BACKGROUND Adenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODS An integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTS Compared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10–4) and MYB/MYBL1 fusions (q = 5.6 × 10–3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSION These observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDING Adenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).
Allen S. Ho, Angelica Ochoa, Gowtham Jayakumaran, Ahmet Zehir, Cristina Valero Mayor, Justin Tepe, Vladimir Makarov, Martin G. Dalin, Jie He, Mark Bailey, Meagan Montesion, Jeffrey S. Ross, Vincent A. Miller, Lindsay Chan, Ian Ganly, Snjezana Dogan, Nora Katabi, Petros Tsipouras, Patrick Ha, Nishant Agrawal, David B. Solit, P. Andrew Futreal, Adel K. El Naggar, Jorge S. Reis-Filho, Britta Weigelt, Alan L. Ho, Nikolaus Schultz, Timothy A. Chan, Luc G.T. Morris
BACKGROUND. Impaired T-cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T-cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients. METHODS. In the present study, we employed high-throughput T-cell receptor Vβ sequencing and T-cell functional profiling to delineate the impact of ACT on T-cell repertoire remodelling in the context of pre-therapy immunity and ACT products. RESULTS. These analyses indicated that a clinical response was coincident with significant changes in the T-cell receptor Vβ landscape post-therapy. This restructuring was associated with the emergence of effector memory (EM) T cells in responding patients, while non-responders displayed dramatic pre-therapy T-cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products. CONCLUSION. These observations demonstrate that immune control following ACT requires significant repertoire remodelling, which may be impaired in non-responders due to the pre-existing immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.
Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna
Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. Methods: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. Results: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. Conclusion: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). Funding: Castleman’s Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
David C. Fajgenbaum, Ruth-Anne Langan, Alberto Sada Japp, Helen L. Partridge, Sheila K. Pierson, Amrit Singh, Daniel J. Arenas, Jason R. Ruth, Christopher S. Nabel, Katie Stone, Mariko Okumura, Anthony Schwarer, Fábio Freire Jose, Nelson Hamerschlak, Gerald B. Wertheim, Michael B. Jordan, Adam D. Cohen, Vera Krymskaya, Arthur Rubenstein, Michael R. Betts, Taku Kambayashi, Frits van Rhee, Thomas S. Uldrick
BACKGROUND. In women with obesity, excess gestational weight gain (≥270 g/week) occurs in two out of three pregnancies and contributes to metabolic impairments in both mother and baby. To improve obstetrical care, objectively assessed information on energy balance is urgently needed. The objective of this study was to characterize determinants of gestational weight gain in women with obesity. METHODS. This was a prospective, observational study of pregnant women with obesity. The primary outcome was energy intake calculated by the energy intake-balance method. Energy expenditure was measured by doubly-labeled water and whole-room indirect calorimetry and body composition as 3-compartment model by air displacement plethysmography and isotope dilution in early (13-16 weeks) and late pregnancy (35-37 weeks). RESULTS. In pregnant women with obesity (n=54), recommended weight gain (n=8, 15%) during the second and third trimesters was achieved when energy intake was 125±52 kcal/d less than energy expenditure. In contrast, women with excess weight gain (67%) consumed 186±29 kcal/d more than they expended (P<0.001). Energy balance affected maternal adiposity (recommended: -2.5±0.8 kg fat mass, excess: +2.2±0.5, inadequate: -4.5±0.5, P<0.001), but not fetal growth. Weight gain was not related to demographics, activity, metabolic biomarkers, or diet quality. We estimated that energy intake requirements for recommended weight gain during the second and third trimesters were not increased as compared to energy requirements early in pregnancy (34±53 kcal/d, P=0.83). CONCLUSIONS. We here provide the first evidence-based recommendations for energy intake in pregnant women with obesity. Contrary to current recommendations, energy intake should not exceed energy expenditure. FUNDING. This study was funded by the National Institutes of Health (R01DK099175; Redman, U54GM104940 and P30DK072476; Core support). TRIAL REGISTRATION. clinicaltrials.gov: NCT01954342
Jasper Most, Marshall St Amant, Daniel Hsia, Abby Altazan, Diana Thomas, Anne Gilmore, Porsha Vallo, Robbie Beyl, Eric Ravussin, Leanne Redman
Background: Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown. Methods: To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements. Results: We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape. Conclusion: We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.
Karthik Suresh, Jarushka Naidoo, Qiong Zhong, Ye Xiong, Jennifer Mammen, Marcia Villegas de Flores, Laura Cappelli, Aanika Balaji, Tsvi Palmer, Patrick M. Forde, Valsamo Anagnostou, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Cheng-Ting Lin, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Dannoff, Franco D'Alessio
BACKGROUND Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.METHODS Participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay.RESULTS Sixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA <100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count.CONCLUSION HIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.FUNDING This observational study, AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321), was supported by the National Institutes of Health (NIAID and NIMH).
Serena Spudich, Kevin R. Robertson, Ronald J. Bosch, Rajesh T. Gandhi, Joshua C. Cyktor, Hanna Mar, Bernard J. Macatangay, Christina M. Lalama, Charles Rinaldo, Ann C. Collier, Catherine Godfrey, Joseph J. Eron, Deborah McMahon, Jana L. Jacobs, Dianna Koontz, Evelyn Hogg, Alyssa Vecchio, John W. Mellors
BACKGROUND In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between β cell function and pathology and clinical characteristics.METHODS Individuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and β cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort.RESULTS Of the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with HLA–/AAb– and HLA+/AAb– Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as “likely pathogenic” (rare exome variant ensemble learner [REVEL] >0.75).CONCLUSION All Medalists retained insulin-positive β cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to β cell function, and many with HLA+ diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.FUNDING Funding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA).
Marc Gregory Yu, Hillary A. Keenan, Hetal S. Shah, Scott G. Frodsham, David Pober, Zhiheng He, Emily A. Wolfson, Stephanie D’Eon, Liane J. Tinsley, Susan Bonner-Weir, Marcus G. Pezzolesi, George Liang King
Background: While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. Methods: We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls. Results: We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. Conclusion: Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.
Joanna Halkias, Elze Rackaityte, Sara L. Hillman, Dvir Aran, Ventura F. Mendoza, Lucy R. Marshall, Tippi C. MacKenzie, Trevor D. Burt
BACKGROUND. African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting. METHODS. A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to Transcription Factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS. Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS. These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.
Danthasinghe Waduge Badrajee Piyarathna, Akhila Balasubramanian, James M. Arnold, Stacy M. Lloyd, Balasubramanyam Karanam, Patricia Castro, Michael M. Ittmann, Nagireddy Putluri, Nora Navone, Jeffrey A. Jones, Wendong Yu, Vlad C. Sandulache, Andrew G. Sikora, George Michailidis, Arun Sreekumar
Background: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). Methods: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. Results: CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. Conclusion: CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. Trial Registration: NCT02546167. Funding: University of Pennsylvania-Novartis Alliance and NIH.
Adam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, J. Joseph Melenhorst, Simon F. Lacey, Eric Lancaster, Dan T. Vogl, Brendan M. Weiss, Karen Dengel, Annemarie Nelson, Gabriela Plesa, Fang Chen, Megan M. Davis, Wei-Ting Hwang, Regina M. Young, Jennifer L. Brogdon, Randi Isaacs, Iulian Pruteanu-Malinici, Don L. Siegel, Bruce L. Levine, Carl H. June, Michael C. Milone
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