Predicting patient response with models trained on cell lines and patient-derived xenografts by nonlinear transfer learning

Preclinical models have been the workhorse of cancer research, producing massive amounts of drug response data. Unfortunately, translating response biomarkers derived from these datasets to human tumors has proven to be particularly challenging. To address this challenge, we developed TRANSACT, a computational framework that builds a consensus space to capture biological processes common to preclinical models and human tumors and exploits this space to construct drug response predictors that robustly transfer from preclinical models to human tumors. TRANSACT performs favorably compared to four competing approaches, including two deep learning approaches, on a set of 23 drug prediction challenges on The Cancer Genome Atlas and 226 metastatic tumors from the Hartwig Medical Foundation. We demonstrate that response predictions deliver a robust performance for a number of therapies of high clinical importance: platinum-based chemotherapies, gemcitabine, and paclitaxel. In contrast to other approaches, we demonstrate the interpretability of the TRANSACT predictors by correctly identifying known biomarkers of targeted therapies, and we propose potential mechanisms that mediate the resistance to two chemotherapeutic agents.

Cerebrospinal fluid abnormalities in first- and multi-episode schizophrenia-spectrum disorders: impact of clinical and demographical variables

Multiple lines of evidence indicate that immunological and inflammatory alterations contribute at least in a subgroup to the pathophysiology of schizophrenia. In this retrospective chart review, we investigated whether clinical factors contribute to altered cerebrospinal fluid (CSF) findings in schizophrenia-spectrum disorders. Clinical data from electronic medical records of patients with psychotic disorders (ICD-10: F20-F29) who received routine CSF diagnostics at the Department of Psychiatry and Psychotherapy, LMU Munich, Germany, were included. Chi² tests for dichotomous outcomes and independent t tests for continuous outcomes were used to compare differences between groups. A total of 331 patients were included in the analyses (43.2% female and 56.8% male). The mean age was 37.67 years (±15.58). The mean duration of illness was 71.96 months (±102.59). In all, 40% (128/320) were first-episode psychosis (FEP) patients and 60% (192/320) were multi-episode psychosis (MEP) patients. Elevated CSF protein levels were found in 19.8% and elevated CSF/serum albumin ratios (QAlb) in 29.4% of the cases. Pleocytosis was found in 6.1% of patients. MEP patients showed significantly higher mean QAlb compared with FEP patients (t(304.57) = −2.75, p = 0.006), which did not remain significant after correcting for age. QAlb elevation occurred more frequently in men (X2(1) = 14.76, p = <0.001). For treatment resistance, family history, and cMRI alterations, no significant differences in CSF-related outcomes were detected. Our work extends other retrospective cohorts confirming a relevant degree of CSF alterations in schizophrenia-spectrum disorders and shows the difficulty to relate these alterations to clinical and disease course trajectories. More research is needed to develop treatment response predictors from CSF analyses.

Antidepressant efficacy of low-frequency repetitive transcranial magnetic stimulation in antidepressant-nonresponding bipolar depression: a single-blind randomized sham-controlled trial

Background To examine the antidepressant efficacy and response predictors of R-DLPFC-LF rTMS for antidepressant-nonresponding BD. Methods We conducted a single-blind randomized sham-controlled trial for 54 (28 sham, 26 active) patients with antidepressant-nonresponding BD (baseline MADRS ≥ 20). Patients received 15 daily sessions of active or sham neuronavigated rTMS (Figure-of-8 coil, five 1 Hz 60 s 110% RMT trains). Outcome measures included depressive response (≥ 50% MADRS reduction, CGI ≤ 2) and remission (MADRS < 7, CGI = 1) rates, treatment emergent hypo/mania (YMRS), depressive and anxiety symptoms (HAM-A). Results 48 patients (25 sham, 23 active) completed treatment, with 3 drop-outs each in active and sham groups. Active rTMS did not produce superior response or remission rates at endpoint or 6 or 12 weeks (ps > 0.05). There was no significant group * time interaction (ps > 0.05) in a multivariate ANOVA with MADRS, HAMA and YMRS as dependent variables. Exploratory analysis found MADRS improvement to be moderated by baseline anxiety (p = 0.02) and melancholia (p = 0.03) at week 3, and depressive onset at weeks 6 (p = 0.03) and 12 (p = 0.04). In subjects with below-mean anxiety (HAMA < 20.7, n = 24), MADRS improvement from active rTMS was superior to sham at week 3 (ITT, t = 2.49, p = 0.04, Cohen’s d = 1.05). No seizures were observed. Groups did not differ in treatment-emergent hypomania (p = 0.1). Limitations Larger sample size might be needed to power subgroup analyses. Moderation analyses were exploratory. Single-blind design. Unblinding before follow-up assessments due to ethical reasons. Conclusions 1-Hz 110% RMT (5 × 60 s trains) R-DLPFC-LF rTMS was not effective for antidepressant non-responding BD but may be further investigated at increased dosage and/or in BD patients with low anxiety. Trial registration CCRB Clinical Trials Registry, CUHK, CUHK_CCT00440. Registered 04 December 2014, https://www2.ccrb.cuhk.edu.hk/registry/public/279

Genetically Engineered Biologic Drugs in Management of Children with Bronchial Asthma

Current article represents the modern clinical guidelines on management of severe bronchial asthma (BA) in children and practical use of genetically engineered biologic drugs. Clinical efficacy and safety of omalizumab has its special role. Efficacy analysis was carried out in real-life' clinical setting (considering high economical expenses of biological treatment) to estimate effective response predictors and principles of patients selection for such therapy. Two years of anti-IgE treatment experience in inpatient pediatric department settings demonstrates that omalizumab inclusion to treatment of children with severe asthma resistant to standard therapy allows to solve asthma symptoms, to forgo high doses inhaled glucocorticosteroids, to improve lung function parameters, and to increase significantly quality of life in 95% of our patients.

Genetically Engineered Biologic Drugs in Management of Children with Bronchial Asthma

Current article represents the modern clinical guidelines on management of severe bronchial asthma (BA) in children and practical use of genetically engineered biologic drugs. Clinical efficacy and safety of omalizumab has its special role. Efficacy analysis was carried out in real-life' clinical setting (considering high economical expenses of biological treatment) to estimate effective response predictors and principles of patients selection for such therapy. Two years of anti-IgE treatment experience in inpatient pediatric department settings demonstrates that omalizumab inclusion to treatment of children with severe asthma resistant to standard therapy allows to solve asthma symptoms, to forgo high doses inhaled glucocorticosteroids, to improve lung function parameters, and to increase significantly quality of life in 95% of our patients.

353 Identification of potential response predictors to maveropepimut-S (DPX-Survivac), a novel T cell activating immunotherapy, in patients with advanced recurrent ovarian cancer

BackgroundEpithelial ovarian cancer (OvCa) is the most lethal of gynecological malignancies. The high mortality is related to a late diagnosis with over 75% being at an advanced stage, high recurrence rates, and ultimately resistance to chemotherapy. Previous studies have consistently demonstrated a strong association between higher tumor T cell infiltration and improved survival in OvCa patients supporting the potential clinical utility of T cell activating immunotherapy approaches. Maveropepimut-S (MVP-S, formerly named DPX-Survivac) is a T cell activating immunotherapy which is a formulation of the proprietary drug delivery platform DPX™ with immunogenic T-cell epitopes derived from the tumor-associated antigen survivin. MVP-S in combination with intermittent low-dose cyclophosphamide has been shown to induce robust and durable antigen-specific T cell responses and anti-tumor clinical activity in recurrent OvCa patients. The current study presents translational data aimed at identifying tumor tissue-based predictive biomarkers for response to treatment with MVP-S.MethodsBaseline and on-treatment tumor biopsies were collected from patients treated with MVP-S primed with immune-modulating low dose cyclophosphamide. Multiplex-immunohistochemistry (mIHC, Akoya Biosciences) and RNAseq analyses (Personalis Inc.) were used to analyze the tumor immune environment and identify potential response predictors to MVP-S.ResultsTwenty-two patients with advanced, recurrent OvCa were enrolled in this study. mIHC analysis demonstrated that higher baseline CD3+CD8+ T cell infiltration in tumor tissue was significantly associated with anti-tumor clinical activity of MVP-S defined as >10% on-treatment tumor regression. Pathway enrichment analyses using the differentially expressed genes associated with anti-tumor clinical activity confirmed these findings. In addition, we identified B cell pathway genes to be significantly upregulated in patients with >10% on-treatment tumor regression. mIHC analyses of paired biopsies available for one subject with clinical response (PR) demonstrated that MVP-S treatment induced increased T and B cell infiltration in the on-treatment biopsy compared to the baseline biopsy. These findings suggest that immunogenic tumors are more susceptible to the MVP-S treatment, in line with its mechanism of action. Pathway enrichment analyses further revealed that upregulation of genes or pathways related to immune-suppression (e.g. WNT pathway) or immune evasion/exclusion (CD276, Arg2) were significantly associated with lack of anti-tumor activity indicative of potential mechanism of primary resistance.ConclusionsCollectively, these results provide insight for possible response predictors to MVP-S based therapyTrial RegistrationNCT02785250Ethics ApprovalThe protocol and patient-informed consent form received approval by Institutional Review Boards. Written informed consent was obtained from all patients. REBs: Comite d’ethique de la recherche du CHUM (Montreal, Canada); Western Institutional Review Board 20161075 (Augusta, GA, USA); FWA #00002505 (NEW YORK, NY, USA); FWA00000161, IRB00000471 (Portland, Oregon, USA); University Health Network REB (Toronto, Canada); FWA00000935, FWA00000934 (Standford, CA, USA); Health Research Ethics Board of Alberta, (Edmonton, Canada)

The landscape of bispecific T cell engager in cancer treatment

T cell-based immunotherapies have revolutionized treatment paradigms in various cancers, however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem. To address this limitation, strategies for redirecting T cells to treat cancer are being intensively investigated, while the bispecific T cell engager (BiTE) therapy constitutes one of the most promising therapeutic approaches. BiTE is a bispecific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis. BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies. However, major mechanisms of resistance to BiTE therapy are associated with antigen loss and immunosuppressive factors such as the upregulation of immune checkpoints. Thus, modification of antibody constructs and searching for combination strategies designed to further enhance treatment efficacy as well as reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTE therapy is always poor. In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.