tbuckley/cabot-search huggingface dataset:
Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity
Authors: Kevin Jan Legscha, Edite Antunes Ferreira, Antonios Chamoun, Alexander Lang, Mohamed Hemaid Sayed Awwad, Gigi Nu Hoang Quy Ton, Danuta Galetzka, Borhane Guezguez, Michael Hundemer, Jean-Christophe Bourdon, Markus Munder, Matthias Theobald, Hakim Echchannaoui
Journal: Journal for ImmunoTherapy of Cancer (2021)

Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored. Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Δ133p53α-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions. Phenotypic analysis of Δ133p53α-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57+ and CD160+ CD8+ T cell populations, and an increased number of less differentiated CD28+ T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Δ133p53α-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Δ133p53α to restore the antitumor response of senescent T cells isolated from multiple myeloma patients. This study uncovered a broad effect of Δ133p53α isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.
Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRAS<sup>G12C</sup> inhibitor, as monotherapy in non-small cell lung cancer (NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101).
Authors: David S. Hong, John H. Strickler, Marwan Fakih, Gerald Steven Falchook, Bob T. Li, Greg Andrew Durm, Timothy F. Burns, Suresh S. Ramalingam, Sarah B. Goldberg, Richard C. Frank, Kristen Marrone, Catherine A. Shu, David R. Gandara, Neelesh Soman, Haby Adel Henary, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2021)

TPS2669 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRAS G12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. The combination of sotorasib with other anticancer therapies may enhance antitumor efficacy. This master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib combinations in patients (pts) with KRAS p.G12C mutated solid tumors. Herein, we overview 1 monotherapy and 11 combination cohorts. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens (Table) in pts with advanced KRAS p.G12C mutated solid tumors. Dose exploration will evaluate the safety and tolerability of sotorasib alone and in combination regimens; dose expansion will then verify the safety and tolerability profile of sotorasib regimens and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in pts who have received ≥1 lines of prior systemic therapy. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (eg, objective response, disease control, duration of response, progression-free survival, and duration of stable disease assessed per RECIST 1.1). Enrollment began in December 2019 and is ongoing. Clinical trial information: NCT04185883. [Table: see text]
LncRNA LINC00525 suppresses <i>p21</i> expression via mRNA decay and triplex‐mediated changes in chromatin structure in lung adenocarcinoma
Authors: Panqi Fang, Hao Chen, Zhifei Ma, Chencheng Han, Wenda Yin, Siwei Wang, Hongyu Zhu, Wenjia Xia, Jie Wang, Lin Xu, Tongyan Liu, Rong Yin
Journal: Cancer Communications (2021)

Abstract Background Emerging evidence suggests that long noncoding RNAs (lncRNAs) play crucial roles in various cancers. In the present study, we aim to investigate the function and molecular mechanism of an up‐regulated and survival‐associated lncRNA, LINC00525, in lung adenocarcinoma (LUAD). Methods The expression level of LINC00525 in tissues was determined by quantitative reverse transcription polymerase chain reaction (RT‐qPCR) and in situ hybridization (ISH). The functional role of LINC00525 in LUAD was investigated using gain‐and loss‐of‐function approaches, both in vivo and in vitro . RNA pull‐down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), triplex‐capture assay, dual‐luciferase assay, gene expression microarray, and bioinformatics analysis were used to investigate the potential underlying mechanisms involved. Results LINC00525 is highly expressed in LUAD cells and tissues. Survival analysis indicated that upregulation of LINC00525 was associated with poor prognosis in patients with LUAD patients. Knockdown of LINC00525 inhibited cell proliferation and cell cycle progression in vitro . In xenograft models, LINC00525 knockdown suppressed tumor growth and tumorigenesis of tumor‐bearing mice. Mechanistically, LINC00525 epigenetically suppressed p21 transcription by guiding Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) to the p21 promoter through an formation of RNA‐DNA triplex with the p21 promoter, leading to increased trimethylation of lysine 27 on histone 3 (H3K27me3) of the p21 promoter. In addition, LINC00525 repressed p21 expression post‐transcriptionally by enhancing p21 mRNA decay. LINC00525 promoted p21 mRNA decay by competitively binding to RNA Binding Motif Single Stranded Interacting Protein 2 (RBMS2). Conclusion Our findings demonstrate that LINC00525 promotes the progression of LUAD by reducing the transcription and stability of p21 mRNA in concert with EZH2 and RBMS2, thus suggesting that LINC00525 may be a potential therapeutic target for clinical intervention in LUAD.
Plasma kallikrein-kinin system as markers of locally advanced breast cancer prognosis.
Authors: Natalia Yu. Samaneva, Liubov Yu Vladimirova, Elena M. Frantsiyants, Anna E. Storozhakova, Elena A. Kalabanova, Sergey N. Kabanov, Anna V. Tishina, Yana V. Svetitskaya, Iuliana S. Shatova, Larisa N. Vashchenko
Journal: Journal of Clinical Oncology (2021)

e13040 Background: The kallikrein-kinin system is a complex multifunctional signaling cascade. Studies confirm its role in the development of cancer, as well as a role of some of its proteins with pro-inflammatory properties. Criteria for assessing the risk of breast cancer (BC) progression are required. The purpose of the study was to reveal the effect of blood levels of plasminogen, plasmin, precallikrein, and kallikrein in patients with triple-negative BC on the disease course. Methods: The study included 162 patients with triple-negative BC divided into 2 groups: group 1 – 58 patients with an early progression within 6 to 12 months after combination treatment; group 2 – 104 patients without progression during 2 years after combination treatment. Blood levels of plasminogen, plasmin, prekallikrein, and kallikrein were measured by ELISA before anticancer therapy and after 8 chemotherapy cycles. The levels in the blood plasma of healthy donors were reference values. Results were statistically processed using the Statistika 6.0 program with the Student’s T-test. Results: In patients with an early progression, plasminogen levels before the treatment were decreased by 1.7 times (p≤0.05), while plasmin was elevated by 1.9 times (p≤0.05). Kallikrein was increased by 1.9 times (p≤0.05), and prekallikrein was similar to the values in healthy donors. In patients with prolonged remission, plasminogen levels before the treatment were decreased on average by 2 times (p≤0.05). Plasmin was elevated by 2.3 times (p≤0.05), and kallikrein – by 1.8 times (p≤0.05). During this period of the study, prekallikrein levels decreased by 2 times (p≤0.05), compared with healthy donors. After chemotherapy, prekallikrein levels in the group with an early progression decreased by 1.4 times (p≤0.05), compared to the values before treatment, and kallikrein increased on the average by 1.3 times (p≤0.05). In patients with prolonged remission, no changes in the studied indices were registered. Conclusions: Patients with an early progression of BC demonstrated decreased levels of prekallikrein and increased kallikrein after the treatment, which allowed predicting resistance to chemotherapy and further tumor progression.
Prognosis of endometrial cancer depends on intracrine ratio of sex steroids.
Authors: Tatiana I. Moiseenko, Elena M. Frantsiyants, Valeria A. Bandovkina, Meri L. Adamyan, Natalia D. Cheryarina, Anna Yu. Ardzha
Journal: Journal of Clinical Oncology (2021)

e17564 Background: Local imbalance of sex steroids (SS) plays a leading role in the development of gynecologic tumors. The purpose of the study was to investigate the effect of changes in SS and E6 protein levels on the course of endometrial cancer (EC). Methods: 50 patients with EC T 1-2 N 0 M 0 (histologically - endometrioid adenocarcinoma, AC), aged 53.4±3.2 years, were recruited. Levels of SS and E6 protein were determined by standard ELISA systems in tumor samples. The coefficient of estrogens to the amount of testosterone and progesterone – C = (E1+E2):(T+P4) was calculated. Intact endometrium (IE) obtained in surgical treatment for uterine fibroids was used as the intact tissue. Results: AC patients demonstrated elevated estrone (E1) levels, compared to IE: by 2.2 times in 88% and by 5.9 times in 12% cases (p &lt; 0.05). Levels of estradiol (E2) were similar in AC and IE. Progesterone (P4) levels in 32 patients were 1.5 times lower than in IE, and testosterone (T) 1.5 times higher (p &lt; 0.05). P4 in 18 patients was 3 times lower than in IE, and T – 1.4 times lower in 12 women and 2.2 times lower in 6 women (p &lt; 0.05). The C coefficient increased in 32 patients by 1.3 times (p&lt; 0.05), in 12 patients by 2.7 times, in 6 patients by 8.2 times (p &lt; 0.05). E6 protein was found in tumor tissue of 18 patients with elevated C. 6 of 18 women with C = 24.54±2.4 and E6 = 420±32 ng/g of tissue developed recurrence during 6 months, and 12 patients with C = 8.15±1.2 and E6 = 28±2.1 ng/g of tissue developed recurrence in a period of 6 months to 1 year. Women with C = 4.04±0.39 without E6 oncoprotein in tumor tissue had a relapse-free period for more than 1 year. Conclusions: An analysis of C and E6 oncoprotein in tumor tissues allows identification of high-risk patients and a personalized approach to adequate treatment.
Preclinical evaluation of novel CDK4/6 inhibitor GLR2007 in glioblastoma models.
Authors: Lei Yin, Zhenglin Yao, Yue Wang, Julius Huang, Michelle Mazuranic, Ang Yin
Journal: Journal of Clinical Oncology (2021)

e14023 Background: Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. CDK4/6 inhibitors palbociclib and abemaciclib are approved for the treatment of breast cancer, but poor blood–brain barrier (BBB) penetration limits their efficacy in GBM. GLR2007 is a novel CDK4/6 inhibitor with potential for improved penetration across the BBB. Here, we report on the activity of GLR2007 in GBM cell lines and its anti-tumor efficacy in mouse xenograft models. Methods: Three in vitro assays were used to assess the activity of GLR2007. Inhibition of CDK4/6 enzymatic activity by GLR2007 or palbociclib was calculated, and cell cycle stages were analyzed in U87-MG cells treated with vehicle control or GLR2007 for 24 h. Cell viability was evaluated in U87-MG and U118-MG cell lines after culture for 72 h with GLR2007 or abemaciclib. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in BALB/c nude mouse GBM xenograft models. Quantitative whole-body autoradiography was used to determine the distribution of [ 14 C]GLR2007 in the tissues of Sprague Dawley rats. Results: GLR2007 potency toward CDK4 and CDK6 was 33.1 and 3.8 times that of palbociclib, respectively. At concentrations &gt;13.72 nM, GLR2007 caused G1 arrest of U87-MG cells. GLR2007 inhibited proliferation in U87-MG cells (IC 50 15.6±2.4 nM) and U118-MG cells (IC 50 23.2±5.2 nM). Anti-tumor efficacy of GLR2007 versus vehicle control was observed in two mouse GBM xenograft models (Table). Studies performed in rats demonstrated the distribution of [ 14 C]GLR2007 in whole brain tissue following a single oral dose, with total radioactivity levels in the brain exceeding those in plasma by 2.3–4.5-fold from 2–6 h after dosing. Conclusions: These preclinical studies demonstrate the potential of GLR2007 as a novel CDK4/6 inhibitor for treatment of GBM. GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors in xenograft models, and evidence of substantial central nervous system penetration. [Table: see text]
Association between treatment duration and overall survival in early-stage HER2+ breast cancer patients receiving extended adjuvant therapy with neratinib in the ExteNET trial.
Authors: Beverly Moy, Masato Takahashi, Shoichiro Ohtani, Ewa Chmielowska, Naohito Yamamoto, Bruno P. Coudert, Feng Xu, Alvin F. Wong, Arlene Chan
Journal: Journal of Clinical Oncology (2021)

540 Background: Completion of planned treatment has been shown to improve clinical outcomes. In the ExteNET trial (NCT00878709), where diarrhea prophylaxis was not mandated, 17% of patients (pts) discontinued neratinib early due to diarrhea. This compares with 3.3% of pts from the CONTROL trial (NCT02400476) who used a neratinib dose-escalation strategy. Prior analyses have shown improved invasive disease-free survival (iDFS) in pts who completed planned duration of neratinib therapy in ExteNET (Table). Here we assess outcomes, including overall survival (OS), for pts who completed planned therapy in 3 groups from ExteNET: intent-to-treat (ITT) population; pts with hormone receptor-positive (HR+) disease who initiated neratinib within 1y after prior trastuzumab (HR+/≤1y, the population neratinib is approved for in the EU); and HR+/≤1y with residual disease post-neoadjuvant therapy (no pathologic complete response [pCR]). Methods: Pts with early-stage HER2+ breast cancer received oral neratinib 240 mg/d or placebo after trastuzumab-based (neo)adjuvant therapy. Pts who completed neratinib therapy (defined as ≥11m or cessation of neratinib if recurrence occurred prior to 11m) were compared with placebo (all randomized pts). iDFS and OS were analyzed using Kaplan-Meier methods; hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional-hazards models. Data cutoff: July 2019. Results: There were 2840 pts in the ITT population. The table shows iDFS and OS in the overall population and in pts who completed planned duration of neratinib therapy. Completion of planned neratinib was associated with improvements in iDFS and OS in all groups evaluated. Conclusions: These descriptive findings suggest that pts who receive the recommended duration of treatment of 1y with neratinib may have improved outcomes. Clinical trial information: NCT00878709. [Table: see text]
Association of Maternal Influenza Vaccination During Pregnancy With Early Childhood Health Outcomes
Authors: Azar Mehrabadi, Linda Dodds, Noni E. MacDonald, Karina A. Top, Eric I. Benchimol, Jeffrey C. Kwong, Justin R. Ortiz, Ann E. Sprague, Laura K. Walsh, Kumanan Wilson, Deshayne B. Fell
Journal: JAMA (2021)

Seasonal influenza vaccination in pregnancy can reduce influenza illness among pregnant women and newborns. Evidence is limited on whether seasonal influenza vaccination in pregnancy is associated with adverse childhood health outcomes.To assess the association between maternal influenza vaccination during pregnancy and early childhood health outcomes.Retrospective cohort study, using a birth registry linked with health administrative data. All live births in Nova Scotia, Canada, between October 1, 2010, and March 31, 2014, were included, with follow-up until March 31, 2016. Adjusted hazard ratios (HRs) and incidence rate ratios (IRRs) with 95% confidence intervals were estimated while controlling for maternal medical history and other potential confounders using inverse probability of treatment weighting.Seasonal influenza vaccination during pregnancy.Childhood outcomes studied were immune-related (eg, asthma, infections), non-immune-related (eg, neoplasms, sensory impairment), and nonspecific (eg, urgent or inpatient health care utilization), measured from emergency department and hospitalization databases.Among 28 255 children (49% female, 92% born at ≥37 weeks' gestation), 10 227 (36.2%) were born to women who received seasonal influenza vaccination during pregnancy. During a mean follow-up of 3.6 years, there was no significant association between maternal influenza vaccination and childhood asthma (incidence rate, 3.0 vs 2.5 per 1000 person-years; difference, 0.53 per 1000 person-years [95% CI, -0.15 to 1.21]; adjusted HR, 1.22 [95% CI, 0.94 to 1.59]), neoplasms (0.32 vs 0.26 per 1000 person-years; difference, 0.06 per 1000 person-years [95% CI, -0.16 to 0.28]; adjusted HR, 1.26 [95% CI, 0.57 to 2.78]), or sensory impairment (0.80 vs 0.97 per 1000 person-years; difference, -0.17 per 1000 person-years [95% CI, -0.54 to 0.21]; adjusted HR, 0.82 [95% CI, 0.49 to 1.37]). Maternal influenza vaccination in pregnancy was not significantly associated with infections in early childhood (incidence rate, 184.6 vs 179.1 per 1000 person-years; difference, 5.44 per 1000 person-years [95% CI, 0.01 to 10.9]; adjusted IRR, 1.07 [95% CI, 0.99 to 1.15]) or with urgent and inpatient health services utilization (511.7 vs 477.8 per 1000 person-years; difference, 33.9 per 1000 person-years [95% CI, 24.9 to 42.9]; adjusted IRR, 1.05 [95% CI, 0.99 to 1.16]).In this population-based cohort study with mean follow-up duration of 3.6 years, maternal influenza vaccination during pregnancy was not significantly associated with an increased risk of adverse early childhood health outcomes.
A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.
Authors: David Michael Jackman, Opeyemi Jegede, Marjorie Glass Zauderer, Edith P. Mitchell, James Zwiebel, Robert James Gray, Shuli Li, Lisa McShane, Lawrence Rubinstein, David R Patton, Paul M. Williams, Stanley R. Hamilton, Barbara A. Conley, Carlos L. Arteaga, Lyndsay Harris, Peter J. O'Dwyer, Alice P. Chen, Keith Flaherty
Journal: Journal of Clinical Oncology (2021)

3087 Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (&lt; 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]