Carrier Cells for Delivery of Oncolytic Measles Virus into Tumors: Determinants of Efficient Loading

Abstract

Oncolytic measles virus (OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies (NAbs) against the hemagglutinin (H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV. Differential loading strategies appear to result in different therapeutic outcomes; despite this, only few studies have reported practical ex vivo loading strategies required for effective treatment. To this end, we systematically evaluated the antitumor efficacy of OMV using different loading strategies; this involved varying the in vitro loading duration and loading dose of OMV. We found that improved oncolysis of carrier cells was achieved by a prolonged loading duration in the absence of NAbs. However, the enhanced oncolytic effect was abrogated in the presence of NAbs. Further, we found that the expression of H protein on the surface of carrier cells was predominantly determined by the loading duration rather than the loading dose. Finally, we showed that NAbs blocked viral transfer by targeting H protein prior to the occurrence of cell-to-cell interactions. Our results provide comprehensive information on the determinants of an effective loading strategy for carrier cell-based virotherapy; these results may be useful for guiding the application of OMV as an antitumor agent in clinical practice.

https://ift.tt/2rIRRDS

Ulcerative Lesions: A Rare Cutaneous Manifestation of Brucellosis

Brucellosis is a disease that is transmitted from animals to humans mainly via the consumption of unpasteurized dairy products, and it can involve any organ all over the body. Here, we report a significant rare case of brucellosis with cutaneous manifestations in a 52-year-old male patient whose disease was diagnosed via a serology test. The patient received standard antibiotic treatment, and his cutaneous lesions healed quickly. Although the cutaneous manifestations of brucellosis are exceedingly rare, in case of encountering ulcerative lesions and other cutaneous findings, particularly in endemic areas, infection with brucellosis should be kept in mind as an important differential diagnosis.

https://ift.tt/2jZ52gA

Peri-operative therapy for operable gastroesophageal adenocarcinoma; past, present and future

Abstract

Surgery represents the only chance of cure for patients with gastroesophageal adenocarcinoma; however surgery alone does not cure most patients. Over the past decade, several multimodality adjunctive treatments have improved survival for patients with operable gastroesophageal adenocarcinoma who are undergoing surgical resection; these include peri-operative chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy and adjuvant chemoradiotherapy. More recently, the results of several large randomised trials are leading to a shift in the peri-operative treatment of gastroesophageal cancer, away from anthracycline-based and towards taxane-based chemotherapy regimens. Emerging data supports an increased focus on patients who are at high risk for poor operative outcomes such as R1 resection, and on patients who are at high risk for relapse following surgery such as those with lymph node metastases (N1+). Future developments may include use of fluorodeoxyglucose-positron emission tomography (FDG-PET) to inform a switch to non-cross resistant chemotherapy pre-operatively and substitution of alternative treatments for chemotherapy in high risk postoperative node positive patients. Conversely, in molecularly selected subgroups such as microsatellite unstable gastroesophageal cancer, peri-operative or adjuvant chemotherapy may not be helpful, and treatments such as immunotherapy may be considered. In this review the most up-to-date clinical trials and translational research in the field of operable gastroesophageal cancer are discussed; with a focus on how best to risk stratify patients with operable disease for peri-operative treatment plus surgery, and how novel therapies might be integrated into standard treatments in order to improve survival outcomes in this patient group.

https://ift.tt/2wHmsaE

Developing a novel approach to existential suffering in cancer survivorship through Socratic dialogue

Psycho-Oncology, EarlyView.


https://ift.tt/2GlH08u

TP53, STK11 and EGFR Mutations Predict Tumor Immune Profile and the Response to anti-PD-1 in Lung Adenocarcinoma

Purpose: By unlocking anti-tumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. Experimental Design: We performed in depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and to PD-L1 expression, and a public clinical database was used to validate the results obtained. Results: We showed that distinct combinations of STK11, EGFR and TP53 mutations, were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T cell density and PD-L1 expression. In this tumor subtype, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. Finally, a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p<0.001) was observed in anti-PD-1 treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Conclusions: Our study reveals that different combinations of TP53, EGFR and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade.

https://ift.tt/2IoMPba

Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation

Purpose: Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults. Experimental Design: In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology. Results: Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05). Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

https://ift.tt/2wN8X9G

Phase I Study of CC-486 Alone and in Combination With Carboplatin or nab-paclitaxel in Patients With Relapsed or Refractory Solid Tumors

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 (n=57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, maximum tolerated dose, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n=112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (once daily, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusion: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943).

https://ift.tt/2IlOxdh