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Biomedical subjects

M W Boyer

Publications and source records attributed to M W Boyer.

9 recordsLinked to original sources
PubMed1997

CD28/B7 interactions are required for sustaining the graft-versus-leukemia effect of delayed post-bone marrow transplantation splenocyte infusion in murine recipients of myeloid or lymphoid leukemia cells.

Graft-vs-leukemia (GVL) can reduce relapse rates after bone marrow transplantation (BMT). Delayed lymphocyte infusion (DLI) post-BMT can mediate a potent GVL effect with less graft-vs-host disease (GVHD) than would be observed if given early post-BMT. In vivo CD28/B7 blockade can reduce GVHD lethality, and B7 ligand expression can augment an antitumor immune response in mice. To examine the role of CD28/B7 interactions in DLI-mediated GVL, we established murine allogeneic BMT models in C57BL/6 (B6) recipients of C1498 (B6 acute myeloid leukemia) or EL4 (B6 acute T cell leukemia) that closely mimic human GVL. Recipients of C1498 and DLI had a marked reduction in relapse. GVL was blocked by anti-B7 mAb infusion. In contrast, recipients of EL4 cells and B10.BR DLI had a more modest GVL effect. The forced expression of B7-1 on EL4 cells markedly augmented the GVL effect of DLI, in contrast to the forced expression of B7-2 on EL4 cells. Relapse rates observed in recipients of C1498-B7-1 and DLI were significantly lower than in recipients of parental C1498 cells. We conclude that the administration of anti-B7 mAbs may impair the GVL effect of DLI and that the forced expression of B7-1 ligands stimulates a GVL effect without adversely affecting the GVHD lethality effect of DLI.

Adoptive Transfer↗
PubMed1997

The role of B7 costimulation by murine acute myeloid leukemia in the generation and function of a CD8+ T-cell line with potent in vivo graft-versus-leukemia properties.

Relapse is more frequent after autologous than allogeneic bone marrow transplantation (BMT), due in part to lack of T-lymphocyte mediated allogeneic graft-versus-leukemia (GVL) effects. Infusions of leukemia-reactive T cells to patients after autologous BMT may be a means for providing a GVL effect. Costimulation of T cells by binding of the CD28 receptor on T cells with B7-counter receptors on antigen presenting cells amplifies antigen-specific T-cell responses. To enhance generation of leukemia reactive cytotoxic T lymphocytes (CTL), the murine B7-1- and B7-2-costimulatory molecule cDNAs were introduced into the MHC class I+, class II-, murine meyloid leukemia cell line C1498. B7-1 expression greatly enhanced the ability of the leukemia cells to generate and expand leukemia reactive CTL in vitro. A highly cytolytic and C1498 specific CD8+ CTL line was generated by B7-1 costimulation. This CTL line proliferated autonomously and produced interleukin-2 when provided B7-1 or B7-2 costimulation by C1498 leukemia cells. To test the in vivo antileukemia properties of this CTL line, irradiated syngeneic BMT recipients were given graded doses of leukemia cells on day 0, followed by CTL infusions beginning on day 1 post-BMT. Recipients of 10(7) CTL had a 3 log reduction in leukemia burden such that 100% of mice were protected from a supralethal leukemic cell dose. Sustained immune responses were detectable up to 3 months postinfusion of the CTL line. B7-1 or B7-2 costimulation in vivo did not augment antileukemia effects of infused CTL post BMT. These results suggest that B7 costimulation of leukemia reactive CTL may be important for their ex vivo generation and expansion for use in human adoptive immunotherapy of leukemia.

Acute Disease↗
PubMed1995

Dependency on intercellular adhesion molecule recognition and local interleukin-2 provision in generation of an in vivo CD8+ T-cell immune response to murine myeloid leukemia.

The immune response to a murine myeloid leukemia (cell line C1498) was studied in vitro and in vivo. Natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTL) were shown to lyse C1498 in vitro through the binding of leukocyte function antigen-1 (LFA-1) on effectors and intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on C1498 target cells. However, the ability of nonimmunized mice to resist an in vivo challenge of a low dose (10(4)) of C1498 was NK-cell, but not T-cell dependent. The failure of T cells to participate in the immune surveillance of a low leukemia burden appeared, in part, because of a lack of expansion of leukemia reactive CTL precursors (CTLp). Leukemia reactive CTLp frequency estimations in naive and leukemia bearing mice were not significantly different (range, 1:20,600 to 1:74,000) in contrast to immunized mice (range, 1:1,400 to 1:4,400). Leukemia reactive CTLp could be expanded to a level that could apparently mediate in vivo immune surveillance of 10(5) leukemia cells by injection of irradiated leukemia cells intraperitoneally (IP) or subcutaneously (SC), but not intravenously (IV). However, IV injection of 10(5) live leukemia cells engineered to secrete interleukin-2 (IL-2) resulted in systemic immunity mediated primarily by CD8+ T cells. We conclude that NK cells can mediate immune surveillance of a low leukemia burden. CD8+ CTL-mediated immune surveillance can eliminate a higher leukemia burden than NK cells, but requires T-cell help, which can be delivered by local IL-2. Both NK and CTL-mediated immune surveillance of C1498 murine myeloid leukemia is dependent on recognition through the LFA-1:ICAM adhesion pathway.

Animals↗
PubMed1995

Use of intracavitary cisplatin for the treatment of childhood solid tumors in the chest or abdominal cavity.

PURPOSE: Intracavitary (IC) delivery of cisplatin (CDDP) has been used in the treatment of a variety of adult malignancies based on the favorable pharmacokinetics obtained locally. Since IC CDDP has not been reported in children, we studied its use in a group of pediatric patients with regard to safety, toxicity, pharmacokinetics, and responses. PATIENTS AND METHODS: Eleven patients with an age range of 8 months to 21 years with diagnoses of rhabdomyosarcoma (n = 5), pleuropulmonary blastoma (n = 2), osteosarcoma (n = 2), Ewing's sarcoma (n = 1), and malignant rhabdoid tumor of the kidney (n = 1) were studied. Eight patients received intrapleural (IPL) CDDP and three received intraperitoneal (IP) CDDP, either at diagnosis (n = 3) or relapse (n = 8), for malignant pleural effusion (n = 3), malignant ascites (n = 2), pleural-based tumor (n = 4), pulmonary metastases (n = 1), or abdominal tumor spillage (n = 1). RESULTS: IC CDDP was well tolerated by pediatric patients. Two patients experienced a transient increase in serum creatinine levels (> two times baseline) and two patients experienced severe neutropenia (absolute neutrophil count < 500/microL). Pharmacokinectic measurements showed a 40-fold advantage for the pleural cavity versus serum after IPL CDDP and serum levels comparable to those achieved with systemic administration of CDDP. Four of five patients who received IC CDDP for malignant ascites or pleural effusion had at least a temporary response. Only three of 11 patients studied had local recurrences following IC CDDP. There are currently four survivors in the study group, including two long-term survivors at greater than 8 years since IPL CDDP treatment. CONCLUSION: The safety, toxicity, and pharmacokinetics of IC CDDP in pediatric patients are similar to that reported in adult patients. The low incidence of local recurrence following IC CDDP in this group of largely relapsed patients suggests that further study of IC CDDP for pediatric patients is warranted.

Abdominal Neoplasms↗
PubMed1989

Thrombosis: the major Hickman catheter complication in patients with solid tumor.

Major complications of Hickman catheter placement (thrombosis and infection) were determined in 168 patients with solid tumor (lung, 79; head and neck, 56; esophagus, 24; and miscellaneous, 9). Catheter-related thrombosis was clinically detected in 22 individuals and was detected at autopsy in six (total 17 percent). The 17 percent figure underestimates the true incidence of thrombosis since only 25 percent of study patients had autopsies. Patients with adenocarcinoma of the lung constituted a high risk group. Nine of 20 (45 percent) of these patients had thrombosis compared to 25, 9, and 16 percent of patients with squamous cell cancers of lung, head and neck and esophagus, respectively (p less than 0.002). Three patients with thrombosis had pulmonary emboli and two died. Thrombosis occurred despite daily heparin catheter flushing. INfections occurred in 11 patients. One had suspected endocarditis, one had a subcutaneous tunnel infection, and nine had exit site infections. All responded to local or systemic antibiotics. Better methods to prevent thrombosis are needed.

Adenocarcinoma↗
PubMed1987

Hickman catheter clots: a common occurrence despite daily heparin flushing.

Central vein thrombosis is the major Hickman catheter complication in our patient population. After noting clots attached to the disposable infusion plug of these catheters, we prospectively determined whether the presence of clots indicated a high-risk group for thrombosis. Forty-three patients (41 with solid tumor, two with acute leukemia) were studied. Catheters were flushed daily with heparin (10 units/ml), and urokinase (5000-10,000 units) was injected when blood could not be drawn. Clots within the catheter lumen were detected visually after expressing, onto a 4 X 4-inch gauze pad, the first 5-10 ml of admixed blood and flush solution or iv infusion fluid drawn from the catheter prior to blood drawing. Clots were detected in 153 of 508 specimens (30%). Forty of 43 patients had clots, varying in length from fragments to 5 cm, in at least one specimen. Inpatients and outpatients had a similar percentage of clotted specimens. Eight patients developed clinical (six) or autopsy-proven (two) thrombosis. There was no difference between patients with and without thrombosis in percent of discards positive for clots. This study indicates that clots are frequently present in the lumina of Hickman catheters. It is likely that these clots embolize to the lungs when catheters are flushed. Consequences of embolization are unknown.

Blood Specimen Collection↗