NRP-1 and PD-1 Antibody Combinations for CD8+ T-Cell Resistance
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Solution Overview
Problem
Existing cancer treatments using PD-1 inhibitors fail to effectively enhance CD8+ T cell-dependent immune responses in some patients, necessitating the identification of new therapeutic mechanisms to overcome resistance.
Innovation Solution
Targeting Neuropilin-1 (NRP-1) on CD8+ T cells through deletion or inhibition, combined with anti-PD1 inhibitors, to induce a synergistic anti-tumoral effect.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1 inhibitors are used to treat cancer, then immune response is activated, but response fails in some patients due to resistance mechanisms
Solution Approach 1:
The patent introduces NRP-1 as an intermediary molecule that mediates the resistance mechanism between PD-1 inhibitors and tumor cells. By targeting NRP-1 on CD8+ T cells, the invention creates a new interaction pathway that overcomes the resistance barrier without interfering with the primary PD-1/PD-L1 checkpoint mechanism.
Solution Approach 2:
The invention segments the immune response enhancement into two independent components: PD-1 inhibition (existing mechanism) and NRP-1 deletion/inhibition (new mechanism). This segmentation allows each component to function independently, with NRP-1 deletion specifically addressing the resistance issue while PD-1 inhibition maintains the primary anti-tumoral activity.
2Reliability
If NRP-1 is deleted or inhibited on CD8+ T cells, then anti-tumoral response is enhanced, but mechanism of action is new and requires validation
Solution Approach 1:
The patent applies parameter changes by modifying the functional state of NRP-1 on CD8+ T cells through deletion or inhibition. This changes the biological parameter of T cell activation and anti-tumoral capability, transforming NRP-1 from a resistance mediator to an enhanced activation target.
Solution Approach 2:
The invention merges two approaches: existing PD-1 inhibition therapy with new NRP-1 deletion or inhibition strategy. This combination creates a synergistic effect where both mechanisms work together to enhance anti-tumoral response, combining proven therapy with innovative targeting.
Data Source
AI summary
Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by unleashing exhausted CD8+ T-cell thereby restoring anti-tumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Here, the inventors show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T-cells, interacts and enhances PD-1 activity. In mice, CD8+ T-cell specific deletion of Nrp1 improves spontaneous and anti PD1 antibody anti-tumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T-cells predicts poor outcome of patients treated with anti-PD1 (e.g. pembrolizumab). Finally, the combination of anti-NRP1 and anti-PD1 antibodies is synergistic in human, specifically in CD8+ T-cells anti-tumor response. Thus the therapeutic inhibition of NRP1 alone or combined with an immune checkpoint inhibitor (e.g. anti-PD1 antibody) could efficiently repress tumor growth in human cancer. The present invention also relates to multispecific antibodies comprising at least one binding site that specifically binds to an immune checkpoint molecule (e.g. PD-1), and at least one binding site that specifically binds to NRP-1. The present invention also relates to a population of cells engineered to express a chimeric antigen receptor (CAR) and wherein the expression of NRP-1 in said cells is repressed.