Abstract
Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (μg/μg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4–5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step.
Highlights
Peptide cancer vaccines have been evaluated in previous studies, but they have far exhibited limited efficacy against advanced cancers
In the higher MIS416 dose group (500–600 μg), the frequency of vascular disorders was 83.3%; these included diastolic hypertension in 50.0%, hypertension in 50.0%, and systolic hypertension in 66.7% of the patients. These results indicate that MIS416 may cause vascular adverse events (AEs)
In line with the results of a previous study [25], we found that the antibody response was stronger in patients who received Cholesteryl pullulan (CHP)-New York esophageal squamous cell carcinoma 1 (NYESO-1) 200 μg than in those who received CHP-NY-ESO-1 100 μg (Table 3)
Summary
Peptide cancer vaccines have been evaluated in previous studies, but they have far exhibited limited efficacy against advanced cancers. TLR stimulants, such as OK-432, CpG or poly-ICLC, have been evaluated in conjunction with the New York esophageal squamous cell carcinoma 1 (NYESO-1) antigen-related cancer vaccine in clinical studies [2,3,4,5,6,7,8]. Muraoka et al [9] reported that immunization with a peptide vaccine without an adjuvant increased apoptosis in vaccine-induced CD8+ T cells; in contrast, immunization with a peptide vaccine with a TLR9 stimulant reduced apoptosis in vaccine-induced CD8+ T cells and induced a significant anti-tumor effect in a mouse model. The stimulation of multiple innate immunity signaling pathways may greatly improve the efficacy of cancer vaccines over that achieved by TLR9 signaling alone
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