Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine. Instead, the nicotine hapten and protein are separately located in the nanostructure to minimize antibody production towards KLH. The cellular uptake study demonstrated that NanoNiccine was ideal for internalization and processing by dendritic cells (DCs). Mice immunized with NanoNiccine produced much lower IgG level against KLH as compared to that immunized with the traditional nicotine-KLH (Nic-KLH) vaccine. In addition, NanoNiccine achieved up to a 400% higher titer of anti-nicotine IgG than the positive control, Nic-KLH. Additionally, the Th1/Th2 index of NanoNiccine suggested that the immune response induced by NanoNiccine was antibody response dominant. Furthermore, NanoNiccine was found to be safe in mice.

Traditional hapten-protein conjugate nicotine vaccines have shown less than desired immunological efficacy due to their poor recognition and internalization by immune cells. We developed a novel lipid-polymeric hybrid nanoparticle-based nicotine vaccine to enhance the immunogenicity of the conjugate vaccine, and studied the influence of particle size on its immunogenicity and pharmacokinetic efficacy. The results demonstrated that the nanovaccines, regardless of size, could induce a significantly stronger immune response against nicotine compared to the conjugate vaccine. Particularly, a significantly higher anti-nicotine antibody titer was achieved by the 100 compared to the 500 nm nanovaccine. In addition, both the 100 and 500 nm nanovaccines reduced the distribution of nicotine into the brain significantly. The 100 nm nanovaccine exhibited better pharmacokinetic efficacy than the 500 nm nanovaccine in the presence of alum adjuvant. These results suggest that a lipid-polymeric nanoparticle-based nicotine vaccine is a promising candidate to treat nicotine dependence.

Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long- term storage. However, stabilized hybrid structures of high cholesterol content tended to fuse with each other during storage, resulting in significant size increase and lowered cellular uptake. Additional experiments demonstrated that PEGylation of NPs could effectively minimize fusion-caused size increase after long term storage, leading to improved cellular uptake, although excessive PEGylation will not be beneficial and led to reduced improvement.

BackgroundThis study compared response rates and outcomes of combined radiotherapy and immunotherapy (iRT) based on the type of checkpoint inhibitor (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) vs antiprogrammed death-1 (PD1)) for metastatic non-small cell lung cancer (mNSCLC).MethodsWe retrospectively reviewed two prospective trials of radiation combined with anti-CTLA4 or anti-PD1 for patients with mNSCLC. Patients undergoing non-salvage stereotactic body radiation therapy (SBRT) to lung sites were selected from both trials and grouped by the immunotherapeutic compound received. Endpoints included in-field and out-of-field response rates, and overall response rate (complete or partial response) (all by response evaluation criteria in solid tumors). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.ResultsMedian follow-up times for the 33 patients (n=17 SBRT+anti-CTLA4, n=16 SBRT+anti-PD1) were 19.6 and 19.9 months. Response rates for out-of-field lesions were similar between anti-PD1 (37%) and anti-CTLA4 (24%) (p=0.054). However, global response rates for all lesions were 24% anti-CTLA4 vs 56% anti-PD1 (p=0.194). The PFS was 76% for anti-CTLA4 vs 94% anti-PD1 at 3 months, 52% vs 87% at 6 months, 31% vs 80% at 12 months, and 23% vs 63% at 18 months (p=0.02). Respective OS values were 76% vs 87% at 6 months, 47% vs 80% at 12 months, and 39% vs 66% at 18 months (p=0.08).ConclusionsBoth anti-CTLA4 and anti-PD1 agents prompt a similar degree of in-field and out-of-field responses after iRT, although the global response rate and PFS were statistically higher in the anti-PD1 cohort. Further dedicated study and biological mechanistic assessment is required.Trial registration numbersNCT02239900andNCT02444741.

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