Establishment of operational tolerance to sustain antitumor immunotherapy
Nana Dang1, Mark Waer1, Ben Sprangers2
1Laboratory of Molecular Immunology, Department `of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Background:
Commonly used immunosuppressive drugs are efficacious in the prevention of transplanted solid organ rejection but, are complicated by an increased rate of malignancies. Treatment of the latter with cancer immunotherapy is frequently associated with increased graft loss from rejection.
Methods:
B16 melanoma was inoculated subcutaneously (s.c.) in the ear of host B6 mice carrying a heterotopic allogenic murine heart. Intratumoral (i.t.) immunotherapy with anti-programmed death-1 (PD-1) and a toll-like receptor 9 (TLR9) agonist was conducted to treat cancer. Cyclosporine A (CsA) therapy or replaced by other immunosuppressive agents was conducted to preserve heart allograft tolerance, respectively.
Results:
Here we show that long-term allograft-bearing mice receiving CsA therapy and challenged with host-type melanoma resist cancer immunotherapy and reject their grafts after CsA withdrawal. However, when CsA therapy is replaced by intermittent administration of the PI4KIIIβ inhibitor UCB9608, effective antitumor immunity is induced while preserving graft tolerance. UCB9608 switch combined with i.t. immunotherapy resulted in donor-specific tolerance with preserved third-party responses. This operational tolerance may not be dependent on regulatory T cells (Tregs).
Conclusions:
Immune effects induced by UCB9608 switch following CsA therapy allow for antitumor immunity, opening up new approaches to establish donor-specific operational tolerance in solid organ transplantation with cancer.
Insights
Switching from Cyclosporine A to UCB9608 preserves transplanted organ tolerance while enabling effective cancer immunotherapy. This novel approach balances anti-cancer immunity with graft acceptance, offering new hope for transplant patients.
Area of Science:
- Immunology
- Transplantation Biology
- Oncology
Background:
- Immunosuppressive drugs prevent organ transplant rejection but increase malignancy risk.
- Cancer immunotherapy can cause graft rejection in transplant recipients.
Purpose of the Study:
- To investigate a novel therapeutic strategy for simultaneous cancer treatment and prevention of organ transplant rejection.
- To evaluate the efficacy of replacing Cyclosporine A with UCB9608 in maintaining graft tolerance during cancer immunotherapy.
Main Methods:
- B16 melanoma was inoculated in mice with heart allografts under Cyclosporine A (CsA) therapy.
- Intratumoral immunotherapy using anti-programmed death-1 (PD-1) and a toll-like receptor 9 (TLR9) agonist was administered.
- CsA therapy was either continued or replaced with the PI4KIIIβ inhibitor UCB9608.
Main Results:
- Mice on CsA therapy resisted cancer immunotherapy and rejected grafts upon CsA withdrawal.
- Replacing CsA with UCB9608 induced effective anti-tumor immunity and preserved graft tolerance.
- UCB9608 combined with immunotherapy led to donor-specific tolerance, potentially independent of regulatory T cells (Tregs).
Conclusions:
- Replacing CsA with UCB9608 allows for anti-tumor immunity while maintaining graft tolerance.
- This strategy offers a new approach for achieving donor-specific operational tolerance in solid organ transplantation patients with cancer.
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