Osel (United States)

503 Background: CBM588 has shown potential to improve clinical outcomes when combined with immune checkpoint inhibitors (ICIs) in untreated mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). Since no significant treatment-related adverse events were related to CBM588 in previous studies, we sought to determine if CBM588 capsules, a novel formulation of this live biotherapeutic, designated MO-03, could be delivered at higher doses with similar tolerability and greater biologic effect. Methods: Patients (pts) with treatment-naïve mRCC and any international mRCC Database Consortium (IMDC) risk were treated with nivo (3 mg/kg q3w ×4, then 480 mg q4w) and ipi (1 mg/kg q3w ×4) plus CBM588 at one of three dose levels (4 × 10⁸, 1.2 × 10⁹, or 4 × 10⁹ CFU BID) in a 3+3 dose-escalation design. The primary endpoint was safety, with secondary endpoints including response rate and progression-free survival. Stool samples collected at baseline and Week 13 were analyzed by metagenomic sequencing to assess microbial composition across CBM588 dose levels. Plasma samples collected at baseline and Cycle 3 were analyzed for soluble mucosal addressin cell adhesion molecule-1 (sMAdCAM-1), a biomarker associated with dysbiosis (Fidelle et al Science 2023). Results: Twelve pts were treated between 6/26/2024 and 9/15/2025. Median age was 69 (range 48-80). All had clear cell histology without sarcomatoid features; two had rhabdoid features. Half the cohort had ≥3 metastatic sites, most commonly involving the lung, lymph nodes, and contralateral kidney. Most patients had favorable (50%) or intermediate (42%) IMDC risk. No dose-limiting toxicities (DLTs) were observed at any dose level, and no dose-dependent increase in immune-related toxicity was noted with CBM588 escalation. Notably, Bacteroides thetaiotaomicron showed a dose-dependent increase in relative abundance across escalating CBM588 levels (P = 0.0043 for Level 3 vs Level 1 and P = 0.0047 for Level 3 vs Level 2, Mann–Whitney U), suggesting a selective modulation of gut microbial composition. Among 11 pts with evaluable disease, 3 were responders (1 complete response, 2 partial responses), 6 had stable disease, and 2 had progressive disease. Baseline sMAdCAM-1 levels were similar between responders (Rs) and non-responders (NRs) (median: 205,196 vs. 206,462 pg/mL). However, percent change from baseline to Cycle 3 demonstrated a diverging pattern, with an early increase in Rs and relative stabilization in NRs (median: +8.2% vs –0.1%). Conclusions: No DLTs were encountered with CBM588 capsules at the highest dose level (MO-03) in combination with nivo/ipi, supporting the dosing strategy in the upcoming phase III SWOG study S2419 (BioFront). Translational studies indicate a dose effect upon microbiome composition, and sMAdCAM-1 dynamics suggest a potential association with response. Clinical trial information: NCT06399419 .

Lactobacillus iners is often associated with vaginal dysbiosis and bacterial vaginosis (BV), which are risk factors for adverse gynecological and obstetric outcomes. To discover natural inhibitors of L. iners, cell-free culture supernatants (CFSs) from 77 vaginal human Lactobacillus strains and 1 human intestinal strain were screened for inhibitory activity. Three active strains were identified, and Lactobacillus paragasseri K7 (K7), a human intestinal strain, produced the most potent L. iners-inhibitory activity. The active material was purified from the K7 CFS and yielded three active peptides, identified as components of two different class IIb, two-peptide bacteriocins, gassericin K7A (GasK7A) and gassericin K7B (GasK7B). The peptides corresponded to the GasK7A α peptide and the GasK7B α and β peptides. While all three peptides exhibited individual activity against L. iners, GasK7B α was the most potent, with an MIC of 23 ng/ml (4 nM). When combined in equal amounts, the GasK7B α and β peptides showed synergistic inhibition, with an MIC of 2 ng/ml (each peptide at 0.4 nM). Among the four major vaginal Lactobacillus species, the K7 bacteriocins selectively inhibited L. iners All 21 strains of L. iners tested (100%) were inhibited by the K7 bacteriocins, whereas <20% of the vaginal Lactobacillus crispatus, L. jensenii, and L. gasseri strains were inhibited. The combination of the BV treatment metronidazole and K7 bacteriocins completely killed both L. iners and Gardnerella vaginalis in a coculture experiment to mimic BV conditions. In contrast, this treatment did not inhibit L. crispatus cultures.IMPORTANCELactobacillus iners is a prevalent species of the vaginal microbiome, but unlike other major vaginal Lactobacillus species, it is not considered protective against BV and can coexist with BV-associated bacteria. L. iners is generally the first Lactobacillus species to emerge following the treatment of BV with metronidazole, and mounting evidence suggests that it may contribute to the onset and maintenance of vaginal dysbiosis. The discovery of highly potent bacteriocins that selectively kill L. iners while sparing protective vaginal lactobacilli may provide novel pharmacological tools to better understand the roles of this enigmatic bacterium in vaginal ecology and potentially lead to new and improved therapies for dysbiosis-related conditions such as BV.

Each year, a growing international collection of researchers meets at the NIH to share and discuss developments in the microbiome HIV story. This past year has seen continued progress toward a detailed understanding of host-microbe interactions both within and outside the field of HIV. Commensal microbes are being linked to an ever-growing list of maladies and physiologic states, including major depressive disorder, chronic kidney disease, and Parkinson disease. PubMed citations for "microbiome" are growing at an exponential rate with over 11,000 in 2018. Various microbial taxa have been associated with HIV infection, and some of these taxa associated with HIV infection have also been associated with systemic markers of inflammation in HIV infected individuals. Causality remains unclear however as environmental and behavioral factors may drive HIV risk, inflammation, and gut enterotype. Much of the work currently being done addresses potential mechanisms by which gut microbes influence immune and inflammatory pathways. No portion of the microbiome landscape has grown as rapidly as study of the interplay between gut microbes and response to cancer immunotherapy. As Dr. Wargo discussed in her keynote address, this area has opened the door to better understanding on how commensal microbes interact with the human immune system.

MucoCept is a biotherapeutic for prevention of HIV-1 infection in women and contains a human, vaginal Lactobacillus jensenii that has been genetically enhanced to express the HIV-1 entry inhibitor, modified cyanovirin-N (mCV-N). The objective of this study was to develop a solid vaginal dosage form that supports sustained vaginal colonization of the MucoCept Lactobacillus at levels previously shown, with freshly prepared cultures, to protect macaques from SHIV infection and to test this formulation in a macaque vaginal colonization model. Vaginally disintegrating tablets were prepared by lyophilizing the formulated bacteria in tablet-shaped molds, then packaging in foil pouches with desiccant. Disintegration time, potency and stability of the tablets were assessed. For colonization, non-synchronized macaques were dosed vaginally with either one tablet or five tablets delivered over five days. Vaginal samples were obtained at three, 14, and 21 days post-dosing and cultured to determine Lactobacillus colonization levels. To confirm identity of the MucoCept Lactobacillus strain, genomic DNA was extracted from samples on days 14 and 21 and a strain-specific PCR was performed. Supernatants from bacteria were tested for the presence of the mCV-N protein by Western blot. The tablets were easy to handle, disintegrated within two minutes, potent (5.7x1011 CFU/g), and stable at 4°C and 25°C. Vaginal administration of the tablets to macaques resulted in colonization of the MucoCept Lactobacillus in 66% of macaques at 14 days post-dosing and 83% after 21 days. There was no significant difference in colonization levels for the one or five tablet dosing regimens (p=0.88 Day 14, p=0.99 Day 21). Strain-specific PCR confirmed the presence of the bacteria even in culture-negative macaques. Finally, the presence of mCV-N protein was confirmed by Western blot analysis using a specific anti-mCV-N antibody.