Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts

Abstract

Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) blockades, have revolutionized the field of cancer immunotherapy. However, there is a growing concern whether PD-1 inhibitors can be administered safely to transplant recipients with advanced cancer, as the T cells activated by checkpoint inhibitors may become reactive not only toward tumor antigens but also toward donor alloantigen, thereby resulting in allograft rejection. Here, immunotherapy with anti-PD-1/toll like receptor 9 agonist was administered to C57BL/6 mice bearing a cardiac allograft that were receiving maintenance immunosuppression or a PI4KIIIβ inhibitor-based tolerogenic regimen. Intratumoral (i.t.), but not systemic, immunotherapy promoted potent antitumor responses, but did not accelerate allograft rejection. This effect was associated with a pro-immunogenic effect induced by i.t. immunotherapy resulting in systemic cellular and humoral immune anti-tumor responses. Furthermore, when the tumor and cardiac allograft shared major histocompatibility complex (MHC) antigens, i.t. immunotherapy promoted immune responses directed against tumor and the cardiac allograft resulting in allograft rejection. The anti-tumor effect was compromised by maintenance immunosuppression with cyclosporin A, indicating that an optimal balance between enhanced anti-tumor immunity and decreased transplant immunoreactivity is critical. A clinically relevant approach could be to temporarily withdraw maintenance immunosuppression and/or replace it with a PI4KIIIβ inhibitor-based tolerance-inducing regimen to allow for effective immunotherapy to take place.

Chemo-immunoablation of solid tumors: A new concept in tumor ablation

“…Recently, there have been many clinical trials focusing on the clinical application of intratumoral immune checkpoint inhibitors with encouraging preliminary results, including the phase I clinical trial of cemiplimab, an intratumoral anti-PD-1 agent (NCT03889912), and the phase I clinical trial of Nivolumab, an intratumoral anti-PD-1 agent (NCT03316274), Phase II and Phase III clinical trials of the intratumoral anti-PD-1 drug ipilimumab or Nivolumab in combination with the anti-CTLA-4 drug Ipilimumab (NCT04090775, NCT03755739), anti-CD40 inhibitor Selicrelumab in combination with the anti-PD-L1 inhibitor Atezolizumab (NCT03892525) and other ( 56 ). For patients with allogeneic transplants, intratumoral anti-PD-1 treatment combined with TLR9 agonist can ensure a strong anti-tumor immune response while avoiding severe transplant rejection caused by systemic immunotherapy, reflecting the unique effectiveness and safety of intratumoral injection ( 57 ). In contrast, the immunosuppressive TME may be responsible for the low systemic immune response and immune checkpoint inhibitor therapy failure.…”

Chemotherapy, targeted therapy and immunotherapy: Which drugs can be safely used in the solid organ transplant recipients?

“…Dang et al . [ 106 ] showed that intratumor, but not systemic, immunotherapy with anti‐PD‐1/toll like receptor 9 agonist promoted potent antitumor responses but did not accelerate allograft rejection in mice recipients of heart allografts with cancer, provided that the tumor and cardiac allograft shared major histocompatibility complex (MHC). However, the antitumor effect was compromised by maintenance immunosuppression with CyA, highlighting the importance of finding an optimal balance between antitumor and antigraft immunity.…”