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Biomedical subjects

E S Vitetta

Publications and source records attributed to E S Vitetta.

At least 19 recordsLinked to original sources
PubMed1998

Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.

Immunotoxins (ITs) are potent cytotoxic agents used in the treatment of cancer, autoimmune disease, and graft-versus-host disease. Results from clinical trials demonstrate that many IT-treated patients, especially those with an intact immune system, develop anti-IT antibodies that may prohibit repeated IT dosing. We, therefore, evaluated a panel of novel immunosuppressive (IS) agents for their ability to inhibit the antitoxin immune response in mice receiving multiple courses of a ricin A chain (RTA)-containing IT and also assessed whether this suppression would result in an increase in IT-mediated antitumor activity. The results indicate that a 3-day pretreatment, plus one additional boost 2 weeks later, of a combination of hCTLA4Ig + anti-CD40L, virtually eliminated the anti-RTA response in normal mice receiving six weekly injections of an IT. When tested in BCL1 tumor-bearing mice, the concomitant use of a combination of hCTLA4Ig + anti-CD40L and six doses of the IT resulted in a 1.5-fold increase in tumor cell killing, as compared with treatment with IT alone. We conclude that a combination of IS + IT therapy should facilitate the administration of multiple courses of IT, as well as enhance its antitumor activity.

Animals↗
PubMed1997

Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor cells.

Monoclonal antibodies (mAbs) that exert antitumor activity can do so by virtue of their effector function and/or their ability to signal growth arrest or cell death. In this study, we demonstrate that mAbs which have little or no signaling activity-i.e., anti-CD19, CD20, CD21, CD22 and Her-2-can become potent antitumor agents when they are converted into IgG-IgG homodimers. The homodimers exert antigrowth activity by signaling G0/G1 arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and, in the case of the anti-CD19 mAb, did not require an Fc portion. These results offer the possibility that homodimers of other tumor-reactive mAbs which have little antitumor activity as monomers might be potent, antitumor agents.

Antibodies, Monoclonal↗
PubMed1997

Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established.

The majority of BALB/c mice immunized with the BCL1 lymphoma-derived idiotype (Id+) IgM and subsequently challenged with BCL1 tumor cells develop a state of tumor dormancy. The vast majority of dormant lymphoma cells are in cell cycle arrest, but there are also residual replicating cells. In the present studies, we attempted to define features of both the dormant lymphoma cells and the host that lead to escape from dormancy. Escape from dormancy occurs at a steady rate over a 2-year period, suggesting that it is a stochastic process. We found that, in the majority of mice, escape was due to the emergence of genetic variants that were no longer susceptible to the anti-Id-mediated induction of dormancy. Ten percent of these variants were Id-; the remainder were Id+ but could grow in the presence of anti-Id antibodies, suggesting that there were mutations in molecules involved in one or more mIg-mediated negative-signaling pathways. In two of five such escapees, alterations in either Syk, HS1, and/or Lyn were observed. In a small percentage of mice, a low titer of circulating anti-Id antibody before tumor challenge correlated with a subsequent, more rapid loss of dormancy.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Highly purified CD25- resting T cells cannot be infected de novo with HIV-1.

Previous studies have demonstrated that the expression of CD25 can distinguish CD25- latently infected cells from CD25+ cells actively producing virus. Our studies were designed to characterize the nature and stability of the viral genome in CD25- quiescent HIV-1-infected cells and to determine whether these cells could be infected de novo with HIV-1. Our results show that: (i) When unfractionated peripheral blood mononuclear cells are first infected with HIV-1 and the CD25- cells then isolated, the latter contain only incomplete DNA transcripts and no full-length DNA or 2-LTR circles. Phytohemagglutinin activation of these CD25- cells results in the generation of full-length viral DNA and p24 production. (ii) When CD25- CD4+ cells are first purified from peripheral blood mononuclear cells and then incubated with HIV-1, viral DNA cannot be detected, suggesting that these purified cells cannot be infected. Furthermore, CD25-adherent cells do not facilitate the infection of CD4+ CD25- T cells when they were present at the time of incubation with HIV-1. Taken together, these studies suggest either that (i) the CD25- cells containing incomplete DNA transcripts are derived from infected-activated CD25+ cells, which subsequently become CD25- or (ii) the presence of CD25+ cells is required for the infection of CD25- cells in vitro.

CD4-Positive T-Lymphocytes↗
PubMed1997

Vascular leak syndrome: a side effect of immunotherapy.

The major dose-limiting toxicity of interleukin-2 (IL-2) and of immunotoxin (IT) therapies is vascular leak syndrome (VLS). VLS is characterized by an increase in vascular permeability accompanied by extravasation of fluids and proteins resulting in interstitial edema and organ failure. Manifestations of VLS include fluid retention, increase in body weight, peripheral edema, pleural and pericardial effusions, ascites, anasarca and, in severe form, signs of pulmonary and cardiovascular failure. Symptoms are highly variable among patients and the causes are poorly understood. The pathogenesis of endothelial cell (EC) damage is complex and can involve activation or damage to ECs and leukocytes, release of cytokines and of inflammatory mediators, alteration in cell-cell and cell-matrix adhesion and in cytoskeleton function. VLS restricts the doses of IL-2 and of ITs which can be administered to humans and, in some cases, necessitates the cessation of therapy. This review discusses the diversity of clinical manifestation, possible mechanisms and therapeutic modalities for VLS induced by IL-2 and ITs.

Capillary Permeability↗
PubMed1997

Prophylactic intervention in RadLV-induced lymphomagenesis with an anti-IL-4 monoclonal antibody.

Intrathymic inoculation of the radiation leukemia virus (RadLV) into C57BL/6 mice induces thymic lymphomas after 4-6 months. During premalignant latency, a population of RadLV-infected prelymphoma (PL) cells (whose survival is dependent on autostimulation with IL-4) persists in the thymus. PL cells explanted from RadLV-inoculated mice can be propagated in cultures containing IL-4, and in vitro growth of PL cells is effectively inhibited by anti-IL-4 antibodies. We subjected RadLV-inoculated mice to prophylactic treatment with anti-IL-4 antibodies and a virus-specific immunotoxin (IT). Administration of IT delayed the onset of lymphoma but was not curative. Anti-IL-4 antibodies had a similar effect when administered at low doses. High doses of anti-IL-4, given 3-5 weeks after virus inoculation, provided complete protection against lymphoma. These results demonstrate the effectiveness of prophylactic intervention during premalignancy by using antagonists that restrain the growth of PL cells.

Animals↗
PubMed1997

Adhesion molecules as targets for cancer therapy.

Adhesion molecules mediate cell-cell and cell-matrix interactions and are essential for numerous physiological and pathological processes. Recent evidence from many laboratories suggests that adhesion molecules play an important role in tumor progression and may promote tumor growth and organ-specific metastasis. Certain adhesion molecules may also function as tumor suppressors. In this review, we describe current concepts concerning the role of the adhesion molecules in the pathogenesis of cancer and the development of therapeutic approaches which make use of this information. Hence, by preventing tumor cells from interacting with each other or with their microenvironment, tumor growth and metastasis can be suppressed. The feasibility of using anti-adhesion strategies to treat cancer has been demonstrated in many animal models. Thus, monoclonal antibodies (MAbs) against adhesion molecules, synthetic peptidic and nonpeptidic analogues of the recognition sequences on their receptors, soluble adhesion molecules and antisense oligonucleotides can inhibit tumor growth and gene therapy can restore the functions of altered tumor-suppressive adhesion molecules.

Animals↗
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↗
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↗