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Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients

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Abstract

The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8+ and CD4+ T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (μg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.

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Data availability

To protect patient information in the clinical trial database, the datasets generated and/or analyzed in the present study are not publicly available, but they are available from the corresponding author on request.

Abbreviations

AE:

Adverse event

ALT:

Alanine aminotransferase

ANC:

Absolute neutrophil count

AST:

Aspartate aminotransferase

CHP:

Cholesteryl pullulan

CR:

Complete response

CTL:

Cytotoxic T lymphocyte

DLT:

Dose-limiting toxicity

ECOG:

Eastern cooperative oncology group

ELISA:

Enzyme-linked immunosorbent assay

GAPDH:

Gyceraldehyde-3-phosphate dehydrogenase

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

IFA:

Incomplete Freund's adjuvant

IFN:

Interferon

mAb:

Monoclonal antibody

MAGE:

Melanoma-associated gene

MDA-5:

Melanoma differentiation-associated gene-5

MHC:

Major histocompatibility complex

MTD:

Maximum tolerated dose

NYHA:

New York heart association

OS:

Overall survival

PCR:

Polymerase chain reaction

PD:

Progressive disease

PD-1:

Programmed cell death-1

Poly(I:C):

Polyinosinic:polycytidylic acid

PR:

Partial response

RECIST:

Response evaluation criteria in solid tumor

SD:

Stable disease

TLR-3:

Toll-like receptor-3

WBC:

White blood cell

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Acknowledgements

We thank Dr. Tadashi Hishida (former CEO of ImmunoFrontier, Inc.) for manufacturing CHP-NY-ESO-1, and Ms. Sahoko Sugino and Ms. Junko Nakamura (Mie University) for technical assistance with ELISA. We are also grateful to Ms. Saeko Tsuchiya (Kyoto Prefectural University of Medicine) for diligently overseeing the patients in this study.

Funding

This study was supported by JSPS KAKENHI Grant Number JP15K10093 and research funds of Kyoto Prefectural University of Medicine and Mie University.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Takeshi Ishikawa, Tetsuya Okayama, Satoshi Kokura & Yoshito Itoh

  2. Departments of Immuno-Gene Therapy and Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, Japan

    Shinichi Kageyama, Yoshihiro Miyahara, Linan Wang & Hiroshi Shiku

  3. Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan

    Eiichi Sato

  4. Department of Immunology, Juntendo University, Tokyo, Japan

    Hideo Yagita

Authors
  1. Takeshi Ishikawa
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Contributions

TI, SK (Mie), SK (Kyoto) and HS contributed to the design of the study. TI, TO, SK (Kyoto) and TI MI contributed to patient recruitment, treatment and clinical data collection. YM contributed to immune reaction data. LW and HY contributed to preclinical data collection and analysis. TI, SK (Mie), YM and HS interpreted the data. TI and SK (Mie) performed the statistical analyses. TI and SK (Mie) wrote the manuscript. All authors contributed to draft revisions and approved the final manuscript.

Corresponding authors

Correspondence to Takeshi Ishikawa or Shinichi Kageyama.

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Conflict of interest

CHP-NY-ESO-1 was supplied by ImmunoFrontier Inc. (Osaka, Japan). Hiroshi Shiku is a stockholder of ImmunoFrontier Inc. Shinichi Kageyama, Yoshihiro Miyahara, and Hiroshi Shiku received research funds from ImmunoFrontier Inc. The other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in our studies involving human participants were conducted in accordance with Japanese Ethical Guidelines for Clinical Research, Japanese Guidelines for Medical and Health Research Involving Human Subjects, and the Helsinki declaration. The Institutional Review Board reviewed and approved the protocol and the informed consent documents and their amendments before use (Kyoto Prefectural University of Medicine approval number RBMR-C-941–2). All animal experiments were conducted in accordance with the Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions and approved by Mie University (approval number 24–14).

Animal source

Female BALB/c mice aged 6–10 weeks were purchased from Japan SLC, Inc. (Shizuoka, Japan).

Cell line authentication

The CT26 cell line was purchased from the American Type Culture Collection (Virginia, USA). A human NY-ESO-1 transfected CT26 cell line was established as described previously [21].

Informed consent

Written informed consent to participate in the study and for the use of clinical data for research and publication was obtained from all patients included in the studies: Kyoto Prefectural University of Medicine approval number: RBMR-C-941–2.

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Ishikawa, T., Kageyama, S., Miyahara, Y. et al. Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients. Cancer Immunol Immunother 70, 3081–3091 (2021). https://doi.org/10.1007/s00262-021-02892-w

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