Phase I clinical trial of vaccination with LY6K-derived peptide in patients with advanced gastric cancer

Abstract

Background Lymphocyte antigen 6 complex locus K (LY6K) has been identified as a tumor-associated antigen in lung cancers and esophageal squamous cell carcinomas. The immunogenicity of LY6K-177 peptide vaccine therapy has been demonstrated in patients with advanced esophageal cancer. This study extends this treatment to gastric cancer. Methods LY6K expression in clinical samples obtained from gastric cancer patients was examined by immunochemistry. As a phase I clinical trial, the safety and immunogenicity of LY6K-177 peptide vaccine emulsified with Montanide ISA 51 was evaluated in six patients with unresectable advanced gastric cancer. LY6K-177 peptide (1 mg in 1 ml sterile saline) was emulsified with incomplete Freund's adjuvant (1 ml) and intracutaneously administered to the inguinal region or axilla. One treatment course comprised four vaccinations, performed weekly for the first and second treatment courses and biweekly for the third treatment course. Results LY6K expression was confirmed in 85 % of gastric cancer tissues. Induration and redness at the vaccination site (grade I), possibly a delayed-type hypersensitivity reaction, was observed in all patients; however, no systemic toxicology was identified in any patient throughout the observation period. Three of the six patients had stable disease, and a tumor contraction effect was observed in one patient.Conclusions LY6K was expressed in 85 % of observed gastric cancers. Vaccination with LY6K-177 peptide/ Montanide ISA 51 appeared to be tolerated by advanced gastric cancer patients, and moreover anticancer efficacy was suggested. This trial was registered with ClinicalTrial.gov (no. NCT00845611).

Peptide-Based Treatment: A Promising Cancer Therapy

“…Recently, clinical trials in patients with gastric cancer (GC) have been conducted using peptide-based vaccines, including vascular endothelial growth factor receptor 2- (VEGFR2-) 169, VEGFR1-1084, and lymphocyte antigen 6 complex locus K (LY6K-177) epitope peptides [ 30 , 31 ].…”

Trial Watch

“…These studies were performed on patients affected by a large panel of solid (but not hematological) neoplasms, including glioma, 40 lung carcinoma, 48 , 52 sarcoma, 59 , 62 melanoma, 41 , 50 , 61 esophageal squamous cell carcinoma, 51 gastric cancer, 55 hepatocellular carcinoma, 43 , 56 , 60 pancreatic cancer, 47 colorectal carcinoma, 42 , 45 , 53 metastatic renal cell carcinoma, 49 , 54 castration-resistant prostate cancer, 26 , 46 , 49 ovarian carcinoma, 58 gynecologic malignancies, 63 and various other tumors 44 , 57 . The TAAs specifically targeted in these clinical trials (most of which were Phase I studies) encompassed cancer-testis antigens such as NY-ESO-1, 46 , 48 , 50 , 58 , 78 TTK protein kinase (also known as MOS), 51 , 52 , 79 lymphocyte antigen 6 complex, locus K (LY6K, best known as URLC10), 51 , 52 , 55 , 80 , 81 insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, best known as IMP3), 51 , 82 , 83 ring finger protein 43 (RNF43), 45 , 53 , 84 - 86 and translocase of outer mitochondrial membrane 34 (TOMM34); 45 , 53 , 87 , 88 carcinoembryonic antigens like glypican-3; 43 , 56 , 60 , 89 , 90 differentiation antigens such as melan-A (MLANA) and premelanosome protein (PMEL, best known as gp100); 50 , 91 - 93 tumor-restricted TAAs, such as the SYT-SSX fusion (which is selectively expressed by synovial sarcomas as a result of a t(X;18)(p11;q11) chromosomal translocation); 62 , 94 , 95 as well as so-called “shared TAAs” (antigens that are overexpressed by malignant cells but also produced in normal amounts by one or several healthy tissues), including vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, 44 , …”

“…The TAAs specifically targeted in these clinical trials (most of which were Phase I studies) encompassed cancer-testis antigens such as NY-ESO-1, 46 , 48 , 50 , 58 , 78 TTK protein kinase (also known as MOS), 51 , 52 , 79 lymphocyte antigen 6 complex, locus K (LY6K, best known as URLC10), 51 , 52 , 55 , 80 , 81 insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, best known as IMP3), 51 , 82 , 83 ring finger protein 43 (RNF43), 45 , 53 , 84 - 86 and translocase of outer mitochondrial membrane 34 (TOMM34); 45 , 53 , 87 , 88 carcinoembryonic antigens like glypican-3; 43 , 56 , 60 , 89 , 90 differentiation antigens such as melan-A (MLANA) and premelanosome protein (PMEL, best known as gp100); 50 , 91 - 93 tumor-restricted TAAs, such as the SYT-SSX fusion (which is selectively expressed by synovial sarcomas as a result of a t(X;18)(p11;q11) chromosomal translocation); 62 , 94 , 95 as well as so-called “shared TAAs” (antigens that are overexpressed by malignant cells but also produced in normal amounts by one or several healthy tissues), including vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, 44 , 52 - 54 , 57 , 96 , 97 survivin, 47 , 50 , 61 , 98 , 99 Wilms tumor 1 (WT1), 63 , 100 , 101 telomerase reverse transcriptase (TERT), 49 , 102 and p53 42 , 103 , 104 . Thus, a relatively heterogeneous panel of approaches and indications has been explored during the last 13 mo to get further insights into the safety and clinical potential of peptide-based anticancer vaccines.…”

“…Moreover, the authors of most of these studies could document the ability of TAA-derived peptides to elicit an immune response, most often as (1) an increase in circulating TAA-specific CTLs, 42 , 43 , 45 - 54 , 56 - 58 , 61 , 94 (2) a surge in serum TAA-targeting antibodies, 42 , 58 (3) a delayed type hypersensitivity (DTH) reaction developing at the injection site; 55 , 62 , 63 , 94 (4) the infiltration of neoplastic lesions by CD4 + or CD8 + T lymphocytes, 40 , 60 or (5) the activation of transcriptional programs associated with CTL effector functions in peripheral blood mononuclear cells 44 . Often, but not always, 50 such an immune response to vaccination was associated with (at least some degree of) clinical benefit 40 , 47 , 51 - 54 , 56 , 61 .…”

Multimodal Anti-tumor Approaches Combined with Immunotherapy to Overcome Tumor Resistance in Esophageal and Gastric Cancer

“…Feasibility studies evaluated vaccination with tumor-specific antigens in gastric cancer patients (123,124). Vaccination was well-tolerated and showed an increase in antitumor immuno-response.…”