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NIH grant 1R41AI197604-01: Immune Checkpoint Blockade Therapy to Treat Chronic Bone and Joint Infections
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: John Linforth Daiss. Award: $302408.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY
Implant-associated bone infections pose a significant challenge in orthopaedic surgery. Staphylococcus aureus,
a major human pathogen, remains the leading cause of chronic bone implant-associated infections, including
periprosthetic joint infections (PJI). Remarkably, infection rates during orthopaedic procedures have remained
constant over the last fifty years, reinforcing the orthopaedic paradigm that S. aureus infections of bone are
broadly incurable. Unfortunately, the emergence of multidrug-resistant S. aureus strains such as MRSA has led
to very high reinfection (up to 40%) and treatment failure rates (as high as 38%). Given the growing burden and
severity of this disease, alternatives to standard-of-care antibiotic therapy, such as adjuvant immunotherapies,
are urgently needed.
We conducted studies on host immunity utilizing a humanized mouse model of osteomyelitis, and
discovered that implant-associated bone infections are marked by increased bacterial load, bone osteolysis, and
compromised T cell function, as indicated by elevated expression of immune checkpoint proteins and functional
exhaustion. Furthermore, we examined human infections and found that these proteins were upregulated in the
serum of patients with chronic S. aureus osteomyelitis. Notably, we determined that the checkpoint protein TIM-
3 (T cell immunoglobulin and mucin-domain-containing-3) was highly predictive of adverse outcomes
(arthrodesis, reinfection, amputation, and septic death) following revision surgery in human cases, achieving an
accuracy of nearly 90%.
T cells that highly express TIM-3 exhibit significantly reduced self-renewal capacity and cytokine
production, leading to impaired effector function. The blockade of TIM-3 and other immune checkpoint proteins
as a treatment to enhance T cell and immune system activation has become a standard of care for cancer
patients with advanced disease. Based on our research findings and intellectual property, this proposal aims to
complete critical proof of concept studies that immune checkpoint blockade therapies can reverse the
osteomyelitis phenotype, decrease infection severity, and increase the success of revision surgery. Specifically,
this Phase I STTR proposal will establish the safety, pharmacokinetics, and preliminary efficacy of TIM-3
blockade therapy in a humanized mouse model of S. aureus implant-associated osteomyelitis through a dose
escalation study. Successful completion of these Phase I studies will establish the feasibility of further developing
TIM-3 blockade as a transformative adjuvant immunotherapy for chronic orthopaedic infections.document fetched 2026-09-20 02:42