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Biomedical subjects

P L Triozzi

Publications and source records attributed to P L Triozzi.

At least 37 records · Page 2Linked to original sources
PubMed1996

Antitumor and accessory immune activities of peripheral blood stem cells mobilized with granulocyte-macrophage colony-stimulating factor.

The characteristics of PBSC mobilized with GM-CSF, which has been shown to augment monocyte/macrophage (Mo/Mx) antitumor and accessory activities, were evaluated. Patients with metastatic cancers were treated with GM-CSF at 5 micrograms/kg sc, days 1 to 7; leukaphereses were performed on days 6 and 7. A mean of 3.3 x 10(10) mononuclear cells were collected, 59% of which were lymphoid and 32%, monocytoid. Spontaneous Mo/Mx tumor cell cytotoxicity was not detectable in the leukapheresis product, either before or after cryopreservation; Mo/Mx tumor cell cytotoxicity, however, was inducible in vitro with IFN-gamma. Likewise, spontaneous lymphocyte cytotoxicity was not detectable in the leukapheresis product; lymphokine-activated killer cell activity was inducible in vitro with IL-2. Whereas lymphoproliferative responses to tetanus toxoid of cryopreserved PBSC were less than that of freshly collected PBSC, the capacity of Mo/Mx from cryopreserved PBSC to function as accessory cells in the lymphoproliferative response was maintained. These results indicate that significant numbers of immune cells can be mobilized with GM-CSF alone. Cryopreserved, GM-CSF-mobilized PBSC do not demonstrate spontaneous antitumor cytolytic activity; however, accessory activity is present and antitumor cytolytic activity mediated by both monocytoid and lymphoid cells is inducible.

Adult↗
PubMed1995

Expansion of mucin-reactive T-helper lymphocytes from patients with colorectal cancer.

The ability to identify and expand effector cells with reactivity against tumor-associated antigens (TAA) is critical for effective adoptive cellular therapy. The purpose of this study was to assess lymph node lymphocytes sensitized in vivo to the shed TAA TAG-72 as a potential source of cells for adoptive cellular therapy. Lymph nodes containing microscopic tumor and/or shed TAG-72+ mucin were localized using radiolabeled CC49 monoclonal antibody and a gamma detector at the time of exploratory colorectal surgery. Lymph nodes containing microscopic tumor and shed mucin exhibited approximately 40-fold expansion in short-term (< 21 days) cultures with either IL-2 or IL-1 plus IL-2; the combination of IL-2/anti-CD3 monoclonal antibody (mAb) resulted in significantly higher expansion. Cultures generated with IL-2 alone favored the expansion of CD8+ and CD56+ cells, whereas addition of IL-1 or anti-CD3 mAb to IL-2 promoted outgrowth of CD4+ T-cells. The IL-2/anti-CD3 expanded cells exhibited low levels of cytolytic activity in vitro against autologous and allogeneic colon tumor targets. However, CD4+ cells expanded in IL-2/anti-CD3 retained the ability to proliferate in response to TAG-72 mucin-expressing autologous tumor as well as bovine submaxillary mucin (BSM) a soluble TAG-72+ mucin. In addition, CD4+ cells expressed mRNA for IL-2, IL-4, tumor necrosis factor-beta and IFNg, and retained the ability to secrete IL-2 after expansion. Thus, noncytolytic, cytokine-secreting, mucin-reactive T- cells can be expanded from lymph nodes of patients with colorectal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Neoplasm↗
PubMed1995

Phase I trial of escalating doses of interleukin-1 beta in combination with a fixed dose of interleukin-2.

PURPOSE: Interleukin-1 (IL-1) and IL-2 have synergistic antitumor and myelostimulatory activities. We investigated the clinical and biologic effects of IL-1/IL-2 therapy. PATIENTS AND METHODS: Twenty patients with metastatic cancer, divided into five cohorts, were treated with escalating doses of IL-1 beta (0.005 to 0.2 micrograms/kg/d) administered as a 30-minute intravenous (IV) infusion on days 1 to 4, combined with a fixed dose of IL-2 (0.1 mg/m2/d) administered by continuous IV infusion on days 1 to 4. The 4-day cycles were repeated weekly for up to 8 weeks in the absence of toxicity and/or progressive disease. RESULTS: Patients tolerated up to 0.2 microgram/kg/d of IL-1 beta in combination with IL-2 without severe adverse effects. Peripheral-blood CD4-to-CD8 ratios and lymphokine-activated killer (LAK) activity were higher at the lower doses (0.005 to 0.05 microgram/kg/d) of IL-1 beta and higher than that of a cohort of patients treated with IL-2 alone. WBC counts, primarily neutrophils, increased significantly with higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d). Platelet counts were not significantly altered. Increases in serum IL-6, interferon gamma (IFN-gamma), and soluble IL-2 receptor levels were observed, but did not vary with IL-1 beta dose. Tumor regressions were observed in patients with colorectal cancer, melanoma, and renal cell carcinoma. CONCLUSION: IL-1 beta cancer be administered in combination with IL-2 with acceptable toxicity. Our results suggest that the addition of even low-dose IL-1 beta to IL-2 may be associated with potentially beneficial biologic activity; higher doses of IL-1 beta (0.1 to 0.2 microgram/kg/d) may add potentially beneficial hematologic activity.

Adjuvants, Immunologic↗
PubMed1995

Subunit peptide cancer vaccines targeting activating mutations of the p21 ras proto-oncogene.

Activating mutations of the p21 ras proto-oncogene are involved in the development of many common malignancies. Because activating mutations are limited in number, occur within otherwise completely conserved regions, and can be expressed by premalignant lesions, ras is an attractive target for subunit peptide vaccine approaches. Several studies in transplantable tumor models support the possibility that protection against tumors bearing activated ras can be achieved using peptide-based immunogens. We have identified an autochthonous tumor model, A/J mouse lung, which parallels human tumors in the progression of proliferative lesions from premalignant to malignant and which is a very sensitive in vivo system for the detection of activated ras. Although T-cells recognizing a number of activating substitutions can be elicited in this model, peptide immunogens corresponding to the most commonly observed activating mutations are weakly immunogenic. We have engineered a chimeric immunogen incorporating a promiscuous T-cell epitope to enhance the immunogenicity of an oligopeptide corresponding to a weakly immunogenic substitution. These and other challenges associated with developing subunit peptide vaccines to prevent tumors bearing activated ras are discussed.

Amino Acid Sequence↗
PubMed1994

Localization of tumor-reactive lymph node lymphocytes in vivo using radiolabeled monoclonal antibody.

BACKGROUND: Lymph node lymphocytes vary in their responsiveness to tumor. A technique has been developed that uses radiolabeled monoclonal antibody (MoAb) against the tumor-associated mucin, TAG-72, and a gamma-detecting probe by which lymph nodes containing microscopic tumor and/or shed TAG-72 can be identified in vivo. The immunologic characteristics of these lymph nodes were examined. METHODS: Patients with colon cancer received 125I-labeled MoAb CC49 by intravenous injection preoperatively. During laparotomy lymph nodes that appeared normal on inspection and palpation but which contained radiolabeled MoAb were identified using a hand-held gamma-detecting probe. These lymph nodes and other lymph node and tumor specimens were resected for analysis. RESULTS: Lymph nodes identified by the probe were found by immunohistochemical studies to contain microscopic tumor and/or shed antigen associated with germinal centers. They were characterized by greater CD4+:CD8+ ratios, rates of expansion, and cytolytic activity compared with lymphocytes from lymph nodes with macroscopic tumor, noninvolved lymph nodes, and tumors. All lymph node lymphocytes identified by the probe demonstrated significant proliferative responses to autologous tumor and, in contrast to lymphocytes from noninvolved lymph nodes, significant proliferative responses to allogeneic TAG-72+ tumor cells and to soluble TAG-72+ mucin. CONCLUSIONS: By locating lymph nodes with microscopic tumor and/or shed antigen, the use of radiolabeled MoAb in vivo can be used to reproducibly identify tumor-reactive lymph node lymphocytes. This technique may be useful in identifying cells for use in adoptive immunotherapy programs and in studying the regulation of immune responses in vivo.

Antibodies, Monoclonal↗
PubMed1994

Application of chemical immunomodulators to the treatment of cancer and AIDS.

A number of potential advantages, development of promising new agents, and the discovery of synergy with cytokines or cell products continue to spur research into the application of chemical immunomodulators for the treatment of cancer and AIDS. In preclinical in vitro and in vivo systems, chemical immunomodulators definitely modulate the immune system and have therapeutic efficacy. Although clinical trials have shown the ability of these agents to modulate the human immune system, thus far chemical immunomodulators have generally not fulfilled the therapeutic promise generated in animal models for the treatment of human diseases. While the discrepancy in results between animal models and human trials is obvious, the basis is not apparent. Species differences in elimination kinetics, presentation of active drug at the site of action, and the development of tachyphylaxis have been postulated as reasons for the minimal activity of these agents in humans. In addition, the use of investigational techniques established for cytotoxic agents may not be appropriate for immunomodulators. As with any immunomodulator, determining an optimal immunostimulatory dose and schedule and applying the therapy to patients with minimal tumor burden would perhaps be more appropriate than use of a maximally tolerated dose in patients with advanced disease. A dose-immunological effect relationship has recently been demonstrated for levamisole at doses higher than those used for many years in levamisole trials (99). While research and clinical investigation have identified several potentially useful chemical immunomodulators, the elementary understanding of the biochemical mechanisms involved in immunoregulation remains basic. Future research must elucidate these mechanisms, particularly in humans, to maximize the benefits of chemical immunomodulators as single agents or combined with cytotoxic chemotherapeutic agents, surgery, radiation therapy, other immunomodulators, and antiviral agents.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Identification and activation of tumor-reactive cells for adoptive immunotherapy.

The use of adoptive immunotherapy to treat cancer has several potential advantages. Although extensive evaluation has been undertaken, issues regarding the source of cells and methods of ex vivo activation continue to be controversial. A number of potential effector cells, including natural killer cells, monocytes/macrophages, cytolytic T cells and helper T cells, are exploitable and are the focus of clinical trials. A number of methods of activating these cells, including the use of recombinant cytokines, tumor cells, monoclonal antibodies, and gene insertion, have been developed. Varying specificities, trafficking and lytic potentials have been observed. In addition, the logistics of activating and expanding the various effectors ex vivo vary considerably. Although the optimal methods of identifying and activating cells have not been established, adoptive therapy with immunologically active cells can effect clinically significant responses in selected patients. Efforts to build upon the initial preclinical and clinical observations are in progress.

Animals↗
PubMed1993

Aci-reductones enhance interleukin-2-induced lymphocyte cytotoxicity.

Arachidonic acid (AA) metabolites and reactive oxygen species (ROS) are implicated in the suppression of interleukin-2 (IL-2) activity. We investigated the effects of aci-reductones, compounds that function both as inhibitors of AA metabolism and as scavengers of ROS, on the generation of IL-2-induced, lymphokine activated killer (LAK) activity. Aci-reductones belonging to the 4-aryl-2-hydroxytetronic acid system improved the in vitro generation of LAK activity from IL-2-treated human peripheral blood mononuclear cells (PBMC) approximately 4-fold. Those aci-reductones belonging to the 3,4-dihydroxyhenzofuranone class were less effective. LAK activity improvement was comparable to that produced by indomethacin with superoxide dismutase plus catalase and comparable to the improvement produced by depleting PBMC of monocytes. Aci-reductones completely suppressed the production of prostaglandin E2 from PBMC in response to IL-2 and partially suppressed superoxide anion production. Daudi cell and lymphocyte subset proliferation and monocyte viability were not affected. Less improvement in LAK activation was observed when PBMC depleted of monocytes were exposed to IL-2 and aci-reductones. We conclude that aci-reductones improve LAK generation from PBMC in vitro. This property may be mediated via effects on monocyte AA and ROS metabolism.

Adjuvants, Immunologic↗
PubMed1993

Radioimmunoguided surgery for colorectal cancer.

This article provides a basic understanding of the RIGS (radioimmunoguided surgery) technique and reviews the evolution of the technology from its inception as an experimental technique in animal models to the current clinical trials in patients. A review of published data from the laboratory and from preclinical and clinical trials is updated by a statement of the current status of RIGS. A look at the future of RIGS as an experimental and clinical tool highlights current areas of investigation based on this technology.

Animals↗
PubMed1992

Modulation of adhesion molecules on human large granular lymphocytes by interleukin-2 in vivo and in vitro.

The modulation of adhesion molecules on human large granular lymphocytes (LGL) by interleukin (IL)-2 was investigated both in vivo and in vitro. Intercellular adhesion molecule-1 (ICAM-1; CD54) expression increased on LGL of cancer patients receiving IL-2 adoptive immunotherapy. ICAM-1 expression on LGL isolated by Percoll gradient centrifugation, LGL purified, and expanded by adherence to plastic surfaces and LGL identified by Leu 19 (CD56) monoclonal antibody were increased significantly in response to IL-2 in vitro. Exposure of LGL to IL-1, interferon (IFN)-gamma, and tumor necrosis factor (TNF) in vitro did not induce ICAM-1. The expression of LFA-1 (CD11a/CD18), a receptor for ICAM-1, and other leukocyte adhesion molecules, including Mac-1 (CD11b/CD18) and p150,95 (CD11c/CD18), was only maintained by IL-2. IL-2 induction of ICAM-1 and the maintenance of CD18 complex expression on small lymphocytes separated by Percoll gradients were similar to that on LGL. We conclude that IL-2 enhances the expression of ICAM-1 on multiple human lymphocyte populations including LGL effectors. Expression of the CD18 complex on LGL does not appear to be highly regulated by IL-2. These findings may have implications relevant to the role of these adhesion molecules in the activities of LGL modulated by IL-2.

Antigens, CD↗
PubMed1992

Modulation of leukemic cell sensitivity to lymphokine-activated killer cytolysis: role of intercellular adhesion molecule-1.

The role of CD11/CD18 leukocyte adhesion molecules and their ligands in mediating non-major histocompatibility complex (MHC) restricted lymphocyte cytotoxicity is controversial. In order to examine the role of target cell intercellular adhesion molecule-1 (ICAM-1; CD54), a ligand of lymphocyte function-associated antigen (LFA-1) (CD11a/CD18), we exposed the human leukemia cell line, HL-60, to a variety of agents implicated in modulating ICAM-1 expression and/or sensitivity to lymphocyte cytolysis. Exposure of HL-60 cells to retinoic acid (RA), interferon (IFN)-alpha, IFN-beta, and IFN-gamma induced protection from lymphokine-activated killer (LAK) cytolysis. Only RA and IFN-gamma induced ICAM-1 expression. Tumor necrosis factor and vitamin D3, which also induced ICAM-1 expression, increased HL-60 sensitivity to LAK lysis. Granulocyte-macrophage colony-stimulating factor also increased sensitivity to LAK lysis; ICAM-1 was not induced. The state of cellular differentiation and expression of class I and II MHC antigens also did not correlate with sensitivity to LAK cytolysis. Exposure of untreated HL-60 cells and HL-60 cells expressing ICAM-1 to monoclonal antibody (mAb) versus ICAM-1 did not modulate LAK sensitivity. Exposure of LAK cells to mAb versus LFA-1 partially inhibited cytolysis; mAb versus CD18 inhibited cytolysis more completely. HL-60 cells were resistant to natural killer lysis; exposure to the various experimental agents did not alter sensitivity. We conclude that leukemic cell sensitivity to LAK cytolysis can be modulated by a variety of agents. Although our results suggest a role for leukocyte CD11/CD18 adhesion molecules in LAK cytolysis, the poor correlation between ICAM-1 expression and sensitivity to LAK lysis suggest that interactions other than LFA-1/ICAM-1 conjugation may be more central to the processes involved.

Antibodies, Monoclonal↗
PubMed1992

Modulation of hematologic and immunologic effects of high dose chemotherapy by interleukin-2 in a murine tumor model.

To determine if intensive chemotherapy consisting of cyclophosphamide (C), etoposide (E), and cisplatin (P) (CEP) may be usefully combined with recombinant human interleukin-2 (rhIL-2), we examined a murine tumor model designed to approximate a common clinical situation: macroscopic, drug-resistant cancer. Using C57BL/6 mice with extensive tumor burden 10 days after intravenous B16 melanoma cell injection, we observed (1) C, E, and P synergize to enhance survival but do not cure mice at the highest tolerable dose (C = 200 mg/kg, E = 60 mg/kg, and P = 3 mg/kg); (2) rhIL-2 at 3 x 10(5) U (subcutaneously) daily for 4 days administered 10-18 days after B16 injection significantly improves survival; (3) CEP plus rhIL-2 is more effective than CEP alone only when rhIL-2 is administered before CEP; (4) CEP suppresses IL-2-induced lymphokine-activated killer cell activity in the spleen; and (5) rhIL-2 protects mice incompletely from the immunologic and hematologic suppression of CEP. Our results suggest that intensive chemotherapy combined with rhIL-2 may be beneficial. The success of any such combination may be schedule dependent.

Animals↗
PubMed1991

Interleukin-2 therapy enhances salicylate oxidation by blood granulocytes.

These studies determined the effect of interleukin-2 (IL-2) immunotherapy on the oxidative metabolism of the blood granulocytes of eight patients with metastatic renal cancer. We quantitated the rate of the hexose monophosphate shunt activity (HMPS), hydrogen peroxide (H2O2) production, and salicylate oxidation of the unstimulated and phorbol myristate acetate (PMA)-stimulated granulocyte cultures before, during, and after a 5-day continuous infusion of IL-2. There was no change in the rate of HMPS activity. However, the rate of salicylate oxidation of the unstimulated and PMA-stimulated cultures of these patients was significantly increased after the therapy was complete. Overall, there was no increase in the rate of H2O2 production, although the PMA-stimulated cultures of three of eight patients had a twofold higher production of H2O2 after treatment compared with the pretreatment values. The enhanced rate of salicylate oxidation by the granulocytes after treatment indicates that these cells were "stimulated" in vivo to produce a potent oxidant, which is most likely hydroxyl radical or an oxidant of comparable activity. Further, the granulocytes were primed ("activated"), since they had an augmented response to PMA. IL-2 did not stimulate the oxidative metabolism of granulocyte cultures in vitro, suggesting that the IL-2 effect in vivo is not a direct one. Our results indicate that IL-2 immunotherapy is associated with the activation of blood granulocyte oxidative metabolism and that these activated granulocytes may be related to some of the toxic side effects of IL-2 therapy such as the capillary leak syndrome. Further oxidant injury to the granulocytes may explain the reported defect in chemotaxis.

Carcinoma, Renal Cell↗