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Biomedical subjects

E S Vitetta

Publications and source records attributed to E S Vitetta.

At least 55 records · Page 3Linked to original sources
PubMed1996

The roles of Fas and perforin in LAK T-cell/bispecific antibody-mediated killing of the murine B-lymphoma cells, BCL1.

The aim of this study was to construct bispecific F(ab')2 [anti-CD3 x anti-BCL1 idiotype (Id)] Abs (BsAbs) which would enable lymphokine-activated killer (LAK) T cells to kill Id+ mouse BCL1 lymphoma cells, and to determine the mechanism(s) underlying cell death. Using 4-day activated LAK T cells from either perforin-knockout mice or FasL-deficient gld mice, we show that the Fas pathway, but not perforin, is required for BsAb-mediated LAK T-cell-induced killing of BCL1 cells.

Animals↗
PubMed1996

Combination immunotoxin treatment and chemotherapy in SCID mice with advanced, disseminated Daudi lymphoma.

We describe the use of an immunotoxin (IT) cocktail (anti-CD22- and anti-CD19-ricin A chain) and any 1 of 3 chemotherapeutic drugs (doxorubicin, cytoxan or camptothecin) to treat advanced disseminated Daudi lymphoma in SCID mice (SCID/Daudi). In a previous report, we demonstrated that this regimen was curative when given the day following tumor cell inoculation. Here, we show that combination therapy in mice with advanced tumor significantly increased their survival, although it was not curative. Importantly, the outcome of therapy was dependent upon the temporal order in which IT and chemotherapy were administered. Thus, the best anti-tumor effect was achieved when an IT cocktail was given before or at the same time as chemotherapy. When the IT was given after chemotherapy, there was no additional therapeutic benefit. Our results confirm the rationale of using combination therapy in the treatment of advanced B-cell neoplasia and suggest that ITs should be administered prior to or during chemotherapy.

Animals↗
PubMed1996

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.

IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48-hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs.

Adult↗
PubMed1996

The use of cyclosporine, FK506, and SDZ NIM811 to prevent CD25- quiescent peripheral blood mononuclear cells from producing human immunodeficiency virus.

It has been shown that the combined use of two pharmacologic agents can inhibit human immunodeficiency virus (HIV) production by peripheral blood mononuclear cells in vitro. One, an anti-CD25 immunotoxin (IT), kills activated T cells that produce virus; the other, the immunosuppressive drug cyclosporine, prevents the quiescent cells, which harbor HIV, from becoming activated. The present study compares the antiviral activities of two agents, SDZ NIM811 and FK506, to that of cyclosporine. In combination with the anti-CD25 IT, these drugs significantly suppressed virus production. In the absence of prior addition of the IT, the ability of the drugs to inhibit virus production was much lower, suggesting that they work effectively in latently infected cells. In the case of SDZ NIM811, the inhibition of virus production was accompanied by a modest inhibition of cell proliferation. In contrast, FK506 exerted strong antiproliferative activity. Cyclosporine was both moderately antiproliferative and a potent antiviral agent.

Antiviral Agents↗
PubMed1996

T cell activation and human immunodeficiency virus replication after influenza immunization of infected children.

BACKGROUND: T cell activation plays a major role in the ability of HIV to remain latent or to establish a productive infection. It has been hypothesized that vaccination-mediated immune stimulation can activate T cells and enhance HIV replication. Our study was designed to determine whether influenza immunization would induce T cell activation and increase HIV burdens in HIV-infected children. METHODS: Blood samples from 16 HIV-infected children ages 6 months to 14 years were obtained immediately before and 2 and 6 to 8 weeks after the administration of influenza vaccine. The percentage of activated (CD25+) T cells was determined by flow cytometry, and HIV viral load was measured by quantitative cultures of peripheral blood mononuclear cells and plasma HIV RNA. RESULTS: The administration of influenza vaccine was associated with significant increases in HIV viral load in 5 of 16 children evaluated. These increases in HIV burden were transient, and in four of five patients the plasma HIV RNA copy number returned to baseline 6 to 8 weeks after immunization. There was no correlation between the patient's immunologic or clinical category according to the CDC classification and either the initial viral load or the likelihood of having a significant increase after immunization. Four of the five patients who experienced increases in viral load after influenza immunization were not receiving antiretroviral therapy. CONCLUSIONS: Our results emphasize the need for additional studies that examine the effect of routine immunizations on T cell activation and HIV replication in HIV-infected children.

Adolescent↗
PubMed1996

Immunotoxins: an update.

The use of immunotoxins (ITs) in the therapy of cancer, graft-vs-host disease (GvHD), autoimmune diseases, and AIDS has been ongoing for the past two decades. ITs contain a targeting moiety for delivery and a toxic moiety for cytotoxicity. Theoretically, one molecule of a toxin, routed to the appropriate cellular compartment, will be lethal to a cell. Newly developed MoAbs, toxins, and molecular biological technologies have enabled researchers to construct ITs that can effectively kill many different cell types. In fact, phase I/II clinical trials have given promising results. Although nonspecific toxicity and immunogenicity still limit the use of IT therapy, these agents hold enormous promise in an optimal setting to treat minimal disease.

Animals↗
PubMed1996

Effect of sublethal irradiation of SCID mice on growth of B-cell lymphoma xenografts and on efficacy of chemotherapy and/or immunotoxin therapy.

Severe combined immune deficiency (SCID) mice obtained from different vendors vary in their capacity to accept human tumor xenografts, and in some instances mice must first be irradiated. It has been reported that SCID mice are particularly sensitive to irradiation which, in addition, can partially restore their immune system so that they are no longer totally immunologically incompetent. For the past several years we have used nonirradiated SCID mice to grow human B-cell lymphomas. When we changed vendors, we found it necessary to irradiate the mice before xenografting. Sublethal irradiation of at least one source of SCID mice before tumor cell inoculation improved tumor take and dissemination, but irradiation changed the response of these mice to chemotherapy and immunotoxins. Thus the irradiated mice did not respond to chemotherapy, but the two immunotoxins used for therapy became more effective in extending survival of the mice. It then appears that irradiation affects the immune system of SCID mice in such a way as to change their response to the therapeutic regimens used here.

Animals↗
PubMed1996

Decreases in levels of serum fibronectin predict the severity of vascular leak syndrome in patients treated with ricin A chain-containing immunotoxins.

The major dose-limiting adverse effect of ricin A chain-containing immunotoxin (IT) therapy is vascular leak syndrome (VLS). Since plasma fibronectin (Fn) plays a role in maintaining microcirculatory integrity and since the gradient between plasma and tissue Fn can be altered in various pathological situations, we determined whether the administration of IT-ricin A chain to patients resulted in changes in the levels of serum Fn and, if so, whether these changes correlated with the severity of VLS. We also measured the serum levels of tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine which has been implicated in tissue damage and in interleukin 2-mediated VLS. Our results indicate that the most severe manifestations of VLS were associated with the highest pretreatment levels of Fn, the largest decreases in Fn immediately after starting IT therapy, increases in the levels of serum TNFalpha, higher concentrations of circulating IT, and the lowest numbers of circulating tumor cells. These parameters should, therefore, be useful for predicting which patients will have severe VLS.

Adult↗
PubMed1995

The in vivo anti-tumor activity of immunotoxins containing two versus one deglycosylated ricin A chains.

We have compared the in vitro and in vivo activities of three deglycosylated ricin A chain (dgA)-containing immunotoxins (ITs) with one versus two molecules of dgA per molecule of IgG. Two of the ITs (anti-CD19-dgA2 and anti-CD25-dgA2) had 3-0-fold improvements over their dgA1 counterparts in vitro. However, the in vivo anti-tumor activity of both constructs of each IT was the same. In contrast, anti-CD22-dgA2 was 7-fold more potent in vitro and significantly more potent in vivo than its dgA1 counterpart. These studies suggest that monoclonal antibodies must be individually tested to determine whether the addition of two versus one dgA will improve cytotoxic activity in vivo.

Animals↗
PubMed1995

Expression of CD25 defines peripheral blood mononuclear cells with productive versus latent HIV infection.

The present studies were designed to further determine whether the CD25 marker could distinguish between cells productively and latently infected with HIV. This was accomplished by combining immunotoxin (IT)-mediated killing of CD25+ cells, highly sensitive indirect immunofluorescence to detect remaining CD25+ cells, and PCR-mediated amplification of proviral DNA in immunotoxin-treated vs untreated HIV-infected cells. Our results demonstrate that: 1) By direct immunofluorescence 3 to 8% of PBMCs are CD25+, whereas by indirect immunofluorescence 30% are CD25+. The increased number of CD25+ cells is due to their detection by the highly sensitive indirect immunofluorescence assay. Up to 60% of the CD25+ cells are CD4+ and 12% are CD8+. 2) Treatment of HIV-infected PBMCs with an anti-CD25 IT for 6 days eliminated both CD25high and CD25low cells and decreased the production of p24 by 99%. 3) Differences in the HIV proviral genome were detected in the unfractionated PBMCs vs PBMCs from which CD25+ cells had been eliminated by IT treatment. Hence, PBMCs containing both CD25+ and CD25- cells express all intermediate proviral species and full-length double-stranded proviral DNA. In contrast, CD25- quiescent cells contain predominantly intermediate species. These results confirm and extend our previous observations that expression of CD25 can distinguish latently infected cells from cells producing virus.

Base Sequence↗
PubMed1995

Staphylococcal enterotoxin B induces the expression of activation markers on murine memory T cells in the absence of proliferation or lymphokine secretion.

Superantigens have been used to study peripheral tolerance in CD4+ T cells. The superantigen SEB induces T cell anergy by promoting the differentiation of SEB-activated virgin T cells into anergic memory T cells. Memory T cells from SEB or antigen-primed mice do not proliferate when they are cultured with SEB. The present studies were performed to determine whether memory T cells fail to interact with SEB antigen-presenting cells or whether SEB promotes incomplete or negative signals in memory T cells. When murine virgin and memory T cells were separated on the basis of CD45RB expression and cultured with SEB-pulsed B cells, SEB induced the expression of CD25, which then mediated proliferation when IL-2 was added to the cultures. In addition, SEB promoted the expression of the CD40L, which is required for T helper cell function. Finally, PMA induced a costimulatory signal leading to the proliferation of these cells. Surprisingly, the agents, i.e., IL-2 and PMA, which induced TM cell proliferation in conjunction with SEB failed to induce lymphokine secretion. However, in the presence of IL-4 plus IL-5, the T memory cells induced the SEB-pulsed B cells to secrete IgM and IgG. These results suggest that memory T cells are not simply unresponsive to SEB but are actively anergized.

Animals↗
PubMed1995

Tumor dormancy and cell signaling. II. Antibody as an agonist in inducing dormancy of a B cell lymphoma in SCID mice.

Tumor dormancy can be induced in a murine B cell lymphoma (BCL1) by immunizing BALB/c mice with the tumor immunoglobulin (Ig) before tumor cell challenge. In this report, we have investigated the immunological and cellular mechanisms underlying the induction of dormancy. BCL1 tumor cells were injected into SCID mice passively immunized with antibody against different epitopes on IgM or IgD with or without idiotype (Id)-immune T lymphocytes. Results indicate that antibody to IgM is sufficient to induce a state of dormancy. Antibodies against other cell surface molecules including IgD and CD44 (Pgp1) had no effect on tumor growth. Id-immune T cells by themselves also had no effect on tumor growth in SCID mice. However, simultaneous transfer of anti-Id and Id-immune T cells enhanced both the induction and duration of the dormant state. In vitro studies indicated that antibody to IgM induced apoptosis within several hours and cell cycle arrest by 24 h. Hyper cross-linking increased apoptosis. The Fc gamma RII receptor played little or no role in the negative signaling. Antibodies that did not negatively signal in vitro did not induce dormancy in vivo. The results suggest that anti-IgM plays a decisive role in inducing tumor dormancy to BCL1 by acting as an agonist of IgM-mediated signal transduction pathways.

Animals↗
PubMed1995

Anti-CD54 (ICAM-1) has antitumor activity in SCID mice with human myeloma cells.

Recent studies have suggested that ICAM-1 (CD54) is involved in the pathogenesis of human multiple myeloma. A monoclonal antihuman CD54 antibody has been generated by immunizing BALB/c mice with human myeloma cell lines. SCID mice injected with human ARH-77 myeloma cells develop disseminated myeloma which is similar in several respects to multiple myeloma in humans. The mice have monoclonal gammopathy and succumb to hind leg paralysis caused by infiltration of tumor cells into the thoracolumbar vertebrae, resulting in compression of the spinal cord. In the absence of treatment, the mean paralysis time of the SCID/ARH-77 mice is 29 days. When the SCID/ARH-77 mice received four consecutive daily i.v. injections of anti-CD54 mAb commencing 1 day after tumor inoculation, they survived for 150 days, at which time the experiment was terminated. Histopathological analyses indicated that prior to death all control SCID/ARH-77 mice had myeloma cells in the vertebrae and skull. At this time, the anti-CD54-treated mice had no evidence of tumor. High levels of human immunoglobulin were detected in the sera of control, but not treated mice. F(ab')2 fragments of the anti-CD54 antibody also had similar, albeit, slightly less antitumor activity in vivo, suggesting that antibody effector function may account for some, but not all the antitumor activity of anti-CD54. In vitro studies indicate that anti-CD54 does not inhibit homotypic adhesion, the binding of myeloma cells to murine bone marrow stromal cells, or cell proliferation. By exclusion, we propose that the CD54-mediated homing of these ARH-77 cells to certain anatomical sites is crucial for their growth in vivo.

Animals↗
PubMed1995

Immunotherapy of multiple myeloma.

In 1994, an estimated 12,700 new cases of multiple myeloma (MM) will be diagnosed in the USA and 9,800 patients will die from this disease. At present, a cure for MM has not been achieved with any chemotherapeutic regimen. Therefore, it is important to develop novel therapeutic approaches to treat this fatal disease. This review focuses on new concepts in the immunotherapy of MM. Thus far, interferons and anti-human interleukin (IL)-6 monoclonal anti-bodies (MAbs) have been used to treat patients with this disease. Bone marrow transplantation using autologous marrow purged with MAbs and complement, with anti-myeloma immunotoxins (ITs), or MAb-magnetic bead conjugates has been reported. Adoptive cellular therapy, in vivo with anti-CD3 and IL-2, as well as transplantation of purified autologous CD34+ peripheral blood stem cells, is now being evaluated in clinical trials. Anti-human IL-6 receptor (IL-6R) and anti-CD54 (ICAM-1) MAbs have shown promising results in the therapy of human myeloma cell lines in SCID mice, while an IL-6 antagonist protein, anti-gp130 MAbs, recombinant soluble gp130, anti-B7, anti-HLA-DR, and recombinant soluble CD16 also inhibit the growth of myeloma cell lines in vitro. These experimental therapeutic modalities hold promise for use in humans and may also provide further insights into the pathogenesis of MM.

Antibodies, Monoclonal↗
PubMed1995

Phase I trial of an anti-CD19 deglycosylated ricin A chain immunotoxin in non-Hodgkin's lymphoma: effect of an intensive schedule of administration.

In a phase I trial, eight patients with non-Hodgkin's B-cell lymphoma received mouse IgG1k monoclonal antibody HD37 specific for CD19 conjugated to deglycosylated ricin A chain (dgA) administered in four doses at 4-h intervals with total doses ranging from 4-12 mg/m2. This schedule generated serum levels of immunotoxin which were sustained over 36 h. The plasma half-life of HD37-dgA was 17 +/- 4 (SD) h. The HD37-dgA conjugate was stable in vivo as demonstrated by serum levels of HD37-dgA conjugate comparable to those of total HD37 antibody. Peak serum levels attained after the fourth dose ranged from 0.36 to 5.63 micrograms/ml. Two of seven evaluable patients developed modest human anti-immunotoxin antibody responses. Toxicity in patients 1-7 consisted of dose-dependent capillary leak syndrome with hypoalbuminemia, orthostatic hypotension, and weight gain. Patient 8 died on day 8 with severe capillary leak, bronchopneumonia, and rhabdomyolysis. All patients had progressive disease at 4 weeks except patient 8, who exhibited a near-complete remission before his death. This intensive schedule appears to produce inordinate toxicity with a maximal tolerated total dose of 8 mg/m2.

Adult↗
PubMed1995

Tumour dormancy and cell signalling--III: Role of hypercrosslinking of IgM and CD40 on the induction of cell cycle arrest and apoptosis in B lymphoma cells.

Polyclonal anti-IgM antibodies were more effective than monoclonal antibodies in inducing dormancy in SCID mice bearing a murine B lymphoma (BCL1). Under saturating conditions, both polyclonal and monoclonal anti-Ig antibodies induced cell cycle arrest (CCA) in both BCL1 cells and human B lymphoma cells (Daudi) but polyclonal antibodies were far more effective at inducing apoptosis. A mixture of several monoclonal antibodies specific for noncrossreactive epitopes on C mu mimicked the effects of a polyclonal anti-mu. Hypercrosslinking mIgM by a polyclonal antibody against the primary monoclonal anti-mu markedly increased apoptosis and CCA. Hence, the extent of crosslinking of IgM and the resultant singnalling may be a major factor in inducing and maintaining dormancy and in determining whether lymphoma cells respond by apoptosis or CCA. In contrast to mIgM, another B cell receptor, CD40, which induces CCA when crosslinked did not induce apoptosis after hypercrosslinking. The results are consistent with the hypothesis that aspects of the CCA and apoptotic pathways are independent. When anti-CD40 was added with anti-mu to Daudi cells, the proportion of cells undergoing apoptosis was increased.

Animals↗
PubMed1995

Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy.

We have characterized a murine IgM monoclonal antibody, TEC-11, that recognizes endoglin and may be suitable for targeting cytotoxic agents to human tumor vasculature. TEC-11 strongly stains endothelial cells in a broad range of solid human tumors while staining endothelial cells in the majority of normal, healthy adult tissues relatively weakly. Human umbilical vein endothelial cells (HUVECs) in sections of the umbilical vein react weakly with TEC-11, whereas proliferating HUVECs in tissue culture react strongly and uniformly. HUVEC cultures grown to confluence and then rested contain two subpopulations having high and low levels of endoglin expression. Flow cytometry revealed that a significant proportion of cells with high endoglin expression are cycling, having markedly increased levels of cellular protein, RNA, and DNA by comparison to low endoglin-expressing cells, which appear to be noncycling. Taken together, the increased binding of TEC-11 to tumor vasculature and to dividing as opposed to noncycling HUVECs in vitro suggests that endoglin is an endothelial cell proliferation-associated marker. An immunotoxin [TEC-11.deglycosylated ricin A chain (dgA)] composed of TEC-11 and dgA was 3000-fold more potent at inhibiting protein synthesis in proliferating HUVEC cultures than in confluent cultures. The confluent cells were no more sensitive to TEC-11.dgA than they were to an isotype-matched immunotoxin of irrelevant specificity. These findings suggest that TEC-11.dgA might have therapeutic value in the treatment of solid tumors in humans by selectively killing dividing endothelial cells which are prevalent in such tumors.

Adult↗