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International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

BACKGROUND AND OBJECTIVE Methamphetamine (MA) substance use disorder (SUD) does not have an efficacious pharmacotherapy. We developed a MA vaccine and investigated its potential to attenuate MA induced responses. METHODS We examined a novel adjuvant, E6020, a Toll-like receptor-4 (TLR-4) agonist combined with tetanus-toxoid conjugated to succinyl-methamphetamine (TT-SMA) adsorbed on aluminum hydroxide (alum). Adult BALB/c female mice received the vaccine and booster injections at weeks 0, 3, and 6. The efficacy of the vaccine was assessed by the level and affinity of anti-MA antibodies elicited, its ability to attenuate MA induced locomotor activation and its reduction in the amount of MA entering the brains of vaccinated mice. RESULTS The TT-SMA vaccine containing alum and E6020 adjuvant produced anti-MA antibodies with nanomolar affinities and showed threefold greater peak titer levels than without E6020 (700 vs 250 μg/ml). These antibodies significantly decreased MA-induced locomotor activation (p

PURPOSE OF REVIEW: We review emerging evidence regarding the impact of gut microbes on anti-tumor immunity, and ongoing efforts to translate this in clinical trials. RECENT FINDINGS: Pre-clinical models and human cohort studies support a role for gut microbes in modulating overall immunity and immunotherapy response, and numerous trials are now underway exploring strategies to modulate gut microbes to enhance responses to cancer therapy. This includes the use of fecal microbiota transplant (FMT), which is being used to treat patients with Clostridium difficile infection among other non-cancer indications. The use of FMT is now being extended to modulate gut microbes in patients being treated with cancer immunotherapy, with the goal of enhancing responses and/or to ameliorate toxicity. However significant complexities exist with such an approach, and will be discussed herein. SUMMARY: Data from ongoing studies of FMT in cancer will provide critical insights for optimization of this approach.

The field of cancer therapy has been revolutionized through the use of immunotherapy, and treatment with these therapies now spans from early to late stage, and even into prevention. However, there are still a significant proportion of patients who do not derive long-term benefit from monotherapy and even combined therapy regimens, and novel approaches are needed to enhance therapeutic responses. Additionally, ideal biomarkers of response to immunotherapy are lacking and are critically needed. An emerging area of interest in immuno-oncology (IO) is the microbiome, which refers to the collection of microbes (and their genomes) that inhabit an individual and live in symbiosis. There is now evidence that these microbes (particularly those within the gut) impact host physiology and can impact responses to immunotherapy. The field of microbiome research in immuno-oncology is quickly emerging, with the potential use of the microbiome (in the gut as well as in the tumor) as a biomarker for response to IO as well as a therapeutic target. Notably, the microbiome may even have a role in toxicity to therapy. The state of the science in microbiome and IO are discussed and caveats and future directions are outlined to provide insights as we move forward as a field.

Background and Objectives We previously reported that an anti-methamphetamine (MA) vaccine attenuated drug-conditioned effects in mice, but it used a carrier protein and adjuvant not available for clinical use. Here we produced a vaccine with the same hapten (succinyl-methamphetamine, SMA) but attached to tetanus toxoid (SMA-TT) and adsorbed to aluminum hydroxide, components approved for use in humans. We then assessed the vaccine's ability to generate anti-MA antibodies, alter acquisition and reinstatement of MA place conditioning, and prevent MA brain penetration. Methods Mice were administered SMA-TT at weeks 0 and 3 and non-vaccinated mice received saline. Anti-MA antibody concentrations were determined at 8 and 12 weeks. Place conditioning began during week 9 in which vaccinated and non-vaccinated mice were divided into groups and conditioned with .5, or 2.0 mg/kg MA. Following acquisition training, mice were extinguished and then a reinstatement test was performed in which mice were administered their original training dose of MA. Separate groups of non-vaccinated and vaccinated mice were administered .5 and 2.0 mg/kg MA and brain MA levels determined. Results and Conclusions Anti-MA antibody levels were elevated at week 8 and remained so through week 12. The SMA-TT vaccine attenuated acquisition and reinstatement of MA place conditioning. Significantly greater proportions of vaccinated mice during acquisition and reinstatement tests showed conditioned place aversion. Moreover, MA brain levels were decreased in vaccinated mice following administration of both doses of MA. Scientific Significance Results support further development of anti-MA vaccines using components approved for use in humans. (Am J Addict 2015;XX:XX--XX)

10067 Background: Metastatic melanoma pt outcomes have been revolutionized by targeted therapy (TT) and immune checkpoint blockade (ICB), which are now being evaluated in the neoadjuvant (neoadj) setting. While tumor-based biomarkers may help predict response, predictors of response obtained by less invasive strategies could greatly benefit pt care and allow real-time treatment response monitoring. Radiomic signatures derived from computerized tomography (CT) images have recently been shown to predict response to ICB in stage IV pts. However, the association of radiomic features with pathological response following neoadj therapy has not been assessed. We sought to determine if radiomic assessment predicts pCR in pts receiving neoadj TT and ICB. Methods: We collected data for a cohort of melanoma pts with locoregional metastases who were treated with neoadj TT (n = 33) or ICB (n = 30). Pts received systemic therapy for 8-10 weeks prior to planned surgical resection. Responses were evaluated radiographically (RECIST 1.1) and via pathological assessment (evaluating for pathologic complete response; (pCR) versus < pCR). Thirty two pts (19 ICB; 13 TT) were included in the radiomics analysis based on the availability of appropriate CT imaging. A total of 310 unique radiomic features (10 histogram-based and 300 second-order texture features) were calculated from each extracted volume of interest (VOI). Feature extraction was performed on baseline and initial on-treatment pre-operative CT scans. Features associated with pCR were assessed using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of pCR to ICB or TT. Leave-One-Out Cross-Validation was performed to evaluate the robustness of the estimates. Results: Out of 310 radiomic features, three features measured at baseline were able to predict a pCR to neoadj ICB or TT with sensitivity, specificity and accuracy of 100%, though these signatures were non-overlapping. In the on-treatment pre-operative scans, 3 distinct features (also non-overlapping and distinct from the predictive pre-treatment signatures) also predicted pCR to ICB and TT with 100% sensitivity, specificity and accuracy. Conclusions: Radiomic signatures in baseline and on-treatment CT scans accurately predict pCR in melanoma pts with locoregional metastases treated with neoadj TT or ICB. These provocative findings warrant further investigation in larger, independent cohorts.

Genotypic status of the signal peptide region of transforming growth factor beta1 (TGF-beta1) showed a significant difference in C/C-genotype frequency at +29 position (codon 10) between a range of viral hepatitis patients and controls (P = 0.009, OR = 3.15, CI = 1.29-7.678), contributed by those who were infected with hepatitis B virus (HBV) alone or HBV + hepatitis delta virus (HDV) (P = 0.003, OR = 5.0, CI = 1.78-13.97).

SUMMARY: Focal segmental glomerulosclerosis (FSGS) is a heterogeneous group of disorders with respect to aetiology, morphology, clinical course and response to treatment. The present study assessed the expression of complement receptor 1 (CR1), decay accelerating factor (DAF) and membrane inhibitor of reactive lysis (CD59) on the erythrocytes of FSGS patients using flow cytometry compared with their expression on the erythrocytes of minimal change nephrotic syndrome (MCNS) patients. Significantly reduced expression of CR1, DAF and CD59 was observed on the erythrocytes of FSGS patients compared with the reduced expression of CR1 and enhanced expression of DAF on the erythrocytes of MCNS patients. A significant inverse relationship was demonstrated between CR1 expression and proteinuria levels in FSGS patients (r = 0.55, P < 0.01). A follow-up study of 12 patients with FSGS after immunosuppressive therapy showed that the levels of complement regulatory proteins are significantly increased when the disease goes into remission. However, in patients not responding to immunosuppressive therapy, levels of these proteins remained low. MCNS patients showed significant increases in CR1 and decreases in DAF expression during remission of the disease.