1671P - Phase I clinical trial of cancer vaccine combined with chemotherapy targeting both tumor antigen and immune tolerance against advanced solid tumors

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Drug Development
Cancer Immunology and Immunotherapy
Presenter Mutsunori Murahashi
Authors M. Murahashi1, Y. Hijikata1, Y. Tanaka2, H. Inoue2, T. Marumoto2, Y. Nakanishi3, K. Yoshida4, T. Tsunoda4, Y. Nakamura5, K. Tani2
  • 1Department Of Advanced Cell And Molecular Therapy, Kyushu University Hospital, 812-8582 - Fukuoka/JP
  • 2Medical Institute Of Bioregulation, Kyushu University, Fukuoka/JP
  • 3Research Institute For Diseases Of The Chest, Kyushu University Hospital, JP-812-8582 - Fukuoka/JP
  • 4Cancer Immunology, OncoTherapy Science, Inc., Tokyo/JP
  • 5Institute Of Medical Science, University of Tokyo, Tokyo/JP

Abstract

Background

Antitumor immunotherapy to target tumor antigens and evade immune tolerance is considered reasonable and promising. However, no combined immunotherapy has been established. We designed a phase I trial of cancer vaccine combined with chemotherapy to investigate safety as the primary endpoint, and immune responses and clinical benefits as secondary endpoints.

Methods

Patients positive for HLA-A2402 who showed locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer were evaluated in a phase I clinical trial of cancer vaccine and chemotherapy. Cyclophosphamide (CPM) was administered 4 days before vaccination to eliminate regulatory T cells (Treg). 18 patients were treated in cohorts of six patients, each with escalating CPM dose (150, 300 and 600 mg/m2). Five HLA-A2402-restricted tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1, and MPHOSPH1 were injected once a week for 4 weeks. Patients without gastrointestinal bleeding, pleural effusion or ascites also received low dose IL-2 every after vaccination.

Results

The treatment was tolerated well without any associated adverse events above grade 3. The study included primary disease with 9 cases of colorectal cancer, 3 cholangiocellular carcinoma, 3 lung cancer, and one each of esophageal, gastric and cervical cancer. Nine of 13 patients (69%) assessed by Elispot assay showed cytotoxic T lymphocytes (CTL) specific for TAA to more than one of five antigens after vaccination. Log-rank test among these demonstrated that CTL responses induced by vaccine contributed significantly to overall survival (MST: 9.2 vs 3.9 months, P = 0.003). In addition, a significantly broader antigenic repertoire was found in longer survivors (p = 0.033). Treg number dropped from baseline with dose just after CPM administration. This seems to reflect direct inhibition of CPM on Treg. Interestingly, reduced Treg correlated significantly with longer overall survival (P = 0.024), suggesting CPM augmented, vaccine-induced CTL responses through Treg reduction.

Conclusion

This phase I clinical study demonstrated promising survival associated with Treg inhibition, as well as CTL responses that warrants further clinical studies.

Disclosure

K. Yoshida: I am a research staff of the company, OncoTherapy Science Inc. providing the peptide vaccines used in this study.

T. Tsunoda: I am the President and CEO of the company, OncoTherapy Science, Inc. providing the peptide vaccines used in this study.

Y. Nakamura: I am one of the major stock holders of the company, OncoTherapy Science, Inc.

K. Tani: Our department obtained the partial research funding in 2007 from the comapany, OncoTherapy Science, Inc.

All other authors have declared no conflicts of interest.