To evaluate the therapeutic efficacy of neoantigen-specific T cells, a cellular therapy model was established by transferring activated MISTIC T cells and interleukin 2 into lymphodepleted mice bearing tumors. Our investigation into the factors governing treatment response incorporated flow cytometry, single-cell RNA sequencing, and a dual approach of whole-exome and RNA sequencing.
Isolation and characterization of the 311C TCR revealed a high affinity for mImp3, coupled with the absence of any cross-reactivity with wild-type structures. The MISTIC mouse was manufactured for the explicit intention of supplying mImp3-specific T cells. The infusion of activated MISTIC T cells, part of an adoptive cellular therapy model, caused rapid intratumoral infiltration and remarkably potent antitumor effects, ultimately leading to long-term cures in a majority of GL261-bearing mice. Mice not benefiting from adoptive cell therapy exhibited retained neoantigen expression, a concurrent factor being intratumoral MISTIC T-cell dysfunction. Heterogeneous mImp3 expression within murine tumors resulted in the diminished efficacy of MISTIC T cell therapy, demonstrating the hurdles to targeted approaches for treating the complexity of polyclonal human tumors.
We pioneered the generation and characterization of the first TCR transgenic targeting an endogenous neoantigen within a preclinical glioma model, subsequently demonstrating the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse serves as a potent, innovative platform for fundamental and translational research into anti-tumor T-cell responses within glioblastoma.
Our team generated and characterized the first TCR transgenic targeting an endogenous neoantigen within a preclinical glioma model, and demonstrated the therapeutic potential of the adoptively transferred neoantigen-specific T cells. Glioblastoma's antitumor T-cell responses are subject to fundamental and translational analyses using the innovative MISTIC mouse platform.
Anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapies encounter resistance in some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC). The effectiveness of this agent might be augmented when employed alongside other agents. A phase 1b open-label, multicenter trial focused on the combined effect of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, and the anti-PD-1 antibody tislelizumab.
Patients diagnosed with locally advanced/metastatic NSCLC were enrolled in Cohorts A, B, F, H, and I, with 22 to 24 individuals in each cohort (N=22-24). Patients in cohorts A and F had been subjected to systemic therapy before, displaying anti-PD-(L)1 resistance/refractoriness in either non-squamous disease (cohort A) or squamous disease (cohort F). Cohort B's patient population comprised individuals who had received prior systemic therapy, presenting with anti-PD-(L)1-naive non-squamous disease. Patients in cohorts H and I lacked prior systemic therapy for metastatic disease, past anti-PD-(L)1/immunotherapy, and presented with PD-L1-positive non-squamous histology (cohort H) or squamous histology (cohort I). Each patient received sitravatinib 120mg orally daily and tislelizumab 200mg intravenously every three weeks, continuing until study completion, disease progression, unmanageable side effects, or death. The primary focus of the study, encompassing all treated patients (N=122), was safety and tolerability. Investigator-assessed tumor responses and progression-free survival (PFS) were among the secondary endpoints.
The median duration of observation was 109 months, with a spread from a minimum of 4 months to a maximum of 306 months. selleck chemicals llc Adverse events stemming from treatment, or TRAEs, were observed in 984% of the patients, while 516% experienced Grade 3 TRAEs. A 230% rate of patient discontinuation for either drug was linked to TRAEs. The following response rates were observed in cohorts A, F, B, H, and I: 87% (2/23; 95% CI 11%–280%), 182% (4/22; 95% CI 52%–403%), 238% (5/21; 95% CI 82%–472%), 571% (12/21; 95% CI 340%–782%), and 304% (7/23; 95% CI 132%–529%), respectively. No median response time was established for cohort A, while other cohorts experienced response durations between 69 and 179 months. The percentage of patients achieving disease control spanned a remarkable range of 783% to 909%. The median progression-free survival (PFS) spanned a considerable range, from a low of 42 months in cohort A to a high of 111 months in cohort H.
In patients with locally advanced/metastatic non-small cell lung cancer (NSCLC), the combination of sitravatinib and tislelizumab showed a tolerable safety profile, presenting no unexpected safety signals and with safety data comparable to known safety characteristics of each agent. Objective responses were noted across all groups, encompassing patients who had not previously received systemic or anti-PD-(L)1 therapies, and those with anti-PD-(L)1-resistant/refractory disease. Further research is suggested by the results, focusing on selected NSCLC populations.
The NCT03666143 trial.
This document pertains to NCT03666143 and its implications.
Murine CAR-T cell therapy has yielded positive clinical outcomes in patients suffering from relapsed/refractory B-cell acute lymphoblastic leukemia. However, the potential for the murine single-chain variable fragment domain to induce an immune response could impair the persistence of CAR-T cells, resulting in a relapse.
A clinical investigation was undertaken to determine the security and power of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy (hCART19) for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). In the interval between February 2020 and March 2022, fifty-eight patients, whose ages spanned 13 to 74 years, were enrolled and treated. Key performance indicators for the analysis included complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety.
A substantial proportion, 931% (54 of 58), of patients achieved either a complete remission (CR) or a complete remission with incomplete count recovery (CRi) by day 28, with an additional 53 cases showing minimal residual disease negativity. Following a median observation period of 135 months, the estimated one-year overall survival and event-free survival rates were 736% (95% confidence interval 621% to 874%) and 460% (95% confidence interval 337% to 628%), respectively, with a median overall survival and event-free survival of 215 months and 95 months, respectively. Human antimouse antibody levels remained essentially unchanged after infusion, as indicated by a non-significant result (p=0.78). The period of time during which B-cell aplasia was observed in the blood reached an unprecedented 616 days, surpassing the duration seen in our prior mCART19 trial. Reversibility characterized all toxicities, including severe cytokine release syndrome, which was observed in 36% (21/58) patients, and severe neurotoxicity, observed in 5% (3/58) patients. A difference in event-free survival was observed between the hCART19 treated patients and those in the prior mCART19 trial, with hCART19 showing a longer duration without an increase in toxicity. Subsequent to hCART19 therapy, our data indicate that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplants or CD22-targeted CAR-T cell treatments, demonstrated improved event-free survival (EFS) compared to the group without this consolidation therapy.
In R/R B-ALL patients, hCART19's short-term efficacy is noteworthy, along with its manageable toxicity profile.
The study NCT04532268.
NCT04532268.
Phonon softening, a widespread characteristic of condensed matter systems, is often intertwined with charge density wave (CDW) instabilities and anharmonicity. caveolae mediated transcytosis The intricate dance between phonon softening, charge density waves, and superconductivity is a topic of intense discussion and disagreement. This research investigates the influence of anomalous soft phonon instabilities on superconductivity, employing a newly developed theoretical framework. This framework incorporates phonon damping and softening within the Migdal-Eliashberg theory. Model calculations showcase that phonon softening, identifiable by a sharp dip in the phonon dispersion relation, either acoustic or optical (including the situation of Kohn anomalies common to CDW systems), can amplify the electron-phonon coupling constant manifold. This phenomenon, consistent with Bergmann and Rainer's optimal frequency principle, can, under specific circumstances, yield a significant rise in the superconducting transition temperature, Tc. To summarize, our findings indicate a potential pathway to high-temperature superconductivity through the utilization of momentum-space-confined soft phonon anomalies.
Following initial treatments' failure to address acromegaly, Pasireotide long-acting release (LAR) is a viable second-line therapy option. Prescribing pasireotide LAR at an initial dose of 40mg every four weeks is suggested, potentially escalating to 60mg monthly for cases of uncontrolled IGF-I levels. thyroid autoimmune disease Employing a pasireotide LAR de-escalation protocol, we treated three patients, whom we present here. Treatment for a 61-year-old female diagnosed with resistant acromegaly involved pasireotide LAR 60mg, administered every 28 days. Following the achievement of the lower age range of IGF-I, the therapy utilizing pasireotide LAR was diminished, progressing from 40mg to 20mg. In the years 2021 and 2022, the IGF-I level remained consistent with the normal range. Three cranial surgeries were performed on a 40-year-old female who presented with intractable acromegaly. Part of the 2011 PAOLA study protocol included her receiving pasireotide LAR 60mg. Given the observed IGF-I overcontrol and radiological stability, the therapy was adjusted downward to 40mg in 2016, and then reduced again to 20mg in 2019. Hyperglycemia manifested in the patient, prompting treatment with metformin. In 2011, a 37-year-old male diagnosed with treatment-resistant acromegaly received pasireotide LAR 60mg for treatment. IGF-I overcontrol necessitated a decrease in therapy dosage to 40mg in 2018, and a further reduction to 20mg in 2022.