Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients

Shinichi Kageyama, Hisashi Wada, Kei Muro, Yasumasa Niwa, Shugo Ueda, Hiroshi Miyata, Shuji Takiguchi, Sahoko H Sugino, Yoshihiro Miyahara, Hiroaki Ikeda, Naoko Imai, Eiichi Sato, Tomomi Yamada, Masaharu Osako, Mami Ohnishi, Naozumi Harada, Tadashi Hishida, Yuichiro Doki, Hiroshi Shiku, Shinichi Kageyama, Hisashi Wada, Kei Muro, Yasumasa Niwa, Shugo Ueda, Hiroshi Miyata, Shuji Takiguchi, Sahoko H Sugino, Yoshihiro Miyahara, Hiroaki Ikeda, Naoko Imai, Eiichi Sato, Tomomi Yamada, Masaharu Osako, Mami Ohnishi, Naozumi Harada, Tadashi Hishida, Yuichiro Doki, Hiroshi Shiku

Abstract

Background: Cholesteryl pullulan (CHP) is a novel antigen delivery system for cancer vaccines. This study evaluated the safety, immune responses and clinical outcomes of patients who received the CHP-NY-ESO-1 complex vaccine, Drug code: IMF-001.

Methods: Patients with advanced/metastatic esophageal cancer were enrolled and subcutaneously vaccinated with either 100 μg or 200 μg of NY-ESO-1 protein complexed with CHP. The primary endpoints were safety and humoral immune responses, and the secondary endpoint was clinical efficacy.

Results: A total of 25 patients were enrolled. Thirteen and twelve patients were repeatedly vaccinated with 100 μg or 200 μg of CHP-NY-ESO-1 with a median of 8 or 9.5 doses, respectively. No serious adverse events related to the vaccine were observed. Three out of 13 patients in the 100-μg cohort and 7 out of 12 patients in the 200-μg cohort were positive for anti-NY-ESO-1 antibodies at baseline. In the 100-μg cohort, an antibody response was observed in 5 out of 10 pre-antibody-negatives patients, and the antibody levels were augmented in 2 pre-antibody-positive patients after vaccination. In the 200-μg cohort, all 5 pre-antibody-negative patients became seropositive, and the antibody level was amplified in all 7 pre-antibody-positive patients. No tumor shrinkage was observed. The patients who received 200 μg of CHP-NY-ESO-1 survived longer than patients receiving 100 μg of CHP-NY-ESO-1, even those who exhibited unresponsiveness to previous therapies or had higher tumor burdens.

Conclusions: The safety and immunogenicity of CHP-NY-ESO-1 vaccine were confirmed. The 200 μg dose more efficiently induced immune responses and suggested better survival benefits. (Clinical trial registration number NCT01003808).

Figures

Figure 1
Figure 1
Antibody responses to recombinant NY-ESO-1 protein as determined by ELISA. Sera from 13 patients in Cohort 1 (100-μg dose) and 12 patients in Cohort 2 (200-μg dose) were collected at each vaccination, and serially diluted by 400, 1,600, 6,400, 25,600 and 102,400. Reciprocal titers were determined based on the maximally diluted sera, which showed a higher OD (optical density of 450–500) value than the cut-off level for NY-ESO-1 antibody positivity.
Figure 2
Figure 2
Kaplan-Meier survival curves of patients who were alive after the CHP-NY-ESO-1 vaccinations. A: Progression-free survival (PFS) of patients assigned to Cohort 1 (100-μg dose, n = 13) or Cohort 2 (200-μg dose, n = 12). The probability of PFS of the patients who received 200 μg of the vaccine and those who received the 100-μg dose were similar (log-rank test, p = 0.748). B: Overall survival (OS) of patients assigned to Cohort 1 or Cohort 2. The patients who received 200 μg of the vaccine survived longer than those who received the 100-μg dose. (log-rank test, p = 0.050). C: OS of patients vaccinated with either 100 μg or 200 μg of CHP-NY-ESO-1 compared between patients who responded to previous therapies and those who never responded. The patients who responded to previous therapies and were vaccinated with CHP-NY-ESO-1 survived longer than non-responders. (log-rank test, p = 0.0050). D: OS of patients vaccinated with 100 μg or 200 μg of CHP-NY-ESO-1 who never responded to previous therapies. The patients who received 200 μg of the vaccine survived longer than those who received the 100-μg dose (log-rank test, p = 0.029). E: OS of patients vaccinated with 100 μg or 200 μg of CHP-NY-ESO-1 compared with either baseline tumor burdens of >30 mm (sum of the tumor diameters) or 30 mm or less including non-measurable lesions. The patients with a tumor burden higher than 30 mm had reduced survival compared to those with smaller burdens (log-rank test, p = 0.021). F: OS of patients who received 100 μg or 200 μg of CHP-NY-ESO-1 who had baseline tumor burdens greater than 30 mm. The patients who received 200 μg of the vaccine survived longer than those who received the 100-μg dose (log-rank test, p = 0.037).

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