to surgery. Four patients (27 %) presented a major pathologic response. Significant tumor target response in positron emission tomography computed tomography (PET-CT) was detected in all 4 pathologic responders. Nevertheless, the PET findings mismatched the tumor load in some patients. A PD-L1 expression ≥10 % in the pretreatment biopsy was associated with at least major pathologic response. Five patients (33 %) presented grade 2-3 treatment related adverse events (TRAE), the overall postoperative morbidity was 7 % and 30-day mortality was 0 %. CONCLUSION: Neoadjuvant pembrolizumab is a feasible therapy in surgical lung cancer patients. It was associated with tolerable toxicity and did not compromise tumor resection.

Cancer-related microangiopathic hemolytic anemia in patients with advanced gastric cancer: A retrospective single-center analysis.

BACKGROUND: Microangiopathic hemolytic anemia (MAHA) with thrombocytopenia and organ failure caused by tumor-associated thrombotic microangiopathy (TMA) is a life-threatening oncological emergency. Rapid diagnosis and precise distinction from other forms of TMA is crucial for appropriate therapy, which aims at treating the underlying malignancy. However, the prognosis of patients with cancer-related (CR)-MAHA is limited. To date, less than 50 patients with gastric cancer and CR-MAHA have been reported, mainly as single case reports, and detailed information on treatment strategies and outcome are scarce. We analyzed the characteristics and outcomes data of CR-MAHA patients with gastric cancer treated at our center between 2012 and 2019. AIM: To gain knowledge about CR-MAHA and the course of disease. METHODS: We retrospectively analyzed patients using an institutional prospectively maintained database. Patients who had CR-MAHA but other cancer types or cancer of unknown primary were excluded. The basic requirements for inclusion were: Histologically proven gastric adenocarcinoma; and clinical diagnosis of hemolytic anemia with schistocytes with or without thrombocytopenia. The observation period for each patient started with the first day of documented symptoms. The follow-up period for this analysis ended on February 1, 2020. RESULTS: We identified eight patients with a median age of 54 years. Histologically, all patients had (partial) diffuse subtypes of gastric adenocarcinoma with partial or complete signet cell morphology. All patients had metastatic disease and one patient had a microsatellite instability-high (MSI-H) tumor. In three patients, clinical signs of MAHA preceded the diagnosis of cancer, and in two patients, CR-MAHA indicated recurrent disease. All patients had severe hemolytic anemia and thrombocytopenia. Six patients experienced severe bone pain, and five patients had dyspnea. Systemic, 5-fluorouracil-based combination chemotherapy was initiated in six patients, which resulted in rapid initial response with significant improvement of clinical symptoms and blood values. Progression-free survival (PFS) of the whole cohort was 1.9 wk and median overall survival (OS) was 1.9 wk. For patients with chemotherapy, PFS was 9.0 wk and OS was 10.3 wk. The patient with the MSI-H tumor has been undergoing immunotherapy for more than 3 years. CONCLUSION: The benefit of chemotherapy in CR-MAHA patients is limited. Immunotherapy for patients with MSI-H tumors may lead to long-term tumor control even in CR-MAHA patients.

The Role of 68Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience.

For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Methods:68Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of 68Ga-FAPI-04 and 68Ga-FAPI-46 was quantified by SUVmax and SUVmean After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUVmax of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by 68Ga-FAPI PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by 68Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. 68Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.

Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology.

Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and "stemness". Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.

COOLHAIR: a prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing (neo)adjuvant chemotherapy for early breast cancer.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing side effect for women with breast cancer undergoing chemotherapy. Scalp cooling is a method aiming to prevent CIA, but its efficacy is not well defined. Randomized trials until recently and at the time this trial was designed have been lacking. METHODS: Patients undergoing (neo)adjuvant chemotherapy for early breast cancer (EBC) were randomized to scalp cooling (CAP) or observation (NoCAP). All patients received 18-24 weeks of anthracycline- and/or taxane-based chemotherapy. The primary endpoint was patient-reported rate of alopecia according to a modified version of the Dean Scale. Hair preservation was defined as hair loss ≤ grade 2 (≤ 50%). Secondary endpoints were rate of alopecia determined by medical staff, rate of wig/scarf use, tolerability as well as quality of life (QoL). RESULTS: Seventy-nine patients were randomized. Hair preservation was observed in 39.3% of patients in the CAP arm versus 0% in the NoCAP arm (p < 0.001). Wig/scarf use was significantly less frequent in the CAP group (40.7% vs 95.5% outside home before cycle 3, p < 0.001). The drop-out rate was 31.7% and 34.2% in the CAP and NoCAP arm, respectively. Main reasons for drop-out were hair loss, adverse events (CAP), and randomization into control arm. We observed no differences in efficacy between anthracycline-based and non-anthracycline-based regimens. QoL did not differ between the study arms. CONCLUSIONS: This trial adds to the evidence that scalp cooling effectively prevents CIA in a meaningful number of patients. This option should be made available for patients undergoing (neo)adjuvant chemotherapy for EBC.

Targeted and immuno-biology driven treatment strategies for triple-negative breast cancer: current knowledge and future perspectives.

Introduction: Accounting for about 15% of breast cancer patients, triple-negative breast cancer (TNBC) is responsible for 25% of disease related deaths, more frequent distant spread and visceral metastasis. However, improving survival in TNBC failed and primary resistance, immunological ignorance and tumor heterogeneity limit clinical activity of novel therapies. In view of recent molecular, genetic and immunologic insights, this review aims to describe the current status of immunological and targeted treatments from a hypothesis driven perspective. Areas covered: Recent preclinical studies and ongoing clinical trials for immune directed and targeted treatments of TNBC are summarized, including immune-checkpoint blockade, resistance mechanisms, inhibition of poly (ADP-ribose) polymerase (PARP), combinatorial strategies as well as preclinical, hypothesis generating studies. Expert commentary: Sustained responses have been observed with immune-checkpoint blockade and PARP inhibitors demonstrated remarkable efficacy in germline BRCA mutated TNBC. In order to generate clinical success of many other, to date ineffective, targeted and immune therapies, the integration of multidimensional, large amounts of data, will be essential and likely accelerate treatment progress of TNBC.

CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer.

PURPOSE: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. RESULTS: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. CONCLUSION: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

High-Throughput Screening of Combinatorial Immunotherapies with Patient-Specific In Silico Models of Metastatic Colorectal Cancer.

Solid tumors are rich ecosystems of numerous different cell types whose interactions lead to immune escape and resistance to immunotherapy in virtually all patients with metastatic cancer. Here, we have developed a 3D model of human solid tumor tissue that includes tumor cells, fibroblasts, and myeloid and lymphoid immune cells and can represent over a million cells over clinically relevant timeframes. This model accurately reproduced key features of the tissue architecture of human colorectal cancer and could be informed by individual patient data, yielding in silico tumor explants. Stratification of growth kinetics of these explants corresponded to significantly different overall survival in a cohort of patients with metastatic colorectal cancer. We used the model to simulate the effect of chemotherapy, immunotherapies, and cell migration inhibitors alone and in combination. We classified tumors according to tumor and host characteristics, showing that optimal treatment strategies markedly differed between these classes. This platform can complement other patient-specific ex vivo models and can be used for high-throughput screening of combinatorial immunotherapies.Significance: This patient-informed in silico tumor growth model allows testing of different cancer treatment strategies and immunotherapies on a cell/tissue level in a clinically relevant scenario. Cancer Res; 78(17); 5155-63. ©2018 AACR.

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

Genomics and emerging biomarkers for immunotherapy of colorectal cancer.

Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.

Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors.

Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination.Experimental Design: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers.Results: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.Conclusions: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. Clin Cancer Res; 24(9); 2128-37. ©2018 AACR.

Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer - the multinational MATEO study.

BACKGROUND: The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer. METHODS: The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life. Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy. DISCUSSION: MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy. TRIAL REGISTRATION: NCT02128243 (date of registration: 29-04-2014).