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In order to take advantage by both the anticancer effects and reconstruction of antitumor immunity, we compared the feasibility of a combination of CTL transfer and chemotherapy (ChT) for patients (pts) with malignant ascites due to carcinomatous peritonealitis of refractory gastric cancer to that of ChT only and/or cellular immunotherapy after failing ChT. A total of 22 pts, 8 underwent only conventional ChT (Group A), 6 performed cellular IT after failing ChT (Group B) and 8 underwent combination therapy (Group C), were enrolled in this retrospective study. ChT was based on conventional conditioning regimen with a standard dose for gastric cancer cases: S-1 (80-120 mg/body) plus paclitaxel (60-80 mg/m2), or CPT-11 (70-80 mg/m2) plus CDDP (80 mg/m2). Autologous tumor cells stimulated with T lymphocytes (AuTL), a kind of CTL, were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells separating from the ascites. IT was performed for pts of Group B and C. AuTLs were administered twice prior to ChT for pts of Group C, and were injected 1 x /2 weeks directly into the peritoneal cavity. The treatment was repeated at least three cycles with one-week interval. The mean survival period of Group A, B and C was 8.4, 5.2 and 11.3 months, respectively, and 1 pt in Group A and 3 pts in Group C survived over one year. Adverse events related to both of the ChT and AuTL transfer at all doses were minimal. Ascites had decreased or disappeared in 8 pts in this study. Lymphocytes of ascites were evaluated for cytokine production and subset of CD4+CD25+ T cell before the treatment, and after 3 treatments. The group C pts had increased IFN-gamma and IL-12 production with no TGF-beta1 responses by their ascites after 3 treatments. In contrast, the group A and B had no IFN-gamma, IL-12 or TGF-beta1 responses. These data show that combination therapy of CTL transfer and ChT is a feasible option for patients with refractory peritoneal carcinomatous of gastric cancer without serious adverse events. Although it depends on each mechanism of IT and ChT, a more stringent evaluation of CTL transfer combined with ChT for refractory gastric cancer should be performed.

Purpose: We report two patients with refractory recurrent breast cancer (HER2/neu: +) postoperatively, who had failed response to the available conventional chemotherapy of CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and docetaxel, etc. They markedly responded to the combination immunotherapy using intraperitumoral injections of autologous tumor cell-stimulated T lymphocyte (AuTL) and trastuzumab (Herceptin), an anti-HER2 monoclonal antibody., Methods: AuTLs were administrated directly into the recurrent tumor by intraperitumoral injections biweekly and trastuzumab was infused systemically every week. The treatments were repeated for 6 and 11 injections in the patients, respectively. The total administered T cells had reached to 3.8 x 10(9) and 6.4 x 10(9), respectively. The dosage of trastuzumab was 2 mg/kg in each patient., Results: The carcinomatous pleural effusion had disappeared and was well controlled in patient 1 and a marked regression in injected fields in comparison to the size of the recurrent tumor before treatment was observed in patient 2. The tumor marker proteins (CEA, CA15-3, TPA) had also decreased significantly. The adverse effects of the immunotherapy were tolerable with grades 1-2 infusion reaction of fever, tachycardia and hypotension, but no cardiac dysfunction was observed., Conclusions: Clinical responses of recurrent breast cancer were observed in two patients after receiving the intra-peritumoral AuTL injection plus trastuzumab immunotherapy. These results showed that refractory recurrent breast cancer may be controlled effectively and safely by repeating the cellular immunotherapy combined with trastuzumab and suggested utility of combining these agents in clinical trial.

Purpose: To date, no treatment has had a significant impact on pancreatic cancer with liver metastasis. We performed locoregional cellular immunochemotherapy for unresectable pancreatic cancer with liver metastasis., Subjects and Methods: A 71-year-old man was diagnosed for unresectable stage IVb pancreatic cancer. This patient was given intra-arterial infusion of gemcitabine (GEM) 400 mg/body and intravenous infusion GEM 600 mg/body, simultaneously. The day after GEM infusion, he was given intra-arterial autologous tumor cell activated T lymphocytes (AuTL)., Results: Tumor markers, such as CEA and CA19-9, had decreased a little. Primary tumor and metastatic liver tumor were reduced, but he died due to intra-abdominal dissemination within 5 months after diagnosis of unresectable pancreatic cancer., Conclusions: Reduced primary pancreatic tumor and metastatic liver tumor was obtained by locoregional cellular immunochemotherapy. But we could not control intra-abdominal dissemination. In conclusion, we suggest that intra-abdominal AuLT infusion in combination with intra-arterial AuLT infusion may be advisable to patients for unresectable pancreatic carcinoma with intra-abdominal dissemination.

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.

A pilot study has been conducted since January 2002 to investigate whether chemotherapy with docetaxel, 5-FU, CDDP could be an effective regimen for recurrent esophageal cancer. Ten patients with recurrent esophageal cancer were treated with the combination of docetaxel 60 mg/m2 (day 1), CDDP 10 mg/body (days 1-5) and 5-FU 500 mg/body (days 1-5) at intervals of 2-3 weeks. All patients had undergone surgery, had a recurrent tumor and had already been treated with chemo-radiotherapy or chemotherapy with CDDP + 5-FU. Response evaluation in 10 patients with measurable disease: partial response 4 patients, stable disease 2 patients and progressive disease 4 patients. The main NCI-CT grade 3/4 toxicity was leukopenia (8/10). Mild to moderate nausea (> or = grade 2) occurred in 3/10 patients.

Objectives: Autologous tumor-cell stimulated cytotoxic T lymphocytes (AuTLs) were prepared from peripheral blood T cells and the T cells were activated ex vivo over a 2-week culturing process in the presence of IL-2 and autologous biopsied tumor-cells from advanced cancer patients. These AuTLs may have potential for efficacy as a locoregional therapy in patients with refractory cancer., Methods: Twenty-nine of 35 cancer patients (13 esophagus, 5 lung, 3 stomach, 4 breast, 1 melanoma) were enrolled in an early Phase II clinical trial. The patients received direct locoregional intratumoral injection of AuTLs biweekly through medical endoscope or intraarterial infusion reservoir system. Mean 0.25 x 10(9) AuTLs were injected 1 x /2 weeks for 6 weeks., Results: Adverse events related to AuTL were minimal. AuTLs specific for autologous tumor cells were observed in 12 of 29 patients. Seven of these 12 patients (58.3%) had partial response (PR) or stable disease (SD). In contrast, 8 of 23 (34.8%) remaining patients treated by non-specific AuTLs had SD. Infiltration of T effector cells was significantly increased on the biopsied tumor specimens in the immunohistological studies. Furthermore, 11 patients receiving systemic infusion of non-specific LAK/NK T cells without autologous tumor-cell stimulation only had 2 SDs (18.2%)., Conclusions: Our results demonstrated the clinical potential of intra-peritumoral administration of AuTLs. Thus, locoregional immunotherapy with autologous tumor specific AuTLs may be more effective than systemic adoptive immunotherapy using intravenous infusion of autologous tumor non-specific LAK/NK T cells for the treatment of solid cancers.

Since mucosal (T1a) esophageal cancer is well controlled by endoscopic treatment, chemoradiotherapy (CRTx) is not indicated. However, for a submucosal (T1b, N0) esophageal cancer, CRTx may be the first line of treatment, since it can provide a good response rate, with an excellent survival rate comparable to that after esophagectomy. Definitive CRTx is also in the first line of treatment for a T4 esophageal cancer, because there was no difference in the survival rate between CRTx with surgery and CRTx without surgery in our trial. Esophagectomy is indicated only for non-responders or recurrence-salvage surgery. For patients with a potentially-resectable (T2-T3) esophageal cancer, esophagectomy offered a longer survival rate than CRTx did, in our series. However, there remains controversy over the efficacy of CRTx for a T2-T3 esophageal cancer. It has been reported by the National Cancer Center Hospital East Group that definitive CRTx provided the same survival rate as esophagectomy. A prospective trial comparing the survival rate after esophagectomy and that after CRTx for a T2-T3 esophageal cancer is needed.

Recent progress in gene technology has clarified the existence of some cancer-rejection genes and peptides such as MAGE, MART, etc. Many clinical trials with cancer vaccines have been performed. Since the clinical efficacy of HLA class I-restricted peptide vaccines is still poor, many researchers are mainly administering dendritic cell therapies. However, there have been few clinicals trials of cancer-specific immunotherapy for esophageal carcinomas. We have performed cancer vaccine therapy with SART-1 peptide and locoregional adoptive immunotherapy with activated autologous lymphocytes for patients with advanced esophageal carcinoma in a phase I and a phase I/II trial, respectively. The clinical responses were poor in the vaccine trial because of the rapid growth of esophageal cancers and the requirement for more than 2 months to activate and increase killer T cells after in vivo vaccination, while locoregional adoptive immunotherapy was effective for the treatment of esophageal cancers even in advanced stages with organ metastases. Based on these results, we think that a combination immunotherapy with adoptive immunotherapy and vaccine therapy is needed for the treatment of advanced esophageal carcinomas.