Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

Influence of HAART on Alternative Reading Frame Immune Responses over the Course of HIV-1 Infection

Background: Translational errors can result in bypassing of the main viral protein reading frames and the production of alternate reading frame (ARF) or cryptic peptides. Within HIV, there are many such ARFs in both sense and the antisense directions of transcription. These ARFs have the potential to generate immunogenic peptides called cryptic epitopes (CE). Both antiretroviral drug therapy and the immune system exert a mutational pressure on HIV-1. Immune pressure exerted by ARF CD8(+) T cells on the virus has already been observed in vitro. HAART has also been described to select HIV-1 variants for drug escape mutations. Since the mutational pressure exerted on one location of the HIV-1 genome can potentially affect the 3 reading frames, we hypothesized that ARF responses would be affected by this drug pressure in vivo. Methodology/Principal findings: In this study we identified new ARFs derived from sense and antisense transcription of HIV-1. Many of these ARFs are detectable in circulating viral proteins. They are predominantly found in the HIV-1 env nucleotide region. We measured T cell responses to 199 HIV-1 CE encoded within 13 sense and 34 antisense HIV-1 ARFs. We were able to observe that these ARF responses are more frequent and of greater magnitude in chronically infected individuals compared to acutely infected patients, and in patients on HAART, the breadth of ARF responses increased. Conclusions/Significance: These results have implications for vaccine design and unveil the existence of potential new epitopes that could be included as vaccine targets.International AIDS Vaccine Initiative (IAVI

A multidisciplinary consensus on the morphological and functional responses to immunotherapy treatment

The implementation of immunotherapy has radically changed the treatment of oncological patients. Currently, immunotherapy is indicated in the treatment of patients with head and neck tumors, melanoma, lung cancer, bladder tumors, colon cancer, cervical cancer, breast cancer, Merkel cell carcinoma, liver cancer, leukemia and lymphomas. However, its efficacy is restricted to a limited number of cases. The challenge is, therefore, to identify which subset of patients would benefit from immunotherapy. To this end, the establishment of immunotherapy response criteria and predictive and prognostic biomarkers is of paramount interest. In this report, a group of experts of the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Medical Radiology (SERAM), and Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM) provide an up-to-date review and a consensus guide on these issues

Durvalumab for the management of urothelial carcinoma: a short review on the emerging data and therapeutic potential

Capucine Baldini, Stéphane Champiat, Perrine Vuagnat, Christophe Massard Drug Development Department, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France Abstract: Urothelial carcinoma (UC) is the second most frequent urogenital malignancy with high incidence in the United States and Europe. Despite poor prognosis, new treatments have emerged with great efficacy and safety such as immune checkpoint inhibitors. Durvalumab, an anti Programmed Death Ligand 1, has been given breakthrough in UC in 2017 in patients who have disease progression during or following platinum-containing chemotherapy or who have disease progression Keywords: immunotherapy, PD-L1 inhibitor, durvalumab, urothelial carcinoma, bladder cance

Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors

First report of aflatoxin in dried yam chips in Benin

Dried yam (Dioscorea spp.) chips are widely consumed in Bénin but are often attacked by molds. Invasion of food by Aspergillus flavus may lead to aflatoxin contamination. We report here the result of a survey on the sanitary quality of dried yam chips in Bénin. During July and August 2000, 50 dried yam chips samples were collected from different points in the marketing chain; 10 samples were collected from each of 5 stages: producers, wholesalers, retailers, dried yam-based food sellers and consumers. Aflatoxin content was assayed by the bio-luminescence method (1) after methanol/water extraction. Aflatoxins were detected in all dried yam chip samples, with levels ranging from 2.2 to 200 ppb and a mean value of 14 ppb. An aflatoxin concentration higher than the European Union's maximum residue limit (MRL) of 4 ppb was found in 98% of the samples (N = 50), while 6% had an aflatoxin concentration higher than the World Health Organization's MRL of 20 ppb. Molds were analyzed from two samples, each with aflatoxin levels around 5 ppb, on colony unit medium specific for A. flavus (2). Aspergillus spp. were detected in the inner part of dried yam chips of both samples, with a mean level of 9,000 CFU/g. Fusarium colonies were also present but were not identified to species

Yam chip food subsector: hazardous practices and presence of aflatoxins in Benin

A survey of the sanitary quality, particularly concerning aflatoxin contamination and practices of the dried yam chips food sub-sector was carried out in Benin. Producers and intermediaries of the yam chips food production sub-sector were interviewed and samples collected. Aflatoxin content was assessed by a biochemo-luminescence method on a total of 107 samples. Twenty-three per cent of the samples had aflatoxin contents over the 15 μg kg−1 CODEX standard value for total aflatoxin. Moisture content of whole tuber chips was around 20% when producers stopped drying after 3–6 days. Drying was thus not accomplished, but most producers were unaware of this problem. After storage for 7 months, mean moisture content was around 14%, but 41% of the samples stored in rooms had a moisture content over 15%, levels that are still favourable for mould growth. Most producers, wholesalers and retailers complained about storage problems and particularly about insect proliferation, but less than 15% mentioned mould growth as a problem. Mouldy chips are generally washed and dried again. Very rarely are mouldy chips discarded and lack of moulds is not a quality attribute for dried yam chips. Therefore, there is a risk of chronic exposure to aflatoxin for Beninese yam chips consumers