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Biomedical subjects

I D Bernstein

Publications and source records attributed to I D Bernstein.

At least 91 records · Page 5Linked to original sources
PubMed1991

Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma.

The CD34 antigen is expressed by 1% to 4% of human and baboon marrow cells, including virtually all hematopoietic progenitors detectable by in vitro assays. Previous work from our laboratory has shown that CD34+ marrow cells can engraft lethally irradiated baboons. Because the CD34 antigen has not been detected on most solid tumors, positive selection of CD34+ cells may be used to provide marrow cells capable of engraftment, but depleted of tumor cells. In seven patients with stage IV breast cancer and two patients with stage IV neuroblastoma, 2.5 to 17.5 x 10(9) marrow cells were separated by immunoadsorption with the anti-CD34 antibody 12-8 and 50 to 260 x 10(6) positively selected cells were recovered that were 64 +/- 16% (range 35% to 92%) CD34+. The patients received 1.0 to 5.2 x 10(6) CD34-enriched cells/kg after marrow ablative therapy. Six patients engrafted, achieving granulocyte counts of greater than 500/mm3 at 34 +/- 10 (range 21 to 47) days and platelets counts of greater than 20,000/mm3 at 46 +/- 14 (range 28 to 66) days posttransplant. Five of these patients showed durable engraftment until the time of death 82 to 386 days posttransplant. One patient failed to sustain engraftment associated with metastatic marrow disease. Three patients died at days 14, 14, and 17 posttransplant, two of whom had evidence of early engraftment. These studies suggest that CD34+ marrow cells are capable of reconstituting hematopoiesis in humans.

Antigens, CD↗
PubMed1991

WR2721 protection of bone marrow in 131I-labeled antibody therapy.

The use of phosphorothioate radioprotectors such as WR2721 in radioimmunotherapy is attractive because radiation delivered to tumors is usually separated in time from that delivered to the marrow and most normal organs, making protection of tumors of little consequence. However, to be effective radioprotectors must provide continuous protection against radiation of varying dose rates. To evaluate the potential of radioprotectors in radioimmunotherapy we treated normal mice with graded amounts of WR2721 in combination with an LD90/30 (26 MBq) of 131I-labeled antibody. A regimen of 15 doses of WR2721, 200 mg/kg prior to antibody infusion followed by 100 mg/kg ip every 4 h for a total of 72 h, was the maximum tolerated dosage schedule. With this schedule, treatment with radioprotectors failed to prolong survival or delay myelosuppression from the 131I-labeled antibody. In contrast, this regimen of radioprotector provided partial protection from a single treatment of 10 Gy total-body radiation given at 0.2 Gy/min. Protection 30 min after the final dose of WR2721 was greater than 3 h after the 14th dose (60 min prior to the final dose). These results suggest that the potential role of phosphorothioate radioprotectors in a radioimmunotherapy is limited because of the difficulty in achieving continuous protection with nontoxic amounts of drug and possibly because of a limited effect on low-dose-rate radiation.

Amifostine↗
PubMed1991

Blast colony-forming cells and precursors of colony-forming cells detectable in long-term marrow culture express the same phenotype (CD33- CD34+).

We have previously shown that CD33- CD34+ human marrow cells are capable of giving rise to colony-forming cells (CFC) in long-term marrow culture (LTMC) but are mainly depleted of progenitors that directly form colonies in semi-solid media. In contrast, the CD33+ CD34+ population contains most of the CFC but not the precursors of these cells detectable in LTMC. The purpose of the present study was to determine if a form of CFC with self-renewal potential, the blast CFC, is contained within the CD33+ CD34+ or CD33- CD34+ population. The results demonstrate that blast CFC segregate within the CD33- population, representing a distinct progenitor population that may be analogous to progenitors for CFC detectable in LTMC.

Antigens, CD↗
PubMed1990

The role of timing of high-dose cytosine arabinoside intensification and of maintenance therapy in the treatment of children with acute nonlymphocytic leukemia.

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Monoclonal antibody therapy of murine lymphoma: enhanced efficacy by concurrent administration of interleukin 2 or lymphokine-activated killer cells.

Lymphokine-activated killer (LAK) cells have recently been shown to be very efficient effector cells for antibody-dependent cellular cytotoxicity. Thus, we explored, in a murine lymphoma model, administration of LAK-inducing doses of interleukin 2 (IL-2) or adoptive transfer of LAK cells as a means of enhancing therapy with tumor-specific monoclonal antibody (mAb). AKR/Cum (Thy-1.2+) hosts were inoculated on day 1 s.c. with the SL-2 thymoma of AKR/J origin (Thy-1.1+) and developed palpable tumor on day 4. Tumor-specific anti-Thy-1.1 IgG2a mAb, 1A14, was given on days 4 and 8 with 50,000 units/day IL-2 i.p. divided in two doses on days 4-12. Therapy with IL-2 or mAb alone had minimal activity, prolonging control median survival of 22 days to 25 and 29 days, respectively, whereas therapy with IL-2 plus mAb significantly prolonged median survival to 40 days. However, combined therapy did not result in cures and long term survival. The efficacy of combined therapy did not result from alterations in the biodistribution of mAb by concurrent IL-2 infusions, as determined by studies with radiolabeled mAb. The combined effect of in vitro generated LAK (10(8) cells) adoptively transferred i.v. with 1A14 on days 4 and 8 following SL-2 inoculation was also evaluated. This regimen had no detectable toxicity, and treatment of mice with LAK and mAb resulted in 60% long term survival compared with 17% or 0% for mice treated with mAb or LAK alone. Thus, the therapeutic effects of tumor-specific mAb was enhanced by in vivo administration of IL-2 or by adoptively transferred LAK, which may represent means to provide the host with increased antibody-dependent cellular cytotoxicity effector cells. Adoptively transferred LAK has the additional benefit of augmenting mAb therapy of tumor without the toxicity associated with the induction of such cells in vivo with high dose IL-2.

Animals↗
PubMed1990

Human hematopoietic precursors in long-term culture: single CD34+ cells that lack detectable T cell, B cell, and myeloid cell antigens produce multiple colony-forming cells when cultured with marrow stromal cells.

CD34+ human marrow cells not expressing T cell-, B cell-, and myeloid cell-associated antigens (TBM-) were cloned by two-color cell sorting into culture wells containing irradiated marrow stromal cells. After 4 wk of culture, 3.7 +/- 2.1% of these cells generated colony-forming cells (CFC), with each of these cells generating 6.3 +/- 5.3 CFC. This was not due to the 0.5 +/- 0.5% CFC present in the purified CD34+ TBM- cells, as less than 1% of CFC persist in these cultures. This is the first demonstration that single immature precursor cells in human long-term cultures generate multiple CFC progeny. The immature nature of these clonable CD34+ TBM- precursors suggests their candidate status as human hematopoietic stem cells.

Antibodies, Monoclonal↗
PubMed1990

High dose radiolabeled antibody therapy of lymphoma.

A trial has been initiated testing the effects of high dose radiolabeled monoclonal antibody administered in conjunction with marrow transplantation for treatment of lymphoma. This study is based on observations in mice demonstrating that radiolabeled antibody against a normal lymphocyte-associate antigen can induce regression of lymphoma masses. These preclinical studies also showed that large amounts of antibody are needed to achieve adequate biodistribution in vivo and that potentially curative doses of radionuclide induce substantial hematopoietic toxicity. Consequently, in patients with recurrent lymphoma, we are first evaluating the influence of dose on the biodistribution of a pan B-cell antibody, MB-1 (anti-CD37). In four patients, the biodistribution studies indicated that at the highest amount of antibody tested 131I-labeled antibody MB-1 (10 mg/kg) could deliver more radiation to tumor than to normal organs. These patients were treated with antibody MB-1 labeled with 250 to 482 mCi 131I estimated to deliver 380 to 1570 cGy to normal organs and 850 to 4260 cGy to tumor. Myelosuppression occurred in all patients and required infusion of cryopreserved marrow in one patient. Complete tumor regressions were observed in each patient. In three other patients with splenomegaly and/or large tumor burden, biodistribution studies indicated that 131I-labeled antibody could not deliver more radiation to tumor than to normal organs and these patients were not treated. Thus, tumor burden and spleen size may determine the feasibility of treatment with radiolabeled antibody. Treatment with this antibody labeled with high doses of 131I was well tolerated and may prove therapeutically useful. These studies are being continued to determine the maximal doses of radiation that can be tolerated by nonhematopoietic tissues after infusion of 131I-labeled antibody.

Animals↗
PubMed1990

Improving the tumor retention of radioiodinated antibody: aryl carbohydrate adducts.

Improved methods for attaching radioiodine to monoclonal antibodies have been developed. Ten aryl carbohydrate adducts were synthesized by the reductive amination of a carbohydrate with an aryl amine, using sodium cyanoborohydride as a reducing agent. After purification by chromatography and characterization by nuclear magnetic resonance they were iodinated using the chloramine-T method. Iodinated adducts were activated with cyanuric chloride and incubated with protein at room temperature. The immunoreactivity and avidity of radioiodinated tyramine cellobiose (TCB) labeled antibody were fully preserved when compared to electrophilically radioiodinated antibody. Radioiodinated TCB-and tyramine glucose-labeled monoclonal antibodies showed much greater intracellular retention of radioiodine when compared to electrophilically radioiodinated monoclonal antibodies. Neither radioiodinated tyramine nor radioiodinated TCB had any specific tissue uptake or retention. In mice the retention of radioiodinated TCB labeled anti-Thy-1.1 antibody (1A14) by Thy-1.1-bearing lymphoma cells was 2 times greater than that of chloramine-T labeled 1A14 antibody, whereas the plasma clearance curve and uptake in normal tissues was not changed. This method of radioiodinating monoclonal antibodies increases the retention time of radioiodine in tumor and thus may obviate the problem of intracellular deiodination, a perceived disadvantage of electrophilically iodinated antibodies, with respect to tumor retention of radioactivity.

Animals↗
PubMed1990

Treatment of lymphoma with radiolabeled antibody: elimination of tumor cells lacking target antigen.

We have previously shown that 131I-labeled monoclonal antibodies against the Thy1.1 differentiation antigen can induce the regression of Thy1.1 antigen-positive (Thy1.1+) AKR/J SL2 T cell lymphoma nodules in AKR/Cum (Thy1.2+) mice. In this study, we examined the ability of 131I-labeled anti-Thy1.1 antibodies to eliminate tumor nodules containing variant lymphoma cells that do not express the Thy1.1 antigen (Thy1.1-). AKR/Cum mice were sc inoculated with mixtures of 1-2 X 10(7) AKR/J SL2 cells and varying amounts (0.3%-10%) of Lsp3, a Thy1.1 antigen-negative (Thy1.1-) subclone of the SL2. One week later, when an established tumor nodule was present, mice were treated with 1,500-1,700 microCi of 131I-labeled anti-Thy1.1 antibody. Complete regression of tumor was observed in 11 of 12 (92%) mice inoculated with tumor containing 0.3%-1% antigen-negative cells. In contrast, no complete regressions were observed in mice with only antigen-negative tumor cells treated with 131I-labeled anti-Thy1.1 antibody or in mice inoculated with antigen-positive tumor and treated with an 131I-labeled control antibody. Of the mice receiving mixtures containing 3%-10% antigen-negative cells, five of seven showed complete regression. These results demonstrate that radiolabeled antibodies can eliminate small numbers of antigen-negative tumor cells present within a tumor mass.

Animals↗
PubMed1990

Biodistribution of p-iodobenzoyl (PIP) labeled antibodies in a murine lymphoma model.

A monoclonal antibody against the murine T-cell antigen Thy 1.1 was radioiodinated using N-succinimidyl p-iodobenzoate (PIP) in an attempt to decrease deiodination of the labeled antibody. The biodistribution of the PIP labeled antibody was compared to Iodogen labeled antibody in Thy 1.1+ lymphoma bearing AKR/Cum mice, where the antibody was tumor specific, and AKR/J mice where the antibody reacted with both tumor and normal T-cells. PIP labeling resulted in decreased iodine concentrations in stomach and salivary gland as compared to Iodogen labeling. There was little difference in radioiodine concentrations between the two preparations in tumor, lymphoid tissues or other organs. These results suggest deiodination of intact antibody plays little role in the clearance of radioiodinated anti-Thy 1.1 antibody from tissues.

Animals↗
PubMed1990

Stem cell selection--clinical experience.

The ability to isolate large numbers of hematopoietic progenitors will facilitate an understanding of the growth and differentiation of bone marrow. Furthermore, isolating hematopoietic progenitors will have widespread clinical applications to autologous marrow transplantation, allogeneic marrow transplantation, gene therapy, and in vitro marrow expansion. With the development of avidin-biotin immunoadsorption, it is now feasible to isolate large numbers of these progenitor cells for clinical purposes. Successful hematopoietic reconstitution has been demonstrated in lethally irradiated baboons transplanted with CD34+ cells isolated by immunoadsorption with the anti-CD34 antibody 12-8. Recent studies have shown that CD34+ cells enriched from the marrow of patients with metastatic breast cancer can be used for autologous marrow transplantation.

Animals↗
PubMed1990

Positive selection of hematopoietic progenitors from marrow and peripheral blood for transplantation.

The ability to obtain large numbers of purified hematopoietic progenitors (HPC) will facilitate the understanding of elements that influence the growth and differentiation of bone marrow. Furthermore, HPC isolation will have direct application to autologous marrow transplantation (AMT) for malignancies as well as facilitate the transfer of genes in marrow cells for the correction of genetic disorders. The transplantation of HPC will help delineate the cells or factors responsible for graft rejection and graft-versus-host-disease. Or several techniques that have been utilized for the separation of HPC, only the avidin-biotin immunoadsorption (ABIA) method has been shown capable of separating the number of cells required for large animals and man. The application of this technique to AMT in man requires the identification of an antigen found predominantly on HPC in peripheral blood or marrow but not on malignant cells that could potentially contaminate bone marrow. Studies have demonstrated that the CD34 antigen is expressed by the majority of human marrow HPC measured in long-term marrow culture and is expressed on cells capable of autologous engraftment in lethally irradiated baboons. Although the CD34 antigen is not detectable by FACS analysis on peripheral blood cells, ABIA can enrich for such cells. The CD34 antigen is not detected on cells from patients with breast cancer or neuroblastoma thus allowing clinical studies to proceed. Preliminary results suggest that CD34(+)-enriched cells are depleted of tumor cells and are capable of autologous reconstitution in man.

Antigens, CD↗
PubMed1989

Precursors of colony-forming cells in humans can be distinguished from colony-forming cells by expression of the CD33 and CD34 antigens and light scatter properties.

We determined whether human marrow cells that directly form colonies in vitro could be distinguished from cells that generate or become CFC only after LTMC in the presence of irradiated marrow stromal cells. In previous studies, an anti-CD33 antibody, L4F3, and complement (C') were used to lyse nearly all CFC in marrow, and the remaining cells generated CFC in LTMC. In the present studies, marrow cells were treated with L4F3 + C' and the remaining CD33- cells were separated into CD34+ and CD34- populations and placed in LTMC. Only the CD34+ cells were found to generate significant numbers of CFC. To compare the CD33-CD34+ and CD33+CD34+ cells, we isolated each cell population using two-color FACS. Only LTMCs of the CD33-CD34+ cells generated CFC for greater than 5 wk. In contrast, cells that expressed both the CD33 and CD34 antigens, which contained most of the CFC, generated few CFC in LTMC. Fractionation of marrow cells based on right angle and forward light scattering suggested that precursors for CFC have low right angle and low forward light scattering properties. The CD33-CD34+ marrow cells were therefore further fractionated based on light scatter characteristics. Cells with low right angle and low forward light scatter formed few or no colonies on direct culture, yet generated greater numbers of CFC after 4 wk of LTMC than did cells with low right angle and high forward light scatter. Most (87-98%) CFC generated in the LTMCs that were initiated with CD33-CD34+ cells were found to express the CD33 antigen. Thus, hematopoietic progenitors with differing proliferative and differentiative potentials can be directly separated on the basis of their expression of CD33 and CD34 cell surface antigens and their light scatter properties.

Antibodies, Monoclonal↗
PubMed1989

Remission induction in children with acute non-lymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Childrens Cancer Study Group.

Four hundred ninety evaluable patients were treated on an induction regimen consisting of two to four courses of cytosine arabinoside plus an anthracycline. Overall, 78% of patients went into remission, 10% died during induction, and 12% were induction failures. For the first 152 patients, courses consisted of 7 days continuous infusion with cytosine arabinoside (Ara-C, 100 mg/m2) and 3 days of doxorubicin (30 mg/m2). Because of unacceptable toxicity, particularly for children less than 3 years of age, the anthracycline was changed to daunorubicin, and the doses of both induction drugs for children under 3 was reduced. For children aged 3 years and older the change in anthracycline was associated with a significant increase in induction failures (7% to 16%, P = .04) and a decrease in deaths (15% to 8%, P = .09). For younger children, for whom doses were also changed, the effect was greater; Mortality decreased from 29% to 1% (P less than .0001), and the remission induction rate increased from 66% to 88% (P = .005). The therapy modifications also influenced survival following remission induction: Daunorubicin-treated patients, aged 3 years and over, did significantly better than those given doxorubicin (P = .03), but the opposite was seen in younger children (P = .06). Gastrointestinal and skin toxicities and septicemia were significantly more common when doxorubicin was being used, but the extent of myelosuppression was similar for the two anthracyclines.

Age Factors↗
PubMed1989

Interleukin-3, GM-CSF, and G-CSF receptor expression on cell lines and primary leukemia cells: receptor heterogeneity and relationship to growth factor responsiveness.

Recombinant human granulocyte-macrophage (GM) colony-stimulating factor (GM-CSF), G-CSF, and interleukin-3 (IL-3) labeled with 125I were used to study the characteristics and distribution of receptors for these factors on in vitro cell lines and on cells from patients with acute nonlymphocytic leukemia (ANL) and acute lymphocytic leukemia (ALL). Receptors for GM-CSF and G-CSF were restricted to a subset of myelomonocytic cell lines whereas IL-3 receptors were also found on pre-B- or early B-cell lines. Receptors for all three CSFs were broadly distributed on ANL cells, with considerable variability in levels of expression. Measurement of the colony-forming ability of ANL cells in response to the CSFs showed that there was no direct correlation between the ability of the cells to respond to a growth factor and the absolute number of receptors expressed for that growth factor. Binding of radiolabeled IL-3 and GM-CSF to ANL cells produced complex biphasic curves. Further analysis showed that both IL-3 and GM-CSF were able to partially compete for specific binding of the heterologous radiolabeled ligand to cells from several ANL patients, suggesting that heterogeneity may exist in human CSF receptors. These results provide new insights into the complex role that CSFs may play in ANL.

Cell Division↗
PubMed1988

Comparison of combinations of interferons with tumor specific and nonspecific monoclonal antibodies as therapy for murine B- and T-cell lymphomas.

Two murine models, C3H 38C13 B-cell lymphoma and AKR SL2 T-cell lymphoma were used to determine the efficacy of three different interferon preparations, recombinant human hybrid interferon-alpha A/D, recombinant murine interferon (rMIFN)-gamma, and natural MIFN-alpha/beta (greater than or equal to 85% beta), alone and in combination with tumor specific and nonspecific monoclonal antibody therapy. All three interferon preparations have direct in vitro antigrowth activity for 38C13 and SL2. All three interferons have direct antitumor activity in vivo for 38C13 lymphoma at high doses; however, none of these interferons has independent antitumor activity for SL2 in vivo. These data indicate that there is no relationship between in vitro growth cytostasis/cytolysis and in vivo antitumor response. All three interferon preparations will potentiate both tumor specific and nonspecific monoclonal antibody therapy. Natural MIFN-alpha/beta and recombinant human hybrid interferon-alpha A/D, which should share a common cell surface receptor, had similar antitumor activity in both models. Combining recombinant human hybrid interferon-alpha A/D and rMIFN-gamma therapy was not additive for 38C13 lymphoma and a three-way combination with antiidiotype was not significantly more effective than combination therapy with one interferon type. In general, rMIFN-gamma was more effective in in vivo combination therapy against the s.c. T-cell lymphoma than against the i.p. B-cell lymphoma and was more synergistic with anti-Thy1.1 than with antiidiotype.

Animals↗