LUMINOS-102: Lerapolturev with and without α-PD- 1 in unresectable α-PD- 1 refractory melanoma

Lerapolturev (lera, formerly PVSRIPO) is a novel poliovirus based intratumoral immunotherapy that infects both cancer cells and antigen-presenting cells (APCs) via CD155, the poliovirus receptor. Lera has direct anticancer effects while also generating type I/III interferon-dominated inflammation and anti-tumor T-cell priming and activation via infection of local APCs. LUMINOS-102 (NCT04577807) is a multi-center, open-label, two-arm randomized Phase 2 study investigating the efficacy and safety of lera ± α-PD- 1 in patients with unresectable melanoma who failed prior α-PD- 1 therapy. Cross-over to the α-PD- 1 arm is permitted after progression, PR for ≥6 mo or 6 mo on treatment with SD. The maximum initial lera dose was 6x108 TCID50 /visit every 3 or 4 weeks (Q3/4 W). As of March 2022, the maximum lera dose was increased to 1.6 x 109 TCID50/visit, every week (QW) for 7 weeks (induction), followed by Q3/4 W dosing (maintenance). As of 20-Jun- 2022, 21 participants (10 male, 11 female, median 64 yrs) received lera (n = 14 at initial dose, Q3/4 W; n = 4 at increased dose, Q3/4 W; n = 3 at increased dose, QW) ± αPD-1. Five patients are currently on treatment. With the initial regimen, no objective responses and a CBR of 7% were observed. However, with the higher dose regimen, 1 complete response and a CBR of 71% (5/7) has been observed. Two of 4 participants with stable disease have evidence of response (1 with resolution of uninjected lung metastasis, 1 with decreased PET signal in injected and uninjected lesions receiving combination therapy). The only treatment related AE in \u3e1 pt was fatigue (19%, all grade 1 or 2). No dose-limiting toxicities or treatment-related SAEs were reported. Multiplex-IF analysis of on-treatment tumor biopsies will be presented. Lera ± αPD-1 is well tolerated, with early signs of efficacy at the higher dose level. Enrollment and randomization are ongoing

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

5-HT1F receptor-mediated mitochondrial biogenesis for the treatment of Parkinson's disease

Background and PurposeParkinson's disease is characterized by progressive decline in motor function due to degeneration of nigrostriatal dopaminergic neurons, as well as other deficits including cognitive impairment and behavioural abnormalities. Mitochondrial dysfunction, leading to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, is implicated in the pathophysiology of Parkinson's disease. Using the 5-HT1F receptor agonist LY344864, a known inducer of mitochondrial biogenesis (MB), we investigated the therapeutic efficacy of stimulating MB on dopaminergic neuron loss in a mouse model of Parkinson's disease. Experimental ApproachMale C57BL/6 mice underwent bilateral intrastriatal 6-hydroxydopamine or saline injections and daily treatment with 2mgkg(-1) LY344864 or vehicle for 14days beginning 7days post-lesion. Tyrosine hydroxylase immunoreactivity (TH-ir) and MB were assessed in the brains of all groups following treatment, and locomotor activity was evaluated prior to lesioning, 7days post-lesion and after treatment. Key ResultsIncreased mitochondrial DNA content and nuclear- and mitochondrial-encoded mRNA and protein expression was observed in specific brain regions of LY344864-treated naive and lesioned mice, indicating augmented MB. LY344864 attenuated TH-ir loss in the striatum and substantia nigra compared to vehicle-treated lesioned animals. LY344864 treatment also increased locomotor activity in 6-hydroxydopamine lesioned mice, while vehicle treatment had no effect. Conclusions and ImplicationsThese data revealed that LY344864-induced MB attenuates dopaminergic neuron loss and improves behavioural endpoints in this model. We suggest that stimulating MB may be beneficial for the treatment of Parkinson's disease and that the 5-HT1F receptor may be an effective therapeutic target.MUSC Barmore Foundation; National Institute of General Medical Sciences [GM084147]; Biomedical Laboratory Research and Development, VA Office of Research and Development [BX: 000851]12 month embargo; published online: 22 October 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans.

Millions of individuals are diagnosed with type 2 diabetes mellitus (T2D), which increases the risk for a plethora of adverse outcomes including cardiovascular events and kidney disease. Metformin is the most widely prescribed medication for the treatment of T2D; however, its mechanism is not fully understood and individuals vary in their response to this therapy. Here, we use a non-targeted, pharmacometabolomics approach to measure 384 metabolites in 33 non-diabetic, African American subjects dosed with metformin. Three plasma samples were obtained from each subject, one before and two after metformin administration. Validation studies were performed in wildtype mice given metformin. Fifty-four metabolites (including 21 unknowns) were significantly altered upon metformin administration, and 12 metabolites (including six unknowns) were significantly associated with metformin-induced change in glucose (q < 0.2). Of note, indole-3-acetate, a metabolite produced by gut microbes, and 4-hydroxyproline were modulated following metformin exposure in both humans and mice. 2-Hydroxybutanoic acid, a metabolite previously associated with insulin resistance and an early biomarker of T2D, was positively correlated with fasting glucose levels as well as glucose levels following oral glucose tolerance tests after metformin administration. Pathway analysis revealed that metformin administration was associated with changes in a number of metabolites in the urea cycle and in purine metabolic pathways (q < 0.01). Further research is needed to validate the biomarkers of metformin exposure and response identified in this study, and to understand the role of metformin in ammonia detoxification, protein degradation and purine metabolic pathways

Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans.

Millions of individuals are diagnosed with type 2 diabetes mellitus (T2D), which increases the risk for a plethora of adverse outcomes including cardiovascular events and kidney disease. Metformin is the most widely prescribed medication for the treatment of T2D; however, its mechanism is not fully understood and individuals vary in their response to this therapy. Here, we use a non-targeted, pharmacometabolomics approach to measure 384 metabolites in 33 non-diabetic, African American subjects dosed with metformin. Three plasma samples were obtained from each subject, one before and two after metformin administration. Validation studies were performed in wildtype mice given metformin. Fifty-four metabolites (including 21 unknowns) were significantly altered upon metformin administration, and 12 metabolites (including six unknowns) were significantly associated with metformin-induced change in glucose (q < 0.2). Of note, indole-3-acetate, a metabolite produced by gut microbes, and 4-hydroxyproline were modulated following metformin exposure in both humans and mice. 2-Hydroxybutanoic acid, a metabolite previously associated with insulin resistance and an early biomarker of T2D, was positively correlated with fasting glucose levels as well as glucose levels following oral glucose tolerance tests after metformin administration. Pathway analysis revealed that metformin administration was associated with changes in a number of metabolites in the urea cycle and in purine metabolic pathways (q < 0.01). Further research is needed to validate the biomarkers of metformin exposure and response identified in this study, and to understand the role of metformin in ammonia detoxification, protein degradation and purine metabolic pathways

LUMINOS-102: PVSRIPO with or without immune checkpoint blockade in unresectable anti-PD-1 refractory melanoma

PVSRIPO, a novel viral immunotherapy, infects solid tumors and antigen-presenting cells (APCs) via CD155. Infection is lethal in malignant cells, but nonlethal infection of local APCs yields type I/III interferon-dominant induction with subsequent anti-tumor T-cell priming and activation. A phase 1 dose-escalation study (Beasley 2021, JITC) showed PVSRIPO was well tolerated and demonstrated anti-tumor activity in both injected and noninjected lesions in patients (pts) with αPD-1-refractory melanoma. In preclinical models, PVSRIPO-mediated immune activation upregulated the PD-1/L1 pathway, leading to greater anti-tumor response with PVSRIPO and αPD-1 combination therapy. Taken together, these data suggest PVSRIPO is active in αPD-1-refractory melanoma and that PVSRIPO±αPD-1 therapy warrants further clinical investigation. LUMINOS-102 (NCT04577807) is an ongoing multi-center, open-label, randomized phase 2 study investigating the efficacy, safety, and pharmacodynamic effects in the tumor microenvironment following PVSRIPO±αPD-1 therapy in pts with αPD-1-resistant, unresectable, non-uveal melanoma. A safety run-in cohort of 6 pts to characterize PVSRIPO injection in ≥6 lesions/cycle or maximum dose of 6x108TCID50 has fully enrolled; 1:1 randomization of 50 participants to receive PVSRIPO (Arm 1) or PVSRIPO+αPD-1 (Arm 2) is ongoing. Stratification factors include time since last αPD-1 dose and baseline LDH level. Crossover (Arm 1 to 2) is allowed upon confirmed progression, SD at 26 weeks, or PR ≥6 mos. Primary endpoints include safety, ORR per RECIST 1.1, and change from baseline in CD8+ tumor-infiltrating lymphocytes and PD-L1 expression. Key secondary endpoints include DOR, DCR, PFS, and OS. Exploratory endpoints include ORR via iRECIST and additional biomarker analysis evaluating the immune activation phenotype of PVSRIPO