Citations

Abstract Glioblastoma (GBM), the most common primary brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies for this aggressive malignancy. Genomic amplification of epidermal growth factor receptor (EGFR) occurs in 40-60% of primary GBM. Half of all EGFR-amplified cases of GBM also harbor EGFRvIII, a constitutively active, truncated variant of EGFR. The incidence of EGFR alterations in GBM makes inhibition of EGFR/EGFRvIII an attractive therapeutic approach. Depatuxizumab mafodotin (ABT-414) is an antibody-drug conjugate comprised of ABT-806, a mAB against EGFR, and a cytotoxic payload (monomethyl auristatin F). ABT-414 therapy initially showed promising results as an EGFRvIII therapy in vivo and in vitro; however, ABT414 failed to provide a survival benefit in phase I/II clinical trials, potentially due to therapeutic resistance. In this study, we seek to investigate the mechanisms of resistance to ABT-414 by performing whole exome, transcriptome and single cell RNA seq on ABT-414 resistant GBM PDX tumors. Our data showed an enrichment of mutations unique to the ABT-414 resistant tumors, including a point mutation (S466I) in TEK/TIE2 transmembrane angiopoietin receptor. In vitro expression of TEK S466I in GBM cells showed an increase in activation of ERK and STAT3 and increased TEK/TIE2 immunoprecipitation with EGFR compared to the wild-type TEK receptor. Furthermore, gene ontology analysis reveals that ABT-414-treated flank tumors exhibit increased activation of extracellular matrix organization and CNS developmental processes compared to flank tumors in the control treatment groups. ABT-414-treated tumors also demonstrate increased expression of inhibitor of differentiation (ID)1 and ID3, associated with stem-like phenotype in glioblastoma. Taken together, our data indicate that resistance to ABT-414 is mediated by both de novo mutations not detected in the parent tumor and adaptive dysregulation of pathways which may lead to dedifferentiation and therapeutic resistance.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.

Abstract Aims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

PURPOSE This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)–negative. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and retained 14 articles. RECOMMENDATIONS Patients with triple-negative, programmed cell death ligand-1–positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1–negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2–negative MBC for whom chemotherapy is being considered should be offered single–agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible. Additional information is available at www.asco.org/breast-cancer-guidelines .

Abstract Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, in the 2nd line setting and beyond, efficacy remains limited. Pazopanib, the only approved treatment in the refractory setting has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: MSI-H cancer and biliary tract cancer. The activity of envafolimab is similar to other PD-1 antibodies administered intra-venously. Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer that failed three approved chemotherapeutics, similar to the ORR of 28% and 33%, with nivolumab and pembrolizumab, respectively. The rationale for the ENVASARC trial is based on the previously reported efficacy of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ~25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n=80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks intra-venously for four doses (cohort B; n=80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Citation Format: Sandra D'Angelo, Steven Robinson, Joelle Lam, Bonne Adams, James Freddo, Charles P. Theuer, Robert Maki. ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT239.

Abstract Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, including GSK3901961 and GSK3845097, incorporate further genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, enhancing T-cell persistence and increasing helper functions such as Type 1 T-helper anti-tumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of these two therapies and possible subsequent ones. Substudy 1 will assess GSK3901961 in patients with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in patients with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Table 1 lists eligibility criteria. Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting. Funding: GSK (209012; NCT04526509) Initial screening criteriaInclusion criteriaExclusion criteriaSubstudies 1 and 2 (SS and NSCLC)≥18 years of agePrior malignancy that is not in complete remission or clinically significant systemic illnessMeasurable disease per RECIST v1.1 criteriaPrevious treatment with genetically modified NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting antibodyExpression of HLA-A*02:01, A*02:05, or A*02:06Prior gene therapy using an integrating vectorExpression of NY-ESO-1/LAGE-1a in tumor archival or fresh biopsyPrevious allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplantSubstudies 1 and 2 (SS only)Histologically confirmed advanced (metastatic or unresectable) SS diagnosisCentral nervous system metastasesPresence of t(X;18) translocation(Allowed for NSCLC participants on a case-by-case basis)Received, completed, or intolerant to treatment with anthracycline or anthracycline with ifosfamide for advanced (metastatic or unresectable) disease and has progressedSubstudy 1 (NSCLC only)Histologically or cytologically confirmed Stage IV NSCLCReceived or failed ≥3 lines of systemic therapyReceiving or previously received ≥1 prior line(s) of standard of care treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to doublet taxane and platinum chemotherapyPresence of actionable genetic aberration (activation epithelial growth factor receptor, anaplastic lymphoma kinase/c-ros oncogene 1) per NCCN guidelines Citation Format: Adam J. Schoenfeld, Mehmet Altan, Taofeek K. Owonikoko, Sandra D'Angelo, Brian H. Ladle, Jonathan Noujaim, Kai He, David Liebner, Adrian G. Sacher, John B.A.G. Haanen, Jeffrey Yachnin, Chao Huang, Brian A. Van Tine, Aisha Hasan, Thomas Faitg, Emily Butler, Aiman Shalabi, Steven Attia, Dejka M. Araujo. Master protocol to assess the safety and recommended Phase 2 dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT219.

Ghrelin, a 28 amino acid‐containing orexigenic peptide, is an endogenous ligand of the GH secretagogue receptor. It was extracted from the rat stomach, but is present in other organs. The aim of this work was to localize ghrelin by immunohistochemistry in autopsy‐derived non‐tumorous human pituitaries. Immunohistochemistry was performed using the streptavidin‐biotin‐peroxidase complex method and the results were analyzed independently by 3 of the authors. Double Immunostaining was also undertaken to determine which cell type was expressing both the adenohypophysial hormone and ghrelin. Results showed that ghrelin can be localized in the adenohypophysis. It's immunoexpression being cytoplasmic, weak to moderate, and present in only a subset of cells. The neurohypophysis is immunonegative. Double immunostaining showed that ghrelin is co‐localized with GH, ACTH and LH and is present to 51–90% of such cells. PRL, TSH and FSH cells are consistently non‐reactive. The role of ghrelin in adenohypophysial endocrine activity is not clear. It may well be that ghrelin exerts an autocrine‐paracrine effect and can modulate hormone synthesis and release.