Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.
Introduction Lemzoparlimab (also known as TJ011133 or TJC4) is a differentiated CD47 IgG4 antibody targeting a distinct CD47 epitope to enable a unique red blood cell sparing property, while retaining strong anti-tumor activity as demonstrated previously in patients with solid tumors. Lemzoparlimab does not induce significant hematologic toxicity without the need of priming dosing commonly required for other CD47 antibodies. Lemzoparlimab exhibits an enhanced treatment effect when combined with rituximab in lymphoma animal models. Methods This ongoing Phase 1b study (NCT03934814) enrolled relapsed and refractory (R/R) patients with CD20 positive Non-Hodgkin's Lymphoma (NHL) who had at least two prior lines of therapy in a 3+3 dose escalation design followed by a dose expansion. Lemzoparlimab was administered intravenously at doses of 20 or 30 mg/kg weekly with rituximab (375 mg/m2 QW for 5 doses followed by once monthly for 3 doses). Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity based on Lugano criteria were assessed. Preliminary data as of 2 July 2021 are reported here with the updated data set to be presented at the 2021 ASH meeting. Results Eight heavily pre-treated patients with R/R NHL who had progressed on prior CD20 targeted therapies were enrolled to the dose cohorts of 20 mg/kg (n=6) and 30 mg/kg (n=2) of lemzoparlimab in combination with rituximab. The diagnoses included diffuse large B-cell lymphoma (DLBCL) [n=2], mantle cell lymphoma (MCL) [n=1], and follicular lymphoma (FL) [n=5]. Patients had a median age of 63 years (range: 43-83) and a median of 4 prior therapies (range: 2-10). Safety and tolerability: The most common treatment-related adverse events (TRAEs) were infusion-related reactions (n=4), pruritus (n=3), fatigue (n=3), rash (n=2), constipation (n=2), and dyspnea (n=2). All TRAEs were Grade 1 or 2, with one exception who reported Grade 3 TRAEs including pleural effusion, tachycardia, cough, pruritis, fatigue, rash and dyspnea, at 20 mg/kg dose level. Mild hematologic AEs were observed as one isolated episode of anemia and thrombocytopenia, respectively, and no treatment was required. PK and PD: Co-administration of rituximab did not affect the PK or immunogenicity of lemzoparlimab. On average, 80% and 90% CD47 receptor occupancy was detected in biopsied lymph nodes from the patients dosed at 20 and 30 mg/kg, respectively, indicating significant tumor target engagement. Anti-tumor activity: Among 7 efficacy-evaluable patients, 3 complete responses (CR) [1 transformed FL-DLBCL + 2 FL] and 1 partial response (PR) of FL were observed (ORR=57%), together with 3 stable disease (SD duration between 3-6 months). The overall DCR was 100%. Tumor shrinkage was observed in all evaluable patients. One patient was not efficacy evaluable due to clinical disease progression after withdrawal from the study at the first cycle. The median time to an initial response to the treatment was 2 months and all responders remained in clinical response at time of data cutoff. During continued treatment, two patients developed improved responses. One patient with transformed FL-DLBCL improved from PR at 2 nd month to CR at 8 th month and another patient with FL improved from SD at 2 nd month to PR at 4 th month. Conclusion Consistent with the previously reported monotherapy results, lemzoparlimab given at 20 - 30 mg/kg with rituximab is safe and well tolerated in patients with R/R NHL without the need for a priming dose. A high level of intra-tumoral target engagement was reached at both dose levels. The combination therapy exhibited evidence of clinical activity in heavily pre-treated R/R NHL patients who had progressed on prior CD20 targeted therapies. The results provide the basis for RP2D and impetus for accelerated clinical development for NHL. Disclosures Mehta: Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding. Xu: I-Mab Biopharma: Current Employment. Meng: I-Mab Biopharma: Current Employment. Lee: I-Mab Biopharma: Current Employment. Yuan: I-Mab Biopharma: Current Employment. Wang: I-Mab Biopharma: Current Employment. Song: I-Mab Biopharma: Current Employment. Shen: I-Mab Biopharma: Current Employment. Gopal: Genetech: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Teva: Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Nurix Inc: Consultancy, Honoraria; Agios: Research Funding; Servier: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Research Funding; MorphoSys: Honoraria; Kite: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Astra-Zeneca: Research Funding; IGM Biosciences: Research Funding; Incyte: Honoraria; SeaGen: Consultancy, Honoraria, Research Funding.
2511 Background: CD73 is implicated in tumor resistance to checkpoint immunotherapy (CPI) and plays a critical role in adenosine-mediated immune suppression. Uliledlimab, a differentiated CD73 antibody, inhibits the adenosine pathway in a non-competitive and unique intra-dimer binding mode. Uliledlimab suppresses tumor growth when combined with a PD-(L)1 inhibitor in multiple pre-clinical models. Methods: This 3+3 dose-escalation phase 1 study (NCT03835949) evaluated safety, tolerability, PK, PD and preliminary efficacy in cancer patients. Uliledlimab was administered intravenously at doses of 5, 10 or 15 mg/kg weekly (QW) or 15 or 20 mg/kg every 3 weeks (Q3W) alone in the first cycle and in combination with atezolizumab (1,200 mg Q3W) starting on week 4. Soluble CD73 in serum and CD73 receptor occupancy (RO) in circulating CD19+ B cells were measured. Expression of PD-L1, CD73 and A2A receptor was analyzed in baseline tumor specimens (n = 14). Tumor responses were assessed by RECIST/iRECIST. Results: As of 17 January 2021, 20 patients with advanced solid tumors were enrolled (M:F 8:12; mean age = 64; median prior regimens = 3 (range 1-9)). Uliledlimab was well-tolerated with no dose limiting toxicity. The most common treatment-related adverse events were first dose infusion related reactions (65%, n = 13) most commonly comprising chills/rigors, nausea, and vomiting (Grade 1 or 2) that resolved in subsequent infusions. PK appears linear at doses ≥ 10 mg/kg and modelling indicated a mean derived effective half-life of ̃19 days. Soluble CD73 was undetectable and complete RO was achieved in all patients after the first dose at ≥ 10 mg/kg. Anti-drug antibody was detected in 3/20 patients (15%). Among 13 efficacy-evaluable patients dosed at ≥ 10 mg/kg, complete response (CR = 1) and partial response (PR = 2) were observed in 3 patients (ORR = 23%) together with 3 stable disease (SD) patients (DCR = 46%). One PD-(L)1 inhibitor naïve patient with clear cell ovarian cancer achieved CR at 10 mg/kg QW and remains on study after 12 months. Two patients with NSCLC dosed at 15 mg/kg QW and 20 mg/kg Q3W, respectively, achieved PR. One patient failed nivolumab and the other received no prior PD-(L)1 inhibitor treatment. CD73 was expressed on 78% (mean) of malignant cells from archival tumor specimens in responders compared to 23% in non-responders. Conclusions: Uliledlimab is safe and well tolerated up to 20 mg/kg Q3W and 15 mg/kg QW. Full saturation of circulating and cell-bound CD73 was achieved at doses ≥ 10 mg/kg. Uliledlimab exhibited evidence of clinical activity in both PD-(L)1 treatment naïve and refractory cancer patients with high archival tumor expression of CD73. The results of this phase 1 study encourage further clinical investigation to evaluate the efficacy of uliledlimab in the treatment of solid tumors. Clinical trial information: NCT03835949.
Background 500 mg intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary endpoint was occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through Day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through Day 29 were assessed. Results All participants (n = 81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through Day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n = 2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on Day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through Day 29; only 2 participants (3%) had persistently high viral load (≥4.1 log10 copies/mL) at Day 8. Conclusions 2000mg IV sotrovimab was well tolerated, with no safety signals observed.
Background: 500 mg intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary endpoint was occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through Day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through Day 29 were assessed. Results: All participants (n=81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through Day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n=2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on Day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 μg/mL. Viral load decreased from baseline through Day 29; only 2 participants (3%) had persistently high viral load (≥4.1 log10 copies/mL) at Day 8. Conclusions: 2000 mg IV sotrovimab was well tolerated, with no new unanticipated safety signals observed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.