CpG ODN (K3)-toll-like receptor 9 agonist-induces Th1-type immune response and enhances cytotoxic activity in advanced lung cancer patients: a phase I study.

Tomoyuki Otsuka, Sumiyuki Nishida, Takayuki Shibahara, Burcu Temizoz, Masanari Hamaguchi, Takayuki Shiroyama, Keiko Kimura, Kotaro Miyake, Haruhiko Hirata, Yumiko Mizuno, Mayu Yagita, Yusuke Manabe, Etsushi Kuroda, Yoshito Takeda, Hiroshi Kida, Ken J Ishii, Atsushi Kumanogoh

Journal: BMC cancer 2022;22(1):744

PMID: 35799134

Free Full Text on BioMed Central View on PubMed

Abstract

BACKGROUND

Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients' immune responses.

METHODS

The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29.

RESULTS

Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46-181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8 T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p = 0.0039) CD8 T cells significantly increased. The median PFS was 398 days.

CONCLUSIONS

This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined.

TRIAL REGISTRATION

UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649.

Address: Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Department of Medical Oncology, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan.; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan. [email protected].; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.; Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.; Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-4, Shiraganedai, Minato-ku, Tokyo, 108-8639, Japan.; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Department of Medical Innovation, Osaka University Hospital, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.; Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.; Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan.; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.; Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan.

DOI: 10.1186/s12885-022-09818-4

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https://medlineplus.gov/lungcancer.html

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Research Materials:

https://antibodies.cancer.gov/detail/CPTC-CD8A-1

MeSH Terms: Adaptive Immunity, Adjuvants, Immunologic, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Carcinoma, Non-Small-Cell Lung, Cytosine, Guanine, Humans, Lung Neoplasms, Oligodeoxyribonucleotides, Phosphates, Toll-Like Receptor 9