Vactosertib, a novel TGF-β type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma.
James J DriscollEhsan MalekPriyanka RanaMuthulekha SwamydasMichael DaunovMasaru MiyagiElena MurphyJames Ignatz-HooverLeland MethenySeong KimPublished in: Research square (2023)
Functional blockade of the transforming growth factor-beta (TGF-β) signaling pathway improves the efficacy of cytotoxic and immunotherapies. We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF-β type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma patients who had received >2 lines of chemoimmunotherapy. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, while pomalidomide alone historically achieved 20% PFS-6. Following treatment, the immunosuppressive marker PD-1 expression was reduced on patient CD8 + T-cells. Following treatment, vactosertib decreased PD-1 expression on patient CD138 + cells, reduced PD-L1/PD-L2 on patient CD138 + cells and enhanced the anti-myeloma activity of autologous T-cells. Taken together, vactosertib is a safe immunotherapy that modulates the T-cell immunophenotype to reinvigorate T-cell fitness.
Keyphrases
- multiple myeloma
- transforming growth factor
- epithelial mesenchymal transition
- induced apoptosis
- signaling pathway
- case report
- free survival
- poor prognosis
- cell cycle arrest
- physical activity
- binding protein
- body composition
- pi k akt
- clinical trial
- study protocol
- randomized controlled trial
- acute lymphoblastic leukemia
- stem cells
- bone marrow
- emergency department
- hodgkin lymphoma
- mesenchymal stem cells
- oxidative stress
- cell therapy
- phase iii
- combination therapy
- resistance training