Adoptive cellular immunotherapy of cancer in mice using allogeneic T-cells

Background: Adoptive cellular immunotherapy with autologous tumor-infiltrating lymphocytes (TILs) can induce tumor regression in patients with metastatic melanoma but requires both surgical tumor harvest and successful expansion of lymphocytes in vitro. In cases in which tumors are inaccessible or TILs fail to grow, the adoptive transfer of allogeneic TILs, haplotype matched for the restriction element for a common tumor antigen, represents a possible treatment alternative. Such TILs show in vitro cross-reactivity for allogeneic tumors but have not been evaluated for in vivo activity. Methods: An F₁ hybrid mouse (C57BL/6 X DBA-2 [B6D2 F₁]) was used to generate TILs (F₁ TILs) expressing both H-2^b and H-2^d class I major histocompatibility complex (MHC) determinants, which were used to treat established autologous lung metastases in C57BL/6 (B6) parental strain mice. Results: H-2^b mice bearing the fully syngeneic MC-38 tumor were treated with F₁ TILs, and a 98–100% reduction in 4-day-old established lung metastasis was achieved. However, B6 mice bearing MC-38 tumors after preimmunization with H-2^d splenocytes did not show a response to F₁ TILs. Preimmunization of B6 mice by intravenous injection of H-2^d splenocytes at varying times before F₁ TIL administration showed a dramatic reduction in F₁ TIL efficacy when alloimmunization occurred as early as 2 days before therapy. Immunization against an unrelated haplotype (H-2^s) sharing no MHC genes with the F₁ TILs resulted in a smaller reduction of F₁ TIL efficacy, possibly due to shared minor determinants. Conclusion: Allogeneic TILs sharing an MHC restriction element for a common tumor antigen can be used to successfully treat established metastases in the nonallosensitized host. Presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, Houston, Texas, March 17–20, 1994.     

Adoptive immunotherapy using specific cytotoxic T lymphocytes against human lung-cancer-engrafted severe combined immunodeficiency mice.

OBJECTIVE: We studied the ability of human lung-cancer-specific cytotoxic T lymphocytes to suppress the growth of human lung adenocarcinoma (PC-9) engrafted in severe combined immunodeficiency mice. METHODS: PC-9-specific cytotoxic T lymphocytes were generated by multiple stimulation with irradiated PC-9 cells of regional lymph node lymphocytes from lung cancer patients expressing the same human leukocyte antigen-A locus haplotype as PC-9 following expansion due to the administration of immobilized anti cluster of differentiation 3 mAb and interleukin-2. Cytotoxic T lymphocytes showed specific cytotoxicity against PC-9 cells in vitro. Severe combined immunodeficiency mice with a subcutaneous graft of PC-9 were treated with a PC-9-specific cytotoxic T lymphocyte by i.v. injection and/or with interleukin-2 by s.c. injection. RESULTS: Cytotoxic T lymphocyte treatment suppressed PC-9 graft growth significantly an effect, significantly enhanced when combined with interleukin-2 injection. To evaluate the in vivo specificity of anti-PC-9 cytotoxic T lymphocytes, each mouse was subcutaneously inoculated in the right flank with PC-9, and in the left flank with A549 or Sq-1. Cytotoxic T lymphocytes plus interleukin-2 treatment was found to suppress PC-9 growth selectively, but not A549 or Sq-1 growth. CONCLUSIONS: These results provide sufficient rationale for conducting further clinical trials on immunotherapy using cytotoxic T lymphocyte for lung cancer patients.     

Adoptive immunotherapy of advanced cancer patients with immune RNA-sensitized lymphocytes

Tumor cell suspension was prepared from resected tumor tissue of various cancer patients. I-RNA was extracted from lymphoid tissues of rabbits immunized with each tumor cell and CFA. Autologous (in some cases, allogeneic) lymphocytes were prepared with blood cell separator and incubated with I-RNA, then, returned to himself. Twenty five cases of non-curatively resected gastric cancer (group A), 27 cases of stage II-IV of esophageal carcinoma (group B), 21 of lung cancer (group C), 14 of colorectal cancer (group D) and 37 cases with metastatic lesions (group E) were treated with this schedule. Five year cumulative survival rate was 21% in group A, 23% in group B, 46% in group C and 61% in group D, respectively. One case of CR and 5 of PR were recognized in group E. In many cases of the responder, lymphocyte count, ratio of Leu 4+, 3a+ subset in the peripheral bloods increased and skin reaction to autologous tumor cell extract, LAI and LMI became to positive. Interferon activity was also increased in the responder. It was reported on the preliminary study of combination treatment with I-RNA sensitized lymphocytes and IL-2.     

Adoptive immunotherapy using lymphokine-activated killer cells and recombinant interleukin-2 in preventing and treating spontaneous pulmonary metastases of syngeneic Dunning rat prostate tumor

Lymphokine-activated killer (LAK) cells were generated from splenocytes of rats bearing a weakly immunogenic Dunning prostate tumor (R-3227 AT-3) and activated with recombinant interleukin-2 (rIL-2). The maximal LAK activity was obtained from splenocytes of rats bearing tumors for 10 to 14 days after incubation with 1000 U/ml./day of rIL-2 for five to eight days. The majority of these LAK cells expressed high levels of asialo GM1 (89%), laminin (83%), OX-19 (80%) and OX-8 (88%) surface markers. LAK cells exhibited higher cytotoxicity to rat prostate tumor cells and mouse lymphoma in vitro than to other non-prostate tumor cells or normal rat splenocytes and thymocytes. Splenocytes of rats bearing prostate tumors have higher LAK activity than normal splenocytes. The Winn type assay showed that Dunning prostate tumor growth was inhibited effectively by LAK cells at a tumor cell:LAK cell ratio of 1:50. The therapeutic efficacy of LAK cells in the treatment of primary solid prostate tumors and pulmonary metastases of Dunning rats was evaluated. LAK cells in combination with rIL-2 showed a greater therapeutic benefit in 1) prevention of prostate tumor metastases to lung, 2) retardation of the primary tumor growth, 3) regression of spontaneously established pulmonary metastases, and 4) prolongation of survival as compared to untreated controls or those groups treated with LAK cells or rIL-2 alone. The results of this study indicate that the conjunctive therapeutic approach of using surgical therapy to remove primary solid tumors followed by adoptive immunotherapy with LAK cells plus in vivo administration of IL-2 may be potentially valuable in the treatment of prostate tumors, particularly for the spontaneous pulmonary metastases.     

Adoptive immunotherapy of diabetes in autologous nonobese diabetic mice with lymphoid cells ex vivo exposed to cyclosporin plus interleukin 2

Between 12 and 26 wk of age, approximately 80% of female nonobese diabetic (NOD) mice from the inbred Sansum colony develop lymphocytic insulitis and become overtly diabetic. The disease in this animal model is similar to human insulin-dependent diabetes mellitus (IDDM) in both genetics and autoimmune pathogenesis. Cyclosporin A (CsA) has been used for immunosuppression in IDDM of recent onset in humans but has several limiting side effects. Therefore, a different regimen for CsA immunosuppression was investigated. Autologous splenic lymphoid cells from 12-wk-old not-yet-diabetic female NOD mice were cultured for 72 h with CsA plus interleukin 2 (IL-2) before reinfusion into the animal from which they were isolated. After this treatment, only 2 (18%) of 11 mice became overtly diabetic during an observation period of 19 wk, while 18 (86%) of 21 age-matched control mice developed diabetes during the same observation period (P less than .001). These data suggest an ex vivo preferential IL-2 activation of specific suppressor cells for the autoimmune process with CsA blockade of cytolytic/helper activities. Because the in vivo concentrations of CsA with this procedure would be negligible, these findings have implications for the potential nontoxic use of CsA in human protocols as well.     

Adoptive immunotherapy against kidney targets in dog-leukocyte antigen-identical mixed hematopoietic canine chimeras

BACKGROUND: Stable mixed-donor-host-hematopoietic chimerism can serve as a platform for adoptive immunotherapy. Infusions of donor lymphocytes (DLI) sensitized against hematopoietic cells converted mixed hematopoietic into full-donor chimerism in dog-leukocyte antigen (DLA)-identical littermates. Whether sensitization against tissue of solid organs leads to organ-specific immunity that can be transferred by DLI was unknown and was investigated in these experiments using the kidney as target. METHODS: DLA-identical recipients with established stable mixed-donor-host-hematopoietic chimerism were used. In five pairs, hematopoietic stem-cell transplant (HSCT) donors were sensitized by kidney transplantation from the respective chimeras. In a second group, five HSCT donors received vaccinations that were generated from kidney cells of the respective mixed chimeras. Twenty-eight days after sensitization, DLI were administered to the mixed-hematopoietic chimeras. RESULTS: All HSCT donors rejected their kidney grafts from their mixed-chimeric recipients within 22 to 45 days. DLI caused no sustained graft-versus-kidney effects in the mixed-chimeric recipients. However, DLI donors sensitized by kidney transplantation converted 4 of 5 mixed chimeras into virtually complete (>95%) donor-type chimeras, compared with 1 of 5 mixed chimeras given DLI by vaccination from sensitized donors. CONCLUSION: Although DLA-identical kidney grafts from mixed-hematopoietic chimeras were readily rejected by their HSCT donors, subsequent transfusions of sensitized-donor lymphocytes into mixed chimeras converted mixed to all-donor chimerism but failed to induce graft-versus-kidney effects. Vaccination strategies in lieu of kidney grafts failed to convert mixed chimerism.     

Adoptive immunotherapy with adherent lymphokine-activated killer (A-LAK) cells in glioblastoma multiforme

Adherent lymphokine-activated killer (A-LAK) activity has been recently differentiated in recombinant interleukin-2 (rIL-2) activated PBL. A pilot study on A-LAK + rIL-2 injection into the post-surgical cavity of glioblastoma-operated patients is ongoing. Preliminary data support the feasibility of this technique, which may improve the antitumor response of the host.     

Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells

PURPOSE: We assessed the efficacy and safety of adoptive immunotherapy administered to 17 patients with TaGIII or recurrent TaGII superficial bladder cancer following transurethral tumor resection. MATERIALS AND METHODS: Macrophage activated killer (MAK) cells were obtained from autologous mononuclear cells harvested by apheresis, after in vitro culture for 7 days and activation with interferon-gamma on the last day of culture. The patients received 6 weekly intravesical infusions of approximately 2 x 10(8) cells each. Additionally, 5 patients received 2 or 3 more infusions at 3-month intervals. Each patient was followed for 1 year or until tumor recurrence, whichever came first. RESULTS: A total of 112 intravesical infusions were performed. During the 12-month followup period 8 patients experienced 11 common toxicity criteria grade 1 or grade 2 adverse events considered possibly related to protocol. No clinically relevant grade 1 or 2 laboratory test results were reported while the patients received treatment. In 17 patients 8 tumors recurred compared to 34 recurrences during the year before the first MAK cell infusion. This difference was highly significant (p 相似文献   

Adoptive immunotherapy with LAK cell and IL-2 against primary lung cancer

Adoptive immunotherapy using LAK cells and IL-2 was performed against stage III and IV primary lung cancer patients after surgery. A randomized controlled study consisting of control group A, chemotherapy (CDDP + VDS) group B and chemo-immunotherapy (CDDP+VDS, IL2+LAK cells) group C suggested better survival rate in the group C. Direct effects were studied against 8 recurrent or inoperable lung cancer cases. Complete response was obtained against a pleuritis and pericarditis carcinomatosa case when in vitro stimulated LAK cells (St-LAK) were administered locally. Partial response was observed against a inoperable case when LAK-BAI (bronchial arterial infusion) was combined with radiation therapy.     

Adoptive immunotherapy of human meningeal gliomatosis and carcinomatosis with LAK cells and recombinant interleukin-2

Previous in vitro studies have demonstrated that peripheral blood lymphocytes activated with recombinant interleukin-2 (rIL-2) generated cells that were lytic for fresh autologous tumor cells but not for normal lymphocytes or lymphoblasts. Adoptive transfer of autologous lymphokine-activated killer (LAK) cells induced in vitro with rIL-2 was used in two patients: one with meningeal gliomatosis and the other with meningeal carcinomatosis. The adoptive transfer of LAK cells was very effective in reducing the clinical symptoms and signs, and in eliminating the malignant cells from the cerebrospinal fluid. Thus, this therapy is an attractive approach for the treatment of malignant tumors that have poor immunogenicity and are insensitive to several anti-cancer agents, and for patients with severe immunosuppressive conditions induced by repeated radiation therapy or chemotherapy.     

Anti-CD3-enhanced interleukin-2 immunotherapy of pulmonary metastases.

A newly developed monoclonal rat IgG 2b antibody which in vitro can activate both helper and cytolytic T-lymphocytes by binding to the CD3 epsilon subunit of the T-cell receptor complex was tested alone and in combination with Interleukin-2, a growth factor for activated T-cells, for ability to reduce established pulmonary metastases in a murine model. C57BL/6 mice injected iv with a tumor cell suspension of a weakly immunogenic fibrosarcoma, MCA106, were randomly assigned to 1 of 15 treatment groups for intraperitoneal injections with YCD3 (0, 0.1, 1, 10, or 100 micrograms) on Days 3, 5, 7, 10, 12, 17, and 19 or with IL-2 (0, 1000, or 50,000 units bid) on Days 3 through 7, 10 through 12, and 17 through 19. On Day 21 all mice were sacrificed for enumeration of metastases. Pooled splenocytes of three randomly selected mice from each group were assayed for surface expressions of T-cell markers Thy-1, Ly2, and L3T4. Results: High-dose IL-2 (50,000 units bid) in combination with low-dose YCD3 (1 microgram) reduced metastases 60% (P less than 0.005). YCD3 or IL-2 alone was ineffective. Combined high-dose IL-2 (50,000 units) and high-dose YCD3 (100 micrograms) resulted in 100% mortality. Phenotypically, YCD3 induced a dose-dependent depletion of T-cells from 25 to 2.4% (0.1 to 100 micrograms, respectively). These results suggest potential clinical applicability of low-dose anti-CD3 monoclonal antibody to enhance antitumor efficacy of high-dose IL-2. However, the toxicity of high-dose anti-CD3 and high-dose IL-2 cautions for care in selection of dose.     

Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-alpha

In a murine pulmonary metastases model, interleukin-2 (IL-2), a lymphokine capable of expanding all classes of T lymphocytes, synergizes with interferon-alpha (IFN-alpha) to reduce established metastases and prolong survival. We tested whether indomethacin (INDO), which inhibits synthesis of prostaglandin E2 (a potent immunosuppressor), could further augment the antitumor efficacy of these lymphokines. Age-matched C57BL/6 mice bearing pulmonary micrometastases of a weakly immunogenic fibrosarcoma MCA-106 were treated intraperitoneally for 6 consecutive days, starting on day 3 with (1) saline solution, (2) IL-2 (50,000 units twice a day), (3) IFN-alpha A/D (50,000 units per day), and (4) IL-2 and IFN-alpha A/D. Half of each treatment group was given plain water and the rest INDO-treated (14 micrograms/cc) drinking water throughout the duration of the experiment. Pulmonary metastases were enumerated on day 21. IFN or INDO alone had little effect, whereas IL-2 reduced metastases and prolonged survival. All combination treatments, including INDO/IFN, decreased metastases and prolonged survival except INDO/IL-2/IFN in which several early deaths negated any significant survival prolongation. Early mortality (less than 21 days) was seen with IFN/INDO (8.3%), IL-2/IFN (7.7%), and IL-2/IFN/INDO (8.3%) indicating toxicity of these treatments. Spontaneous proliferation of splenocytes from non-tumor-bearing mice treated for 5 days showed that INDO combined with IL-2 or IFN enhanced proliferation measured 3 days after cessation or treatments. A striking reduction in T-cell marker (Thy 1.2+) in groups treated with IL-2/IFN, INDO/IL-2, INDO/IFN, and INDO/IL-2/IFN 3 days after cessation of IL-2 and IFN suggests that a non-T-cell is amplified when INDO is combined with IL-2 or IFN. These results show that INDO can enhance efficacy of IL-2 or IL-2/IFN. Furthermore, INDO/IFN offers an equi-efficacious, albeit similarly toxic, alternative to IL-2 treatment of tumors and may be useful clinically.     

Adoptive immunotherapy of human pancreatic cancer with lymphokine-activated killer cells and interleukin-2 in a nude mouse model

A pancreatic cancer cell line was grown in orthotopic and heterotopic positions in young Swiss/NIH nude mice, which were tested with adoptive immunotherapy. Mice were injected with 1 x 10(7) human cancer cells in the subcutaneous tissue and duodenal lobe of the pancreas. The mice were randomly divided into four groups: group IA (LAK + IL-2) (N = 25) received 2 X 10(7) human lymphokine-activated killer (LAK) cells from normal donors by tail vein injection followed by 10,000 units of human recombinant interleukin-2 (IL-2) given intraperitoneally every 12 hours for 28 days; group IB (IL-2) (N = 27) was given the same dose of IL-2 alone; group IC (RPMI-1640) (N = 18) received a placebo consisting of 1 ml of RPMI-1640 intraperitoneally every 12 hours; and group ID (LAK) (N = 14) received 2 X 10(7) LAK cells but no IL-2. Toxicity was significantly higher in group IB, with a mortality rate of 45.5% (10/22 animals) versus a 0% mortality (0/25) in group IA. None of the group IA or IB animals died of pancreatic cancer during the experiment. The animals that did not receive IL-2 died before 28 days in 14.2% of group IC and in 16.7% of group ID. The area under the growth curve of subcutaneous tumors during the course of treatment and the pancreatic tumor weight at the end of treatment were compared in each group. Subcutaneous tumors had a reduced rate of growth in group IA animals compared to all the other treatments. Pancreatic tumor growth was slowed in group IA. The animals treated with IL-2 alone (group IB) showed some slowing of tumor growth that was intermediate between group IA, group IC, and group ID. A similar experiment was done with irradiated (375 rad) mice. Nine nude mice with tumors were treated with LAK + IL-2 (group IIA), eight received IL-2 alone (group IIB), and seven received placebo (group IIC). The antitumor effect of IL-2 alone was not present in the irradiated mice. A highly significant difference persisted between group IIA and all other groups. There was no difference in the histologic characteristics of tumors in control mice and in mice with inhibited tumor growth treated with IL-2 or IL-2 and human LAK cells. These results show that adoptive immunotherapy with human LAK cells and human recombinant IL-2 is effective against human pancreatic cancer growing in nude mice. This effect is independent from antitumor activity from IL-2 administrations alone.     

Adoptive immunotherapy of metastatic B16 melanoma with allogeneic immune cells sensitized to minor histocompatibility antigens

Host mice bearing pulmonary metastases of B16 melanoma were treated by adoptive immunotherapy with allogeneic donor lymphocytes. Rejection of the allogeneic donor cells by the host was delayed by pretreatment immunosuppression of the host with cyclophosphamide and selection of donors that were matched at the major histocompatibility complex (MHC) but disparate for background minor histocompatibility genes. Adoptively transferred normal nonimmune donor cells exhibited no therapeutic activity. However, allogeneic MHC-matched donor cells that were primed in vivo and secondarily sensitized in vitro to host minor histocompatibility antigens expressed on normal lymphocytes were cytotoxic to B16 tumor cells in vitro and mediated a dose-dependent antitumor effect in vivo following i.v. infusion. The therapeutic activity of sensitized allogeneic cells, which presumably reflected recognition of minor histocompatibility antigens expressed both on normal host tissues and on malignant B16 tumor cells, was not associated with any detectable toxicity to these transiently immunosuppressed tumor-bearing hosts.     

An autopsy case of extraneural metastases of giant cell glioblastoma with intracerebral hemorrhage

We report a case in which a 71-year-old man with a giant cell glioblastoma who had a spontaneous intracerebral hematoma including subarachnoid hemorrhage and extraneural multiple metastases followed by the craniotomy 9 months later. He had complained of nausea and vomiting on 20, October, 1981 and admitted to the Ohara hospital. For that reason, he was admitted to our hospital on 29, October, 1981 and a CT scan showed a large subcortical high dence mass accompanied by adjacent edema in the right frontal lobe. Gradually he got worse with Korsakoff's syndrome and motor weakness of the left side. Total removal of the hematoma and adjacent tissue by transcortical route on 24, November, 1981 was performed, followed by 60Co radiation therapy to the local area, chemotherapy and immunotherapy. The surgical specimen showed typical features of giant cell glioblastoma with intratumoral hemorrhage. After 9 months of the operation, he had complained of the subcutaneous tumor in the supraclavicular region and swelling of the right arm. After the second admission on 30, August, 1982, a biopsy of the tumor revealed malignant tumor cells resembling intracerebral giant cell glioblastoma. He died on 29, November, 1982. At autopsy, extraneural metastases were revealed at some lymph nodes, organs and bones. However, a primary tumor was not found in the other organs. Lymph node: cervical, supraclavicular, mediastinal, bronchial, pancreaticoduodenal, hepatic hilus, mesenteric, retroperitoneal, and parastomach. Organ: esophagus, Ileum, jejunum, adrenal gland and kidney. Bone: vertebra (thoraco-lumbar), sternum, rib. Positive reaction to GFA protein antibody was demonstrated in the tumor cells in the periphery of the surgical specimen of the brain tumor.(ABSTRACT TRUNCATED AT 250 WORDS)     

混合培养的供、受者骨髓细胞过继回输延长小鼠移植心脏存活时间

目的 将供、受者骨髓细胞经混合培养后过继回输,以观察其对同种异体移植心脏存活时间和受者免疫功能的影响.方法 取Balb/c小鼠和C57BL/6J小鼠的骨髓细胞,进行混合培养.配制含Balb/c小鼠和C57BL/6J小鼠脾淋巴细胞的混合淋巴细胞反应体系(MLR)以及含Balb/c小鼠和C3H小鼠脾淋巴细胞的MLR,分别加入混合培养的骨髓细胞,观察其对MLR中细胞增殖的影响.以C57BL/6J小鼠为供者,Balb/c小鼠为受者行腹腔异位心脏移植,实验分为4组:(1)移植对照组,受者仅进行心脏移植,不作其他处理;(2)实验对照组,心脏移植后给予西罗莫司灌胃;(3)实验组,移植手术结束前注射混合培养的骨髓细胞1×10~7个,术后给予西罗莫司;(4)第三方对照组,受者接受C3H小鼠的移植心脏,手术结束前注射混合培养的骨髓细胞1×10~7个,术后给予西罗莫司.记录移植心脏存活时间;移植心脏停跳当日,取受者外周血,检测CD4~+ CD25~+ T淋巴细胞的比例及供者来源的H-2K~b细胞的比例.结果 加入混合培养的骨髓细胞后,Balb/c和C57BL/6J的MLR的淋巴细胞增殖率低于Balb/c和C3H的MLR.实验组移植心脏的存活时间长于其他3组(P<0.05).实验组CD4~+CD25~+T淋巴细胞的百分率高于其他3组(P<0.05).实验组外周血中H-2K~b细胞的比例高于其他3组(P<0.05).结论 受者输注混合培养的供、受者骨髓细胞可在一定程度上调节免疫应答,延长小鼠移植心脏的存活时间,该作用具有供者抗原特异性.     

Adoptive immunotherapy for unresectable or recurrent pancreatic cancer, using lymphokine-activated killer cells or cytotoxic T cells

Adoptive immunotherapy (AIT) has been reported to be effective for malignancies in some cases. We hypothesized that AIT may be effective for the treatment of pancreatic cancer. Seven patients with unresectable or recurrent pancreatic cancer underwent AIT, carried out with lymphokine-activated killer (LAK) cells or cytotoxic T cells (CTLS) and recombinant interleukin-2 (IL-2). The clinical and immunological effects were evaluated. Of four patients who received CTLs, one had a partial response, one had a minor response, and two showed no change. The three patients who received LAK cells had progressive disease. The CTLs had a significantly higher proportion of CD8 positive T cells and cytotoxic T cells than the LAK cells (P < 0.05), while the LAK cells had a significantly higher proportion of NK cells than did the CTLs (84 ± 12% vs 55 ± 15%,P < 0.05). The LAK activity of the CTLs (61 ± 14%) was significantly higher than that of the LAK cells (42 ± 8%,P < 0.05). Seven days after treatment with LAK cells or CTLs, lymphocyte subsets in the peripheral blood were examined. The proportion of CD8-positive T cells after CTL transfer (46 ± 5%) was greater than that before CTL transfer (28 ± 1%,P < 0.05). The proportion of cytotoxic T cells after CTL transfer increased from 23 ± 1% to 37 ± 2% (P < 0.05). However, these changes were not observed during LAK cell transfer. The proportions of suppressor inducer T cells, helper T cells, and suppressor T cells did not change during therapy. These results suggested that AIT, using CTLs, merits further clinical investigation in patients with pancreatic cancer.     

Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer

BACKGROUND: The prognosis of patients with resected pancreatic cancer remains poor. This study evaluated the effect of adoptive immunotherapy (AIT) using intraportal infusion of lymphokine-activated killer (LAK) cells after curative resection and intraoperative radiation therapy (IORT) on advanced pancreatic cancer. METHODS: Twenty-nine consecutive patients with advanced pancreatic cancer (Japan Pancreas Society stage III or IV) were divided into two groups. The control group (n = 17) underwent tumour resection and IORT. The treatment group (n = 12) underwent resection, IORT and intraportal infusion of LAK cells combined with recombinant interleukin 2 (rIL-2). The incidence of liver metastasis and the survival rate of these two groups were compared. RESULTS: Although the overall survival between groups was not statistically different (P = 0.082), there were more patients (four) alive 3 years after operation in the test group (36 per cent versus zero), and the incidence of liver metastases in the treatment group was significantly lower (three of 12 versus ten of 15; P < 0.05). LAK therapy influenced survival positively in multivariate analysis. CONCLUSION: These preliminary observations suggest that AIT warrants further study as a possible adjuvant for patients undergoing curative resection and IORT for pancreatic cancer.