On February 1, 2024, the UW Program for Advanced Cell Therapy
sponsored MARSH phase 1 clinical trial treated its first patient at UW Carbone Cancer Center. This National Institute of Dental and Craniofacial Research (NIDCR) funded study led by Randall Kimple seeks to reverse severe xerostomia secondary to curative radiation therapy for throat cancer. The approach uses culture adapted autologous marrow MSC that are refreshed and interferon-γ activated and injected directly into both submandibular salivary glands under ultrasound guidance. Starting dose is 10 million MSC per gland.
This phase 1 trial is built upon published pre-clinical data which demonstrates that marrow MSC derived from patients with prior chemoradiation for throat cancer can be culture expanded and deploy functional attributes of immune regulation as well as competency in expressing epithelial stem cell morphogens (such as R-spondin) that can rescue dormant gland endogenous LRG5+ epithelial stem cells. Complementary data in a murine model of radiation induced dry mouth also demonstrates that interferon-γ activated MSC deploy enhanced potency in this clinical use case.
The FDA had mandated a pilot study of 6 subjects prior to launch of phase 1 trial, whereas these patients had a singular submandibular gland treated with 10 million MSC. These data were publishedand mild AEs were observed as well as objective responses reflected by durable saliva production de novo whereas none had been observed for more than a few years.
This new phase 1 single site study will enroll 30 subjects at UW Health with a tiered dose escalation and expansion cohort. Secondary endpoints of efficacy will be gathered in particular measurable saliva production.
The bespoke nature of product manufactured and the substantial touch points of marrow collection and latter outpatient MSC administration by Tiffany Glazer under ultrasound guidance makes this cell drug manufacturing scheme particularly well suited for a distributed place-of-care manufacturing. Indeed, MSC manufacture by UW Health PACT team of Ross Meyers, Olga Ganz, Jessica Murphy and Xingyi Tang allows for flexible and timely coordination of manufacturing and clinical administration.
There have been a number of clinical trials of “fresh” MSC delivered directly to diseased tissue without clinical success. However, the use of refreshed MSC was made for the use case of Alofisel™ in perianal Crohn’s fistular disease in the Admire CD clinical trial. Although the use of physiologically optimal refreshed MSC may be necessary for meeting clinical endpoints it is clearly not sufficient, as reflected by the travails of Admire CD II trial. Enhanced potency as reflected by biologically plausible quality attributes arise following interferon-γ activation which may the step change that MSC v2.0 needs to break through the utility gap.
Indeed, the MARSH study stacks all the attributes that would optimize utility of MSCs by local delivery in a clinical indication with unmet needs poised for responsiveness.
From MARSH a MSC phoenix may well arise…
Read the full article at: https://www.linkedin.com/pulse/from-marsh-msc-phoenix-may-arise-uw-madison-program-for-advanced-ce-myfye%3FtrackingId=dQnVBwG6PwYPWDpGxC6zUA%253D%253D/?trackingId=dQnVBwG6PwYPWDpGxC6zUA%3D%3D