title: [The repetitive immune cell transfer therapy combining non-myelosuppressive chemotherapy for patients with advanced and refractory cancer].
abstract: Autologous tumor cells stimulated with T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell lines and may have a potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on the conventional conditioning regimen in order to take advantage by both the anticancer effects and reconstruction of antitumor immunity. Nineteen patients were enrolled in a pilot clinical trial. The two administrations of AuTL were given prior to chemotherapy (ChT) for one treatment cycle. The treatment was repeated at least for three cycles over a one-week interval. The conventional ChT regimen was based on the standard dosage. The pts consisted of 3 of gastric cancer, colon cancer, lung adenocarcinoma, respectively, 6 of esophageal cancer, and 2 of breast and pancreas carcinoma, respectively. AuTLs were administered 1x/2 weeks using direct injection or intraarterial infusion. The median duration of the treatment was over 11.5 months, and the median survival time was 14.8 months. Adverse events related to both the ChT and AuTL transfers at all dosages were minimal. Four of the 13 pts achieved major tumor responses (2 CR: complete regression and 2 PR: partial regression) in this study. Three pts showed progressive disease, and 6 pts had stable disease for over 90 days. PBMC were evaluated for cytokine production prior to the treatment and after 3 treatments. Two and one of 4 CR/PR pts had increased IFN-gamma and TNF-alpha production with no TGF-beta1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after the treatment had high IFN-gamma and TNF-alpha responses and no TGF-beta1 or IL-4 response. TGF-beta1 and IL-4 secretion increased in parallel in 3 out of 3 pts that experienced progressive disease after the treatment. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without serious adverse events and without reducing Th1 cytokine responses in peripheral blood for most of the pts that responded to the treatment. According to each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with non-myeloablative ChT for various kinds of cancers should be performed to manage the immunodeficiency in the pts with advanced cancer and to improve the effect of antitumor AuTLs.
authors.affiliation: Dept of Surgery, Kurume University School of Medicine.
authors.forename: Uhi
authors.initials: U
authors.lastname: Toh
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Fujii
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yanaga
authors.forename: Goro
authors.initials: G
authors.lastname: Yokoyama
authors.forename: Miki
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Teruo
authors.initials: T
authors.lastname: Sasatomi
authors.forename: Shinzo
authors.initials: S
authors.lastname: Takamori
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shirouzu
authors.forename: Naoko
authors.initials: N
authors.lastname: Seki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yamana
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines