Tumor-agnostic baskets to N-of-1 platform trials and real-world data: Transforming precision oncology clinical trial design.

Choosing the right drug(s) for the right patient via advanced genomic sequencing and multi-omic interrogation is the sine qua non of precision cancer medicine. Traditional cancer clinical trial designs follow well-defined protocols to evaluate the efficacy of new therapies in patient groups, usually identified by their histology/tissue of origin of their malignancy. In contrast, precision medicine seeks to optimize benefit in individual patients, i.

Dataset of phase I and II immunotherapy clinical trials used for a meta-analysis to assess the role of biomarkers in treatment outcomes in diverse cancers.

We performed a literature search in PubMed to identify phase I/II clinical trials with immunotherapy drugs approved by the Food and Drug Administration (labeled, off-label, and/or combined with investigational immune checkpoint inhibitors or other treatment modalities) from 2018 to 2020. We used the following key words: clinical trials, phase 1, Phase 2; and the following filters: cancer, humans; and selected the checkpoint inhibitors that had been approved by the FDA by March 2021, i.e.

Molecular tumour boards - current and future considerations for precision oncology.

Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments.

Correlation between biomarkers and treatment outcomes in diverse cancers: a systematic review and meta-analysis of phase I and II immunotherapy clinical trials.

Background: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any.

Methods: A PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed.

Feasibility and Safety of Personalized, Multi-Target, Adoptive Cell Therapy (IMA101): First-in-Human Clinical Trial in Patients with Advanced Metastatic Cancer.

IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro.

Precision Oncology: Evolving Clinical Trials across Tumor Types.

Advances in molecular technologies and targeted therapeutics have accelerated the implementation of precision oncology, resulting in improved clinical outcomes in selected patients. The use of next-generation sequencing and assessments of immune and other biomarkers helps optimize patient treatment selection. In this review, selected precision oncology trials including the IMPACT, SHIVA, IMPACT2, NCI-MPACT, TAPUR, DRUP, and NCI-MATCH studies are summarized, and their challenges and opportunities are discussed.

Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology.

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A).

Clinical trial design in the era of precision medicine.

Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy.

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology.

Background: Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms.

Methods: (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain.

Ipilimumab, Pembrolizumab, or Nivolumab in Combination with BBI608 in Patients with Advanced Cancers Treated at MD Anderson Cancer Center.

: BBI608 is an investigational reactive oxygen species generator that affects several molecular pathways. We investigated BBI608 combined with immune checkpoint inhibitors in patients with advanced cancers. : BBI608 (orally twice daily) was combined with ipilimumab (3 mg/kg IV every 3 weeks); pembrolizumab (2 mg/kg IV every 3 weeks); or nivolumab (3 mg/kg IV every 4 weeks).

T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors.

T-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g.

Prolonged response to treatment based on cell-free DNA analysis and molecular profiling in three patients with metastatic cancer: a case series.

Background: Patients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients' plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications.

Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker.

The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyperprogression have also been reported.

Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis.

Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development, namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat diet (HFD)-induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed a normal diet or an HFD for 16 wk.