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M T Lotze

Publications and source records attributed to M T Lotze.

At least 19 recordsLinked to original sources
PubMed2005

Multianalyte profiling of serum cytokines for detection of pancreatic cancer.

Early detection of pancreatic cancer might improve clinical outcome. Significant alterations in the levels of individual serum cytokines have been reported in pancreatic cancer. We hypothesized that a multicytokine panel could serve as biomarkers for pancreatic cancer. To evaluate the diagnostic utility of such a panel, we have utilized a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. In this study, a panel of 31 serological markers including cytokines, chemokines, growth and angiogenic factors in combination with CA 19-9 was analyzed in sera of pancreatic cancer patients, patients with chronic pancreatitis, and matched control healthy subjects. Statistical analysis identified a multicytokine panel that was able to distinguish pancreatic cancer from healthy controls with a sensitivity of 85.7% and specificity of 92.3%, which was superior to performance of CA 19-9 alone. Importantly, a multicytokine panel allowed the discrimination of pancreatic cancer from chronic pancreatitis with high sensitivity of 98% and specificity of 96.4%. In conclusion, we demonstrated that analysis of multiple serum cytokines using a novel LabMAP technology is a promising approach for development of a diagnostic assay for pancreatic cancer.

Biomarkers, Tumor↗
PubMed2002

Therapeutic and specific antitumor immunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18.

Interleukin-18 is a potent cytokine expressed early in the immune response following cleavage in activated composes. We have investigated the in vivo antitumor effects of intratumoral (i.t.) administration of an adenoviral vector expressing biologically active murine interleukin (IL)-18 (Ad.PTH.IL-18). Substantial antitumor effects were observed when established MCA205 fibrosarcoma was treated in syngeneic immunocompetent mice with intratumoral injection of Ad.PTH.IL-18 (P = 0.0025 versus control vector treatment), generating potent cytotoxic T lymphocytes (CTLs) in culture. In contrast, the antitumor effect was absent, and cytotoxic activity was significantly less (P = 0.021) in gld mice (Fas ligand deficient). To enhance the in vivo antitumor activity of the treatment using Ad.PTH.IL-18, we co-injected immature DC and Ad.PTH.IL-18 i.t. into established, day 7 MCA205 fibrosarcoma and MC38 adenocarcinoma. Co-injection of both Ad.PTH.IL-18 and DC was associated with complete abrogation of injected tumors. Furthermore, the antitumor effects were also observed on distant tumors inoculated i.d. in the contralateral flank of the animal. The induced cytolytic activity was tumor-specific and MHC class I-restricted. As we have previously demonstrated in vitro (Tanaka F et al, Cancer Res 2000; 60: 4838-4844) and consistent with these findings in vivo, NK, T and dendritic cells coactivately mediate the IL-18 enhanced antitumor effect. This study suggests that the coactivate strategy could be used in the clinical setting to treat patients with cancer. do

Adenosarcoma↗
PubMed2001

Mitochondrial lipid alterations during Fas- and radiation-induced apoptosis.

In the present study, we investigated the dynamic alterations in mitochondrial lipids occurring during Fas- and radiation-induced cell death. Cross-linking of CD-95 on Fas-sensitive Jurkat cells produced rapid increases in two species of mitochondrial phosphatidylglycerol. By 2.5 h, phosphatidylglycerol decreases below basal levels, concomitant with an increase in mitochondrial ceramide. In addition, between 1.5 and 3.0 h after anti-Fas crosslinking, there is a continued loss of mitochondrial cardiolipin. When gamma irradiation was used to induce apoptosis, similar lipid changes occurred, although with somewhat slower kinetics. Fas-resistant Jurkat cells exhibited phosphatidylglycerol as the dominant lipid species in their mitochondria. Following Fas ligation, there is a transient decrease in phosphatidylglycerol, but cardiolipin and ceramide remained unchanged. The high basal levels of PG in Fas-resistant cells and the increase in PG levels in Fas-sensitive cells undergoing apoptosis was determined to be due to increased PGP synthase activity. Thus, critical mitochondrial lipids could potentially serve as novel targets in regulating the apoptotic process.

Apoptosis↗
PubMed2001

Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ.

Interleukin-10 (IL-10) is a multifunctional cytokine that can exert suppressive and stimulatory effects on T cells. It was investigated whether IL-10 could serve as an immunostimulant for specific CD8(+) cytotoxic T cell (CTL) in vivo after vaccination and, if so, under what conditions. In tumor prevention models, administration of IL-10 before, or soon after, peptide-pulsed primary dendritic cell immunization resulted in immune suppression and enhanced tumor progression. Injection of IL-10, however, just after a booster vaccine significantly enhanced antitumor immunity and vaccine efficacy. Analysis of spleen cells derived from these latter animals 3 weeks after IL-10 treatment revealed that the number of CD8(+) CD44(hi) CD122(+) T cells had increased and that antigen-specific proliferation in vitro was enhanced. Although cytotoxicity assays did not support differences between the various treatment groups, 2 more sensitive assays measuring antigen-specific interferon-gamma production at the single-cell level demonstrated increases in the number of antigen-specific responder T cells in animals in the vaccine/IL-10 treatment group. Thus, IL-10 may maintain the number of antitumor CD8(+) T cells. In adoptive transfer studies, the ability of IL-10 to maintain CTL function could be enhanced by the depletion of CD4(+) T cells. This suggests that IL-10 mediates contrasting effects on both CD4(+) and CD8(+) T cells that result in either immune dampening or immune potentiation in situ, respectively. Appreciation of this dichotomy in IL-10 immunobiology may allow for the design of more effective cancer vaccines designed to activate and maintain specific CD8(+) T-cell effector function in situ.

Animals↗
PubMed2001

Ceramide mediates tumor-induced dendritic cell apoptosis.

Induction of apoptosis in dendritic cells (DC) is one of the escape mechanisms of tumor cells from the immune surveillance system. This study aimed to clarify the underlying mechanisms of tumor-induced DC apoptosis. The supernatants (SN) of murine tumor cell lines B16 (melanoma), MCA207, and MCA102 (fibrosarcoma) increased C16 and C24 ceramide as determined by electrospray mass spectrometry and induced apoptosis in bone marrow-derived DC. N-oleoylethanolamine or D-L-threo 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibits acid ceramidase or glucosylceramide synthase and then increases endogenous ceramide, enhanced DC apoptosis and ceramide levels in the presence of tumor SN. Pretreatment with L-cycloserine, an inhibitor of de novo ceramide synthesis, or phorbol ester, 12-O-tetradecanoylphorbol-13-acetate reduced endogenous ceramide levels and protected DC from tumor-induced apoptosis. However, other DC survival factors, including LPS and TNF-alpha, failed to do so. The protective activity of 12-O-tetradecanoylphorbol-13-acetate is abrogated by pretreatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Therefore, down-regulation of PI3K is the major facet of tumor-induced DC apoptosis. Tumor SN, N-oleoylethanolamine, or PDMP suppressed Akt, NF-kappaB, and bcl-x(L) in DC, suggesting that the accumulation of ceramide impedes PI3K-mediated survival signals. Taken together, ceramide mediates tumor-induced DC apoptosis by down-regulation of the PI3K pathway.

Animals↗
PubMed2001

Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Adult↗
PubMed2001

Immunization with an antigen identified by cytokine tumor vaccine-assisted SEREX (CAS) suppressed growth of the rat 9L glioma in vivo.

We have reported previously that s.c. immunization of rats with IL-4 transduced 9L gliosarcoma cells (9L-IL-4) induced a potent antitumor immunity against intracranial, parental 9L tumors. Subcutaneous implantation of 9L-IL-4 influenced the systemic humoral response, which was demonstrated by Th2-type isotype-switching and the induction of cellular immune responses, which played a critical role in the rejection of tumors. Serological analyses of recombinant cDNA expression libraries (SEREX), has recently emerged as a powerful method for serological identification of tumor-associated antigens (TAAs) and/or tumor rejection antigens (TRAs). Because IL-4 is known to activate B cells and to promote humoral responses, and inasmuch as induction of humoral responses by central nervous system tumors has been reported to be minimal, we investigated whether the induction of a potent humoral immune response against 9L TAAs or TRAs in rats immunized s.c. with 9L-IL4 could be demonstrated. Screening of 5 x 10(5) independent clones of 9L-expression cDNA library for the presence of reactive antibodies in the serum from a 91-IL-4 immunized rat led to the identification of three different TAAs. One 9L TAA (clone 29) was demonstrated to be calcyclin, a member of the S-100 family of calcium-binding proteins. The second 9L TAA (clone 37) was demonstrated to be the rat homologue of the J6B7 mouse immunomodulatory molecule. The third TAA (clones 158 and 171) was determined to be the rat homologue of the mouse Id-associated protein 1 (MIDA1), a DNA-binding, protein-associated protein. Northern blotting demonstrated that message for calcyclin was overexpressed in 9L cells. Message encoding MIDA1 was highly expressed in parental 9L cells and thymus and, to a lesser degree, in testis, suggesting that MIDA1 was comparable with the cancer/testis category of TAAs. Sera obtained from animals bearing 9L-IL-4 were found to have a higher a frequency and titer of antibodies to these antigens when compared with sera obtained from rats bearing sham-transduced 9L (9L-neo) cells. To determine whether immunization with these TAAs induced antitumor immunity, animals were immunized by intradermal injection with expression plasmids encoding calcyclin or MIDA1. Subsequent challenge of rats with parental 9L resulted in significant suppression of tumor growth in animals immunized with MIDA1, but not with calcyclin. These results indicate that MIDA1 is an effective 9L TRA and will be useful for the investigation of specific antitumor immunity in this glioma model. Furthermore, these results suggest that this approach, termed "cytokine-assisted SEREX (CAS)," may serve as an effective strategy for identification of TRAs for in animal-glioma models of cytokine gene therapy, and potentially in humans undergoing cytokine gene therapy protocols as well.

Animals↗
PubMed2001

Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-gamma production, and expansion of natural killer cells.

We investigated the in vitro effects of combining interleukin-18 (IL-18) and IL-2 on human lymphocytes. The combined use of these two cytokines synergistically enhanced the proliferation, cytolytic activity, and interferon-gamma production of peripheral blood mononuclear cells. Phenotypic analysis revealed a preferential expansion of CD56+CD3- cells and an up-regulation of IL-2 receptor-alpha expression on natural killer cells. Isolated natural killer cells showed a substantial increase in proliferation and cytotoxicity compared with CD4+ and CD8+ T cells. The combined use of IL-18 and IL-2 should be considered a viable strategy to induce an antitumor response in vivo.

CD4-Positive T-Lymphocytes↗
PubMed2001

Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function.

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common extracranial solid tumor in children. NB-derived gangliosides inhibit the functional activity of T and natural killer cells, contribute to tumor-induced bone marrow suppression, and cause multiple alterations of hematopoiesis, resulting in pancytopenia. However, the role of gangliosides in the regulation of dendritic cell (DC) generation (dendropoiesis) has not been studied. Using murine and human NB cell lines, we demonstrated that coincubation of murine bone marrow progenitors or human CD34+ progenitor cells with NB cells resulted in a significant inhibition of dendropoiesis in vitro up to 90%. The number of DCs was assessed by FACScan determination of CD83+ or CD11c+ cells coexpressing MHC class II and CD86 molecules. In addition, inhibition of antigen-presenting properties of DCs cultured in the presence of NB cells was observed in allogeneic mixed leukocyte reaction (33,508 +/- 1,613 cpm for control DCs versus 17,428 +/- 152 cpm for NB-treated DCs; P < 0.05). Treatment of NB cells with 10 microM DL-threo-1-phenyl-2-decanolylamine-3-morpholino-1-propanol HCl, an inhibitor of glucosylceramide synthase, markedly abrogated ganglioside synthesis and was accompanied by blockade of NB ability to inhibit dendropoiesis. Furthermore, purified gangliosides added to DC cultures significantly inhibited DC generation. The percentage of CD83+ cells decreased from 51.8 +/- 6.1% in the control group to 12.9 +/- 2.7% in cultures treated with GD2 (P < 0.05). Thus, our results demonstrate that NB-derived gangliosides inhibit the generation of functionally active DCs and may play a role in tumor-induced immunosuppression and subsequent tumor escape from immune recognition and elimination.

Animals↗
PubMed2001

Potent antitumor effects of intra-arterial injection of fibroblasts genetically engineered to express IL-12 in liver metastasis model of rat: no additional benefit of using retroviral producer cell.

Interleukin-12 (IL-12) mediates significant antitumor effects in animal models but associated with dose-dependent toxicity in human. To achieve local expression of IL-12 at the tumor site without systemic toxicity, we performed intra-arterial administration of fibroblasts genetically engineered to produce IL-12 protein with or without retrovirus (CRIP- IL-12 or 3T3-IL-12) in liver metastasis model. Rat breast cancer cells ( MADB - 106) were injected into the portal vein of syngeneic Fisher rats on day 0, and fibroblasts were injected into the hepatic artery on day 7. On day 21, liver weight and number of liver tumors were examined. As controls, CRIP cells expressing retrovirus carrying lacZ marker gene (CRIP-lacZ) or saline (Hanks balanced salt solution, HBSS) were injected. Administration of CRIP-IL-12 significantly reduced tumor metastasis in liver measured by number of foci (CRIP- IL-12: 45.2 +/- 36.7, CRIP-lacZ: >250, HBSS: >250, P<.05) and by liver weight (CRIP-IL-12: 13.0+/-2.5 g, CRIP-lacZ: 30.4+/-8.5 g, HBSS: 26.0+/-7.6 g, P<.05). 3T3-IL-12, which produced only IL-12 protein but not IL-12 retrovirus, also had significant antitumor effects equivalent to CRIP-IL-12. Intra-arterial injection of IL-12--producing fibroblasts into the liver may be an effective therapy for liver tumors reducing systemic toxicity, and could be developed for clinical application.

3T3 Cells↗
PubMed2001

Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells.

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFNalpha). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNalpha and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.

Animals↗
PubMed2001

Interleukin-12 transduced dendritic cells induce regression of established murine neuroblastoma.

BACKGROUND/PURPOSE: Interleukin 12 (IL-12) is a potent proinflammatory cytokine that enhances cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity. The goal of these experiments was to assess whether adenoviral-mediated IL-12 expression by dendritic cells (DC) could induce an antitumor immune response in a murine model of neuroblastoma. METHODS: Syngeneic A/J mice were inoculated subcutaneously with 1 x 10(6) cells from a murine neuroblastoma-derived cell line (TBJ). Murine DC were transduced in vitro with adCMV-mIL-12, and 1 x 10(6) cells were injected intratumorally. Tumor growth in these mice was compared with control animals injected with enhanced green-filled protein (EGFP) transduced DC or saline. The role of CTL was evaluated through cytotoxicity assays. Immunohistochemical analysis of tumor, spleen, and lymph node was performed to characterize the behavior and fate of various populations of immune effector cells in these tissues. RESULTS: The tumors of mice injected with adIL-12 transduced DC all underwent complete regression over a 3-week period. Splenocytes isolated from mice 7 days after intratumoral injection of adIL-12 DC showed increased cytolytic activity relative to control animals in vitro. Immunohistochemistry of tumor and lymph tissue showed increased amounts of DC and T lymphocyte infiltration and a slight decrease in apoptosis relative to the control groups. CONCLUSIONS: Increased IL-12 production by DC induced a significant antitumor response in a poorly immunogenic murine neuroblastoma model. These results show the vital role of DC in the immunobiology of the disease, and that protection of these cells from tumor induced apoptosis is a critical aspect for immunotherapies treating this aggressive tumor.

Animals↗
PubMed2001

Dendritic cells pulsed with apoptotic squamous cell carcinoma have anti-tumor effects when combined with interleukin-2.

OBJECTIVES: Dendritic cells, the most potent of the antigen-presenting cells, have been widely studied as a promising tool for antitumor immunotherapies. However, little has been determined about the efficacy of dendritic cell-based therapy for the treatment of squamous cell carcinoma (SCC) because there are no known SCC-specific antigens. Recent reports indicate that dendritic cells can acquire antigens in the form of apoptotic cells and induce cytotoxic T-lymphocyte responses. The aim of this study was to test the feasibility of adoptive dendritic cell immunotherapy against SCC by using apoptotic tumor cells as a source of tumor antigens. STUDY DESIGN: A poorly immunogenic SCC line KLN 205 was used to make subcutaneous tumors on the flank of DBA2/J syngeneic mice. Bone marrow-derived dendritic cells were pulsed with ultraviolet B-irradiated (apoptotic) KLN 205 cells in vitro and transferred to the opposite flank subcutaneously. Some of the animals received simultaneous intraperitoneal injections of low-dose interleukin-2. RESULTS: When combined with interleukin-2, adoptive transfers of dendritic cells that were pulsed with apoptotic SCC significantly suppressed the tumor growth (P <.001) without notable side effects. Splenic T cells of treated mice produced greater amounts of interferon-gamma when restimulated with the relevant tumor (P <.001) as compared with control groups, indicative of an effective T-cell-mediated systemic immune response. CONCLUSION: Adoptive transfer of dendritic cells pulsed with apoptotic tumor cells as a source of tumor antigens, can elicit effective antitumor responses in the poorly immunogenic SCC model when combined with interleukin-2.

Animals↗
PubMed2001

Phase II trial of systemic recombinant interleukin-2 in the treatment of refractory nasopharyngeal carcinoma.

BACKGROUND: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. METHODS: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5-6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. RESULTS: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3x) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. CONCLUSION: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

Adult↗
PubMed2001

Dendritic cells prolong tumor-specific T-cell survival and effector function after interaction with tumor targets.

Tumor specific CTLs are susceptible to tumor-mediated activated induced cell death (AICD) after target engagement. The presence of dendritic cells (DCs) at the site of tumors correlates with an improved prognosis in patients with a variety of histological tumor types. We examined whether DCs can modify the survival of tumor specific CTLs during encounter with tumor targets. HLA-A2+ gp100-specific CD8+ CTLs were used as effectors against gp100+, A2+ melanoma FEM-X, and Mel526 (A2-) targets as well as the melanoma target Mel397. Cytolytic assays and [3H]DNA fragmentation (JAM) assays were used to evaluate CTL specificity and tumor-mediated AICD, respectively. A functional assay, ARK (activity of rescued killer cells), was developed to measure cytolytic activity of surviving CTLs after a 12-h coincubation with tumor. In JAM assays, the CTLs proved more susceptible to apoptosis when exposed to the relevant tumors FEM-X and Mel526 than the irrelevant Mel397 (37 and 23% versus 3%; P < .001). The addition of human A2+ monocyte-derived immature DCs significantly (P < 0.001) limited this tumor-induced death of CTLs. In ARK assays, the presence of DCs decreased tumor-mediated suppression of CTLs, with increases in cytolytic function of CTLs reaching up to 2-fold. These findings suggest that DCs may play an important role during the effector phase of the immune response by enhancing the survival and function of CTLs in the tumor microenvironment.

Apoptosis↗
PubMed2001

Immunotherapy of metastasis.

This article provides a basic overview of tumor immunology vaccines, current vaccine trials, and future directions of vaccine strategies for the treatment of metastatic cancers. As dendritic cells are the most potent antigen-presenting cell and central to the regulation, maturation, and maintenance of a cellular immune response to cancer, these cells may be crucial to tumor vaccine strategies. Peptide-based strategies and monoclonal antibodies also have been used with some success in developing a tumor-specific response. Methods promoting a more effective immune response and maintaining T-cell survival through administration of adjuvant cytokines, synthetically modified antigens, and various other immunoadjuvants are discussed.

Adjuvants, Immunologic↗
PubMed2000

Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells.

We hypothesized that antitumor-specific immunity, which is induced by interleukin (IL) 18 treatment in murine tumor models, is promoted by enhancing natural killer (NK)-mediated destruction of tumor and delivery to dendritic cells (DCs). These activated and antigen-pulsed DCs then critically and optimally induce an adoptive immune response, positioning IL-18 as an important bridge between the innate and adoptive immune response. The effect of IL-18 added to cultures of live tumor cells (MCA205, a mouse sarcoma cell line), NK cells, DCs, and T cells was assessed. When recombinant (r) mIL-18 protein was added to this culture, potent NK cytolytic activity with subsequent generation of CTLs was observed in a dose-dependent manner. Without introduction of either rmIL-18 or NK cells into this culture, systemic cytolytic activity was significantly decreased. Following the absence of direct contact of either NK cells or DCs with other cells in this cooperative coculture system using transwell, the systemic cytolytic activity of both NK cells and CTLs was greatly suppressed. The cytolysis mediated by effector cells harvested after completion of the culture was primarily restricted to MHC class I and highly specific for the tumor cells used in the coculture. Furthermore, we examined the efficiency in the induction of cytolytic T cells of other established IFN-gamma inducing T-cell growth factors, IL-2, and IL-12 in this culture system and compared them with that mediated by IL-18. Neither IL-2 nor IL-12 induced tumor-specific cytolytic T cells to the same degree as that mediated by IL-18. Efficacy of this system in induction of tumor-specific CTLs was also observed in the system using MC38 adenocarcinoma cells. These results are consistent with the notion that IL-18 induces tumor-specific immunity through enhancing NK activity, which in turn mediates tumor cell death and activates and primes DCs.

Adenocarcinoma↗