Combined immunotherapy with anti-PDL-1/PD-1 and anti-CD4 antibodies cures syngeneic disseminated neuroblastoma
Valentina Rigo1, Laura Emionite2, Antonio Daga1
1Dipartimento di terapie oncologiche integrate, IRCCS A.O.U. San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132, Genova, Italy.
Abstract:
Anti-PD-1 or anti-PD-L1 blocking monoclonal antibodies (mAbs) have shown potent anti-tumor effects in adult cancer patients and clinical studies have recently been started in pediatric cancers, including high-risk/relapsing neuroblastoma (NB). Therefore, we studied the effects of anti-PD-1/PD-L1 mAbs in two syngeneic models of disseminated NB generated by the injection of either Neuro2a or NXS2 cells, which express PD-L1. In addition, we tested the combination of these agents with the immune-enhancing cytokine IL-21, the Ecto-NTPDase inhibitor POM-1, an anti-CD25 mAb targeting Treg cells, or an anti-CD4 mAb. We previously showed that CD4-transient depletion removes CD4+CD25+ Treg cells and other CD4+CD25- regulatory subsets. Here we show that mono-therapy with anti-PD-1/PD-L1 mAbs had no effect on systemic NB progression in vivo, and also their combination with IL-21, POM-1 or anti-CD25 mAb was ineffective. The combined use of anti-PD-1 with an anti-CD4 mAb mediated a very potent, CD8-dependent, synergistic effect leading to significant elongation of tumor-free survival of mice, complete tumor regression and durable anti-NB immunity. Similar results were obtained by combining the anti-PD-L1 and anti-CD4 mAbs. These findings indicate that both PD-1/PD-L1 and CD4+ T cell-related immune-regulatory mechanisms must be simultaneously blocked to mediate therapeutic effects in these models.
Insights
Combination therapy blocking both PD-1/PD-L1 and CD4+ T cells shows potent anti-tumor effects in neuroblastoma models. This approach leads to significant tumor regression and durable immunity, unlike single-agent treatments.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies are effective against adult cancers.
- Their efficacy in pediatric cancers, such as neuroblastoma (NB), is under investigation.
- Neuroblastoma models expressing PD-L1 were used to study therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of anti-PD-1/PD-L1 monoclonal antibodies (mAbs) in preclinical neuroblastoma models.
- To investigate the synergistic potential of combining anti-PD-1/PD-L1 mAbs with IL-21, POM-1, anti-CD25 mAb, or anti-CD4 mAb.
- To determine the necessity of simultaneously blocking PD-1/PD-L1 and CD4+ T cell pathways for therapeutic effect.
Main Methods:
- Utilized two syngeneic mouse models of disseminated neuroblastoma (Neuro2a and NXS2 cells).
- Administered anti-PD-1/PD-L1 mAbs as monotherapy and in combination with IL-21, POM-1, anti-CD25 mAb, or anti-CD4 mAb.
- Assessed tumor progression, survival rates, and immune response, including CD8-dependent mechanisms.
Main Results:
- Monotherapy with anti-PD-1/PD-L1 mAbs showed no significant effect on systemic neuroblastoma progression.
- Combinations of anti-PD-1/PD-L1 mAbs with IL-21, POM-1, or anti-CD25 mAb were also ineffective.
- Combined blockade of PD-1/PD-L1 and CD4+ T cells (using anti-CD4 mAb) resulted in potent, CD8-dependent synergistic anti-tumor effects, including complete regression and durable immunity.
Conclusions:
- Simultaneous blockade of PD-1/PD-L1 and CD4+ T cell-mediated immune regulation is crucial for therapeutic efficacy in these neuroblastoma models.
- The combination of anti-PD-1/PD-L1 and anti-CD4 mAbs offers a promising strategy for treating neuroblastoma.
- Further research into dual immune checkpoint and regulatory T cell targeting is warranted for pediatric cancers.
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