To overcome the immunosuppressive microenvironment of tumors, toll-like receptor agonists (TLRas) have emerged as a novel class of adjuvants that may enhance anti-tumor T cell responses. Many experimental cancer vaccines are exploring CpG, a DNA motif that agonizes toll-like receptor 9 (TLR9). Because TLR9 is located intracellularly, CpG must be internalized to trigger immune responses. Here, we electrostatically assembled rapidly degradable cationic poly(β-amino esters) (PBAEs) with anionic CpG (Fig. 1a). These polyplexes improve delivery of CpG to activate stronger immune responses. Polyplexes formed over a range of PBAE:CpG ratios displayed increasingly positive charge and stronger binding as PBAE:CpG ratio increased (Fig. 1b). Surprisingly, although higher PBAE:CpG ratios exhibited improved CpG uptake (Fig. 1c), lower ratios—which condensed CpG more weakly— activated tumor specific T cells more effectively (Fig 1d). In mechanistic studies, reduced T cell proliferation correlated with reduced TLR9 signaling, suggesting that decreased polyplex interaction strength improves CpG accessibility to TLRs (Fig. 1e). In line with these results, during a mouse melanoma model, polyplexes with lower binding affinities improved survival compared to polyplexes exhibiting stronger CpG interactions (Fig. 1f). Thus, physiochemical properties, particularly the interplay between charge, uptake, and affinity, play an important role in determining the nature and efficacy of the immune response generated and remain a key consideration in engineering effective immunotherapies.

Polyplex interaction strength impacts potency during cancer immunotherapy

2019 Spring National Meeting

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