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Results for “Combination immunotherapy”

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At least 145 records · Page 8Linked to original sources
PubMed2004

Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation.

A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4(-/-) mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.

Adjuvants, Immunologic↗
PubMed2005

Infiltration of activated dendritic cells and T cells in renal cell carcinoma following combined cytokine immunotherapy.

OBJECTIVES: In a phase I study the feasibility, toxicity and immunological effects of peri-operative cytokine immunotherapy of renal cell carcinoma were studied. Main goals were to determine the maximal tolerable dose and detailed in situ analysis of tumor infiltrates. METHODS: Fifteen patients with renal cell carcinoma, undergoing nephrectomy, received subcutaneous immunotherapy, consisting of low-dose IL-2, IFNalpha and GM-CSF, from day -3 prior, until day +5 following surgery in a dose escalation study. Infiltrates from resected tumor tissues from patients undergoing immunotherapy or control patients that underwent nephrectomy only, were examined using quantitative immunohistological analysis and 3-color immunofluorescence staining and confocal laser scanning microscope analysis. RESULTS: Toxicity was limited and the maximal tolerable dose was established. In peripheral blood an increase was found in total lymphocytes, (activated) T cells, NK cells and monocytes. Quantitative immunohistological analysis of tumor infiltrates showed enhanced numbers of CD3+ T cells, S100+ DC, CD83+ DC and IL-2 receptor positive cells (4-fold, 2-fold, 10-fold and 20-fold, respectively, compared to controls). In treated patients preferential invasion was observed of TNFalpha positive CD8+ T cells and DC, positive for DC-SIGN (CD209), CD83, CD80, IL-12 and the DC specific chemokine, DC-CK1 (CCL18). CONCLUSIONS: These findings show increased infiltration of activated, mature DC and functionally active CD8+ T cells in renal tumors, which may suggest clinical potential of cytokine immunotherapy.

Adult↗
PubMed2003

Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade.

Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic oligodeoxynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses. The results show that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinase-related protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. Interestingly, whereas this combination therapy was effective when administered to tumor-bearing mice (therapeutic protocol), it had no significant effect when applied in the prophylactic mode (i.e., before the tumor challenge). Moreover, the antitumor effect of the combination immunotherapy required the participation of CD4+ and CD8+ T lymphocytes and was accompanied by the induction of antitumor CD4+ T-cell responses. The overall results suggest that peptide vaccination of tumor-bearing mice, applied in combination with a strong adjuvant and CTLA-4 blockade, is capable of eliciting durable antitumor T cell responses that provide survival benefit. These findings bear clinical significance for the design of peptide-based therapeutic vaccines for human cancer patients.

Abatacept↗
PubMed2004

Impaired antigen presentation and effectiveness of combined active/passive immunotherapy for epithelial tumors.

BACKGROUND: Although immunization with tumor antigens can eliminate many transplantable tumors in animal models, immune effector mechanisms associated with successful immunotherapy of epithelial cancers remain undefined. METHODS: Skin from transgenic mice expressing the cervical cancer-associated tumor antigen human papillomavirus type 16 (HPV16) E6 or E7 proteins from a keratin 14 promoter was grafted onto syngeneic, non-transgenic mice. Skin graft rejection was measured after active immunization with HPV16 E7 and adoptive transfer of antigen-specific T cells. Cytokine secretion of lymphocytes from mice receiving skin grafts and immunotherapy was detected by enzyme-linked immunosorbent assay, and HPV16 E7-specific memory CD8+ T cells were detected by flow cytometry and ELISPOT. RESULTS: Skin grafts containing HPV16 E6-or E7-expressing keratinocytes were not rejected spontaneously or following immunization with E7 protein and adjuvant. Adoptive transfer of E7-specific T-cell receptor transgenic CD8+ T cells combined with immunization resulted in induction of antigen-specific interferon gamma-secreting CD8+ T cells and rejection of HPV16 E7-expressing grafts. Specific memory CD8+ T cells were generated by immunotherapy. However, a further HPV16 E7 graft was rejected from animals with memory T cells only after a second E7 immunization. CONCLUSIONS: Antigen-specific CD8+ T cells can destroy epithelium expressing HPV16 E7 tumor antigen, but presentation of E7 antigen from skin is insufficient to reactivate memory CD8+ T cells induced by immunotherapy. Thus, effective cancer immunotherapy in humans may need to invoke sufficient effector as well as memory T cells.

Adjuvants, Immunologic↗
PubMed1999

Effect of combined adoptive immunotherapy and radiotherapy on tumor growth.

Advanced squamous cell carcinomas of the head and neck are difficult to control despite optimal surgery, radiotherapy and/or chemotherapy, and the tumors are usually not immunogenic. Because of the anatomic accessibility of the tumors, local adoptive immunotherapy of these tumors is feasible and may interact with radiotherapy to retard tumor growth. It is hypothesized that antigens released from tumor cells injured by radiation may stimulate, in the presence of interleukin-2, an enhanced immunocytodestruction of live tumor cells by adoptively transferred lymphokine activated killer cells and recruited tumor cytotoxic cells. DBA/2 mice were injected subcutaneously with 5 x 10(5) syngeneic squamous cell carcinoma cells in the thigh and the resulting tumors were treated for two weeks with daily peritumoral injections of interleukin-2 (1,000 International Units) or saline, four radiation treatments of 625 cGy each, and four peritumoral injections of 10(7) lymphokine activated killer cells. The results suggested that radiotherapy combined with peritumoral injection of lymphokine activated killer cells and interleukin-2 resulted in a significant reduction (P < 0.01) of tumor size whereas radiation alone, at the same dose, failed to produce a significant effect. Such results may have direct clinical application in enhancing the response of tumors to radiotherapy and in reducing the incidence of tumor recurrence.

Animals↗
PubMed1987

[Effectiveness of multidisciplinary treatment combined with immunotherapy in esophageal cancer--analysis of 287 cases of carcinoma of the thoracic part of the esophagus in Kyushu and Yamaguchi districts].

The effectiveness of surgical adjuvant immunochemotherapy was studied on 287 patients with thoracic esophageal cancer in the Kyushu and Yamaguchi districts. Pre- and postoperative subcutaneous administrations of BCG, 10 mg once a week and an oral administration of PSK, 3 g a day, for as long as possible after surgery were instituted. The control group was designated as the one which neither PSK nor BCG was given. Most patients received chemotherapy and/or radiotherapy. Significant elongation of survival time was observed in immunotherapy patients with stage III and in those with non-curative resection, both having no lymph node metastasis.

Adult↗
PubMedDate not supplied

A streptococcal preparation (OK-432) enhances monoclonal antibody NCC-ST-421 cytotoxicity against human colon cancer.

The murine IgG3 monoclonal antibody NCC-ST-421 (ST-421), raised against human gastric cancer, shows strong reactivity with the Le(a)/Le(a) (al-fucosylated extended type 1 chain) antigen expressed on gastrointestinal (GI) cancer cells. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) by human peripheral blood lymphocytes (PBL), and complement dependent cytotoxicity (CDC). We investigated combination immunotherapy with OK-432, a streptococcal preparation, and ST-421 in vitro and in vivo. ADCC against Colo 205 (a human colon cancer cell line) was enhanced 2 to 3 fold after preincubation of PBL with OK-432 in vitro. These effect's were strongest when PBL were preincubated with OK-432 at a concentration of 0.5 ng/ml for 24 hours. In vivo, a human colon cancer xenograft model exhibited significant growth suppression after combined treatment with ST-421 and OK-432. Such combination immunotherapy may therefore be clinically useful in GI cancer.

Adjuvants, Immunologic↗
PubMed1998

Immunotherapy and combined assay of serum levels of carcinoembryonic antigen and acute-phase reactants.

Our previous studies have revealed that gastric and esophageal cancer patients with abnormal sialic acid levels had a better response than those with normal levels if they received polysaccharide K (PSK), a nonspecific immunomodulator. Serum levels of carcinoembryonic antigen (CEA) and acute-phase reactants (APR) such as immunosuppressive acidic protein, acid-soluble glycoproteins, alpha1-antichymotrypsin, and sialic acid were analyzed in 872 gastric cancer patients who had undergone resection from March 1979 to September 1993 at the Department of Surgery of Tokai University. The patients were categorized into four groups according to the preoperative serum levels: group A had normal levels of both CEA and APR, group B had abnormal CEA and normal APR levels, group C had a normal CEA level and normal levels of one or more APR, and group D had abnormal levels of both CEA and of one or more APR. Patients in group D who received PSK showed significantly better survival than those without PSK (29.3% versus 6.9%; log-rank test, P = 0.0015; Breslow test, P = 0.0042). CEA-positive patients receiving PSK therapy exhibited a significantly better survival rate than those without PSK (38.1 % versus 18.6%; log-rank test, P = 0.0136; Breslow test, P = 0.0125). Cox's regression analysis showed that PSK therapy was significantly related to survival in group D, but not in the other groups. We conclude that the combined assay of tumor-associated factors (such as CEA) and various nonspecific reactants to the presence of cancer (such as immunosuppressive acidic protein, alpha1-antichymotrypsin, acid-soluble glycoproteins and sialic acid) provides a good set of preoperative indicators on which to base the selection of treatment for individual gastric cancer patients.

Acute-Phase Proteins↗
PubMed2026

Integrating clinical and genomic features to predict response to neoadjuvant therapy in microsatellite-stable rectal cancer.

BACKGROUND: Neoadjuvant therapy (NAT) has shifted rectal cancer management toward organ preservation. However, achieving a complete response (CR) for "watch-and-wait" strategies is hindered by high response heterogeneity. Although immunotherapy-combined NAT has expanded the candidate pools, the predictive significance of molecular alterations remains unclear. OBJECTIVES: This study aimed to evaluate clinical and genomic profiles of rectal cancer patients undergoing NAT to identify response predictors and to develop a nomogram for estimating CR probability. DESIGN: Retrospective, single-center cohort study. METHODS: This study included 437 patients with rectal adenocarcinoma at Fudan University Shanghai Cancer Center between December 2019 and March 2023. Patients underwent paired tumor and germline genomic sequencing (887-gene panel) before NAT. Logistic and Cox regression analyses were performed to identify clinical and genetic risk factors associated with tumor response and long-term survival. RESULTS: Of the 437 patients, 96.6% had microsatellite-stable (MSS) tumors. In the MSS locally advanced rectal cancer cohort (N = 307), the CR rate was 35.5%. Multivariate analysis identified immunotherapy-combined NAT (iTNT) (OR 4.41, 95% CI: 2.42-8.27), SYNE1 mutation (OR 2.12, 95% CI: 1.06-4.26), negative mesorectal fascia (MRF) status (OR 0.34, 95% CI: 0.17-0.66), and lower tumor location (OR 0.48, 95% CI: 0.27-0.84) as independent predictors of CR. KRAS mutation was the sole independent predictor of reduced disease-free survival (DFS; HR 1.93, 95% CI: (1.11-3.36), p = 0.020). KRAS G12D subtype was associated with the worst 2-year distant metastasis-free survival (71.3%) and exhibited a distinct predilection for lung metastasis. The clinical-genomic nomogram yielded strong discrimination (AUC = 0.705) and calibration, with favorable DCA net benefit. CONCLUSION: Clinical and genomic features jointly determine outcomes in MSS rectal cancer. SYNE1 mutation serves as a novel biomarker for CR, while KRAS mutations, especially the G12D subtype, identify patients at high risk for systemic relapse. The clinical-genomic nomogram facilitates individualized selection for organ-preservation strategies.

biomarker↗
PubMed1998

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.

Animals↗
PubMed2003

Characteristic cytokine generation patterns in cancer cells and infiltrating lymphocytes in oral squamous cell carcinomas and the influence of chemoradiation combined with immunotherapy on these patterns.

OBJECTIVES: Cytokines produced by tumor cells and tumor-infiltrating lymphocytes (TIL) appear to regulate tumor cell growth and the cytotoxic activity of TIL. The objectives of the present study were to investigate cytokine generation patterns in tumor cells and TIL and to examine the influence of cancer therapy on this cytokine production and the cytotoxic activity of TIL. METHODS: We determined the levels of cytokines produced by tumor cells and TIL in vitro and measured the cytotoxic activity of TIL against Daudi cells in patients with oral squamous cell carcinoma (OSC) before and 1 week after the start of concomitant chemo-radio-immunotherapy. RESULTS: Before the therapy, OSC cells generated higher levels of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) than did oral keratinocytes isolated from the noninflamed gingivae of healthy individuals, but both kinds of cells generated similar levels of interleukin (IL)-1beta and IL-6. Compared with peripheral blood mononuclear cells (PBMC) of the patients, TIL produced higher levels of IL-1beta, IL-6, IL-10, TNF-alpha and TGF-beta, whereas their production of IL-12 and interferon-gamma (IFN-gamma) was only slightly higher than that in PBMC. After 1 week of therapy, the cytokine production by OSC cells had largely decreased, while the production of TNF-alpha, IFN-gamma, TGF-beta and IL-12 by TIL had increased greatly, although other cytokine levels were almost constant during the investigations. The cytotoxic activity of TIL was higher than that of PBMC before the therapy, and this activity was strongly increased by 1 week of therapy. CONCLUSIONS: These results suggest that the cytokine productivities of TIL and tumor cells differ from those of PBMC and normal keratinocytes, respectively, and that chemo-radio-immunotherapy modulates in situ cytokine generation, which is advantageous for inhibition of tumor cell growth and activation of TIL.

Adult↗
PubMed1985

Synergistic effects of combination sequential immunotherapies in a murine ovarian cancer model.

The antitumor effects of Corynebacterium parvum in a murine ovarian teratocarcinoma model depend upon a sequential activation of neutrophils and macrophages within the peritoneal cavity. We studied the sequential administration of biological response modifiers that independently activate each phase of the response. Tumor-challenged mice treated by i.p. injection of a pyridine-extracted fraction of cell-free Propionibacterium acnes (PA-PE, 1400 micrograms) demonstrated prolonged survival in less than 20% of the cases. An i.p. injection of a detoxified Salmonella endotoxin (DSE) preparation (150 micrograms) had no effect on tumor outgrowth. However, i.p. treatment with PA-PE (1400 micrograms), followed by 150 micrograms of DSE 1 day later, resulted in long-term survival (greater than 100 days) in 40 to 60% of mice. This antitumor effect was only evident when PA-PE was administered first (before DSE) and optimal when DSE was administered 24 h after PA-PE. The synergistic antitumor effect could be duplicated when tumor-challenged mice were first treated i.p. with peritoneal polymorphonuclear leukocytes, elicited by injection of PA-PE, and then treated with DSE 18 h later. These data indicate that appropriately timed injection of biological response modifiers with complementary effects can result in a synergistic prevention of tumor growth.

Animals↗