Elimination of myeloma cells from bone marrow by using monoclonal antibodies and magnetic immunobeads

The efficacy of immunomagnetic beads to purge human myeloma cells from bone marrow ex vivo was evaluated. The optimal conditions for purging were studied first by using three myeloma cell lines: RPMI-8226, SKO- 007, and SKMM-2. Myeloma cells labeled with the vital fluorescent dye Hoechst 33342 were admixed with normal bone marrow cells, and two monoclonal antibodies reactive with the myeloma cells (PCA-1 and BL-3) were added alone or in combination with the cells. Magnetic beads coated with goat antimouse immunoglobulin G were then added, and the tumor cells to which beads were attached were separated from the mixture with a magnet. The efficacy of tumor cell removal was dependent on the bead-to-tumor ratio; a ratio of more than 500 was optimal in the presence of excess normal marrow cells. The combination of monoclonal antibodies PCA-1 and BL-3 increased the tumor cell removal as compared with either antibody alone. Two cycles of treatment were more effective than one cycle was. Under optimal conditions, 2.3 to 4 logs of tumor cells could be removed from the mixture containing 10% myeloma cells without a significant loss of normal hematopoietic progenitors as measured by CFU-GM, CFU-GEM, and BFU-E. When the efficacy of this procedure was tested on fresh bone marrow from patients with multiple myeloma (MM) by using the combination of PCA-1, BL-3, and J-5, 1.6 to 2.5 logs of tumor cells could be removed by one cycle of treatment, even from marrows containing less than 10% myeloma cells. These observations support the use of monoclonal antibody combinations and immunobeads as a reliable and nontoxic method to eliminate contaminating myeloma cells ex vivo in preparation for autologous bone marrow transplantation in patients with MM.     

Integration of monoclonal antibodies and immunoconjugates into the treatment of acute myeloid leukemia

PURPOSE OF REVIEW: This review addresses use of monoclonal antibodies and immunoconjugates to treat acute myeloid leukemia. RECENT FINDINGS: Monoclonal antibodies used in acute myeloid leukemia have been directed against the antigens CD33, CD45, and CD66. Unconjugated monoclonal antibodies such as lintuzumab have modest activity against overt acute myeloid leukemia but can eliminate minimal residual disease in acute promyelocytic leukemia. Most experience with immunoconjugates is with gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody linked to the potent antitumor antibiotic calicheamicin. Gemtuzumab ozogamicin has shown activity both singly, particularly in acute promyelocytic leukemia, and combined with conventional cytotoxic chemotherapy. Radiolabeled monoclonal antibodies against CD45 and CD66 have also been used to intensify the conditioning regimen before stem cell transplantation. The most promising results were obtained with radiolabeled anti-CD45 antibodies. Antibodies reactive with CD66 have been used to deliver targeted radiation to hematopoietic tissues in patients with advanced myeloid malignancies. SUMMARY: Both unlabeled monoclonal antibodies and immunoconjugates appear to have a limited role if used as single agents to treat acute myeloid leukemia. These agents hold promise as potentially useful additions to conventional therapy, but the optimal dosing and timing remain to be defined.     

Elimination of Daudi lymphoblasts from human bone marrow using avidin- biotin immunoadsorption

Biotinylated antibodies and an avidin-Sepharose 6MB column were utilized in a novel approach to deplete selected cell populations from human bone marrow. Fluorescein-labeled Daudi lymphoblasts were mixed with bone marrow mononuclear cells in a model system, and removal of Daudi cells was quantitatively assessed with an inverted fluorescent microscope. Treatment using the biotinylated monoclonal antibody 2H7 reactive with Bp32 antigen (expressed on Daudi cells) followed by passage over avidin-Sepharose produced greater than two logs of Daudi cell removal from bone marrow. An alternative method was tested by treating cells successively with nonbiotinylated monoclonal antibody and biotinylated goat antimouse immunoglobulin followed by passage over avidin-Sepharose. Up to three logs of Daudi cells could be eliminated from bone marrow with quantitative recovery of hematopoietic progenitors. The use of biotinylated goat antimouse immunoglobulin eliminates the need to prepare a biotin conjugate of each individual monoclonal antibody. The clinical application of cellular immunoadsorption using the avidin-biotin system may prove useful in bone marrow transplantation.     

Effect of surface antigen labeling on spleen colony formation: comparison of the indirect immunofluorescence and the biotin-avidin methods

Indirect immunofluorescence techniques for labeling cell surface antigens on murine pluripotent hemopoietic stem cells often result in a reduction of CFU-S numbers. This phenomenon was investigated by comparing indirect immunofluorescence and biotin-avidin methods using anti-T200 and anti-H-2Kk monoclonal antibodies. Mouse bone marrow cells treated with these monoclonal antibodies, alone or in combination with fluorescein conjugates of rabbit antirat or goat antimouse immunoglobulins, respectively, showed reduced numbers of CFU-S. The reduction in CFU-S numbers by anti-H-2Kk antibodies was dependent on the concentration of antibody and on the antigen density on the cells. Near complete CFU-S recovery was obtained with biotin-labeled antibodies and avidin-fluorescein isothiocyanate. The CFU-S recovery obtained was higher with higher numbers of biotin moieties per antibody molecule. Biotinylation itself did not influence the antibody binding properties. The protective effect was independent of the avidin-FITC concentration. Injection of carrageenan, an agent known to block macrophage activity, prevents the reduction of CFU-S recovery caused by anti-H-2Kk antibody treatment. The biotin-avidin procedure permits the measurement of antigen density on pluripotent stem cells through flow cytometry and sorting and full recovery of CFU-S in the in vivo assay.     

Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy

The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma. The protocol involves intratumoral injections of replication-incompetent adenoviral vectors encoding immunoconjugates composed of the Fc region of an IgG1 immunoglobulin conjugated to a tumor-targeting domain. One targeting domain is factor VII that binds to tissue factor expressed on endothelial cells lining the tumor neovasculature and on tumor cells; the active site of factor VII was mutated to inhibit the initiation of blood coagulation. Another targeting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which synthesize and secrete the immunoconjugates. The bloodborne immunoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor VII immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor, and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature, presumably mediated by the factor VII immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is generally expressed on neovascular endothelial cells and tumor cells, a factor VII immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.     

Generation of human monoclonal antibodies reactive with human mammary carcinoma cells.

Lymphocytes from lymph nodes obtained at mastectomy in breast cancer patients have been fused with murine nonproducer myeloma cells to obtain human-mouse hybridoma cultures that synthesize human monoclonal antibodies. To date, 52 hybridoma cultures synthesizing either human IgG or human IgM have been obtained from lymph nodes of 13 patients. Ig production was stable in many of these cloned cultures through 60-200 days of observation. Levels of human Ig synthesis ranged from 0.1 to 20 microgram/ml of supernatant fluid. The immunological reactivities of the human Igs were assayed on tissue sections by using the immunoperoxidase technique. Several of the human monoclonal antibodies demonstrated preferential binding to human mammary tumor cells. One human IgM monoclonal antibody was used to discriminate between mammary carcinoma cells (from 55 of 59 patients) and normal mammary epithelial cells, stroma, or lymphocytes of the same breast. Decreased binding to some of the benign breast tumors tested and to selected non-breast adenocarcinomas was also observed. This same human monoclonal antibody, however, reacted significantly with metastatic mammary carcinoma cells in lymph nodes of breast cancer patients, with no binding to normal lymphocytes or to stroma of the same node. These studies demonstrate that stable clones of human-mouse hybridomas can be generated by using lymph nodes of mastectomy patients and that clones can be selected which synthesize human monoclonal antibodies reactive with human mammary carcinoma cells.     

How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn's disease

The chimeric monoclonal antibody to tumor necrosis factor (TNF), infliximab, is an effective therapy for Crohn's disease. However, the formation of human anti-chimeric antibodies to infliximab (immunogenicity) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions. The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment CDP870 are biologic therapies against TNF that might be effective for Crohn's disease and less immunogenic than infliximab. Other potential alternatives to infliximab for Crohn's disease include the humanized anti-adhesion molecule antibodies natalizumab and MLN-02, the humanized anti-interleukin 12 antibody ABT-874, the humanized anti-interferon g antibody fontolizumab, the humanized anti-interleukin 6 receptor antibody MRA, and human recombinant granulocyte macrophage colony stimulating factor (sargramostim). Some, or all, of these therapies will likely represent important treatments for Crohn's disease in the future.     

Diagnostic and therapeutic applications of monoclonal antibodies in colorectal cancer

PURPOSE: The study contained herein was undertaken to review and summarize the current literature on diagnostic and therapeutic applications of monoclonal antibodies in colorectal cancer. RESULTS: Limitations of traditional imaging techniques have encouraged development of targeted imaging strategies using radiolabeled monoclonal antibodies. Diagnostic immunoscintigraphy can detect lesions not identified by conventional imaging modalities, although it has not proven useful in the management of primary colorectal cancers and in hepatic metastases. Immunoscintigraphy shows promise in cases of local recurrence and rising carcinoembryonic antigen values; however, the impact of immunoscintigraphy on clinical outcomes and cost-effectiveness remains unproven. Radioimmunoguided surgery has been advocated as a method of more accurately detecting tumor extension and accomplishing radical resection. The technique remains controversial, and its use is not widespread. With respect to therapeutic applications, immunotherapy has most often been investigated in the setting of advanced stage disease. Results in this setting have been poor. In contrast, adjuvant immunotherapy after resection of Dukes C carcinoma has achieved convincing results, with improvements in survival comparable with that of adjuvant chemotherapy. Adjuvant trials are now under way to examine the effectiveness of monoclonal antibodies in the postoperative treatment of early-stage (II) tumors and the combination of monoclonal antibodies and chemotherapy in advanced-stage (III) tumors. Bispecific antibodies, or immunoconjugates with cytokines or toxins, represent additional areas of interest and future investigations. CONCLUSIONS: At present, immunoscintigraphy is not sufficient to determine, by itself, resectability of colorectal tumor and has limited usefulness in select cases of recurrent cancer and possibly in cases of rising carcinoembryonic antigen values. Immunotherapy with monoclonal antibodies as a postoperative adjuvant treatment shows promise and is currently being investigated in national trials.     

A bispecific diabody that mediates natural killer cell cytotoxicity against xenotransplantated human Hodgkin's tumors.

CD16/CD30 bispecific monoclonal antibodies can induce remissions of Hodgkin's disease refractory to chemo- and radiotherapy. However, the development of human antimouse immunoglobulin antibodies and allergic reactions precludes repeated applications of the antibody. Moreover, problems of producing and purifying sufficient amounts of material limit the clinical practicability of this novel treatment approach. To overcome these obstacles, we have constructed a bispecific antibody in a diabody form that only employs the variable domains of the CD16/CD30 hybrid hybridoma. The diabody compared favorably with the parent CD16/CD30 bispecific antibody in its ability to activate and target natural killer cells in vitro. Its administration to mice bearing xenografted Hodgkin's lymphoma resulted in a marked regression of tumor growth, thus proving for the first time the capability of a diabody for immune recruitment in vivo. The CD16/CD30 diabody is a novel reagent that should considerably facilitate the immunotherapy of patients with refractory Hodgkin's lymphoma.     

Bacterial meningitis: recent advances in pathophysiology and treatment

PURPOSE: To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the development of adjunctive strategies for treating this disorder. DATA IDENTIFICATION: Studies published from 1975 to 1989 were identified using Index Medicus and by reviewing the bibliographies of identified articles. STUDY SELECTION: We reviewed the experimental and human studies evaluating pathogenesis, pathophysiology, and antimicrobial treatment of bacterial meningitis, as well as those reviews that have contributed to our understanding of meningitis. DATA EXTRACTION: We evaluated the data on the pathogenesis, pathophysiology, and treatment of bacterial meningitis and considered in depth the information from animal models that may have potentially important applications in the treatment of human disease. RESULTS OF DATA SYNTHESIS: Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third-generation cephalosporins have revolutionized the treatment of gram-negative bacillary meningitis; one such agent, ceftazidime, is also useful for treating Pseudomonas aeruginosa meningitis. Modification of subarachnoid space inflammation by anti-inflammatory agents may lessen many of the pathophysiologic consequences of bacterial meningitis. A recent study of adjunctive dexamethasone therapy in infants and children with bacterial meningitis showed that the incidence of long-term neurologic sequelae was lower in the corticosteroid group. CONCLUSION: Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease. Additional studies using monoclonal antibodies against specific virulence factors and investigations into the production of inflammatory cytokines in response to bacterial cell products may lead to additional treatments that decrease the high morbidity and mortality in patients with bacterial meningitis.     

Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention

OBJECTIVE: To review the available information about nitrate tolerance, its potential mechanisms, clinical implications, and strategies for prevention. DATA IDENTIFICATION: A survey of the National Library of Medicine MEDLINE database and bibliographies of the reviewed articles. STUDY SELECTION AND DATA EXTRACTION: Studies were selected from the English language literature with an emphasis on recent studies and, when available, randomized placebo-controlled studies. Old studies were selected on the basis of their historical value and originality. A total of 134 retrieved articles were considered relevant and were reviewed in depth. RESULTS: The available information about the experimental as well as the clinical evidence for tolerance to organic nitrates has been summarized. In addition, information related to potential mechanisms, clinical implications, and possible methods for prevention have been reviewed. CONCLUSIONS: Evidence indicates that prolonged in-vitro exposure to organic nitrates, continuous intravenous or topical administration of nitrates, and frequent in-vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs. This phenomenon leads to the rapid attenuation of the hemodynamic and anti-ischemic effects of nitrates in patients with ischemic heart disease or congestive heart failure, or both. Tolerance development seems to be dose- and time-dependent, and its main mechanism seems to be a depletion of sulfhydryl groups at the vascular cell. Although the repletion of sulfhydryl groups with the use of sulfhydryl-containing drugs may help to prevent tolerance, the efficacy and safety of this approach requires further evaluation. Intermittent therapy allowing a sufficiently long, daily nitrate-washout interval seems to be the most effective and the most safe strategy currently available for the prevention of nitrate tolerance.     

Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma

The generation of murine monoclonal antibodies reactive with human leukemia and lymphoma cells has recently led to clinical trials that have begun to evaluate the use of these reagents in the treatment of various leukemias and lymphomas. Several of these studies have demonstrated that infusion of monoclonal antibody can cause the rapid and specific clearance of leukemic cells from the peripheral blood. Intravenously administered antibody also rapidly binds to bone marrow lymphoblasts, and in one instance, has resulted in the partial regression of tumor cell infiltrates in lymph nodes and skin. Unfortunately, clinically significant responses have not in general been achieved, but these clinical studies have identified specific factors that result in the development of resistance to antibody- mediated lysis in vivo. These factors include the presence of circulating antigen, antigenic modulation, reactivity of monoclonal antibody with normal cells, immune response to murine antibody, and the inefficiency of natural immune effector mechanisms. Current research is now being directed towards developing methods to circumvent each of these obstacles. Future clinical studies utilizing antibodies in vitro or with different specificity may demonstrate greater therapeutic efficacy. In addition, monoclonal antibodies can be used as carriers of other cytotoxic agents and in conjunction with other agents that will reduce the total load. Monoclonal antibodies represent new and powerful reagents that may in the near future become an additional therapeutic modality for patients with malignant disease.     

Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice.

Doxorubicin (DXR) was covalently conjugated to a monoclonal antibody (mAb), 9.2.27 (IgG2a), which recognizes a chondroitin sulfate proteoglycan expressed preferentially on the surface of human melanoma cells. Immunoconjugates with a molar ratio of DXR to mAb ranging from 2:1 to 10:1 were obtained by coupling the drug via an acid-sensitive linker, cis-aconitic anhydride. The immunoreactivity of mAb 9.2.27 was well retained after conjugation. DXR-mAb 9.2.27 conjugates were found to be 2 orders of magnitude more potent in killing tumor cells in vitro (IC50 = 0.1 microM) than free drug targeted to drug receptor(s). Most significantly, DXR-mAb 9.2.27 immunoconjugates specifically suppressed the growth of established tumors in vivo and prolonged the life-span of tumor-bearing nude mice. This suppression of melanoma growth achieved by the immunoconjugate was both tumor and antibody specific. A biodistribution study indicated that DXR-mAb 9.2.27 conjugates delivered at least 4 times more DXR (3.7% total injected dose per g of tumor) as compared to free DXR alone (0.8% total injected dose per g of tumor) in tumor-bearing nude mice 48 hr postinjection. The tumor-suppressive effects of DXR-mAb 9.2.27 conjugates are even more remarkable since free DXR did not suppress tumor growth in vivo and also because this drug per se is known to be quite ineffective for the treatment of human melanoma.     

Plasmodium falciparum-inhibitory monoclonal antibodies produced by human hybridomas

Stable human hybridomas were generated that produced inhibitory anti-Plasmodium falciparum monoclonal antibodies. Peripheral blood lymphocytes, obtained from adults in Liberia, a malaria endemic area, were immortalized with Epstein-Barr virus and then fused with KR4, a human, lymphoblastoid cell line. Stable hybridomas that produced anti-P. falciparum monoclonal antibody were identified by an ELISA assay that used the trophozoite and schizont antigens of both the Honduras I and FCR3 parasite strains. Monoclonal antibodies produced by selected hybridomas derived from lymphocytes of two individuals were subsequently studied. The anti-parasite antibodies were produced at 1-3 micrograms/ml in culture supernatants. All of the monoclonal antibodies bound specifically to trophozoites and schizonts of both strains of parasite in an indirect immunofluorescence assay and inhibited production of ring stage parasites by more than 90% when added to trophozoite or schizont containing erythrocytes in culture. Western immunoblot analysis of antigens obtained from trophozoites and schizonts (parasite age span of 36 to 48 h) was performed using either affinity purified or ammonium sulfate-concentrated monoclonal antibody. Antibody from three hybridomas which bound primarily to antigens of the Honduras 1 strain had Mr of approximately 140,000, 130,000 and 123,000.     

Advances in drug therapy for inflammatory bowel disease

PURPOSE: To identify advances in drug therapy for inflammatory bowel disease, and to evaluate the effectiveness of the new agents in treating both ulcerative colitis and Crohn disease. DATA IDENTIFICATION: Studies published from January 1980 through June 1989 were identified using MEDLINE and through extensive hand searching of bibliographies in identified articles. STUDY SELECTION: One hundred and ten articles directly related to the topic were found and analyzed. Another 42 articles were relevant to the material reviewed. DATA EXTRACTION: Articles were selected on the basis of study quality and their significance with regard to treatment of inflammatory bowel disease. RESULTS OF DATA ANALYSIS: The aminosalicylates are emerging as effective and safe therapy for inflammatory bowel disease. Corticotropin can be considered the drug of choice for certain patients with severe ulcerative colitis, and new rapidly metabolized topical steroids appear to be as effective as traditional forms and have fewer side effects. Immunosuppressive agents, including 6-mercaptopurine and azathioprine, may be useful in treating difficult-to-manage patients with either Crohn disease or ulcerative colitis, whereas cyclosporine appears promising but should be reserved for patients in whom other measures have failed. Patients with refractory perineal Crohn disease and those with Crohn colitis may benefit from metronidazole. Many other drugs including clonidine, cromoglycate, chloroquine, fish oil, methotrexate, antituberculous agents, interferon, and superoxide dismutase have shown enough promise in preliminary studies to warrant controlled clinical trials. CONCLUSIONS: Drug therapy for inflammatory bowel disease, limited for many years to sulfasalazine and some corticosteroids, has been extended to include the aminosalicylates, rapidly metabolized topical steroids, immunosuppressive agents, and metronidazole. Potentially useful newer drugs await further study.     

Improved method increases sensitivity for circulating hepatocellular carcinoma cells

AIM:To improve an asialoglycoprotein receptor(ASGPR)-based enrichment method for detection of circulating tumor cells(CTCs)of hepatocellular carcinoma(HCC).METHODS:Peripheral blood samples were collected from healthy subjects,patients with HCC or various other cancers,and patients with hepatic lesions or hepatitis.CTCs were enriched from whole blood by extracting CD45-expressing leukocytes with monoclonal antibody coated-beads following density gradient centrifugation.The remaining cells were cytocentrifuged on polylysine-coated slides.Isolated cells were treated by triple immunofluorescence staining with CD45antibody and a combination of antibodies against ASGPR and carbamoyl phosphate synthetase 1(CPS1),used as liver-specific markers,and costained with DAPI.The cell slide was imaged and stained tumor cells that met preset criteria were counted.Recovery,sensitivity and specificity of the detection methods were determined and compared by spiking experiments with various types of cultured human tumor cell lines.Expression of ASGPR and CPS1 in cultured tumor cells and tumor tissue specimens was analyzed by flow cytometry and triple immunofluorescence staining,respectively.RESULTS:CD45 depletion of leukocytes resulted in a significantly greater recovery of multiple amounts of spiked HCC cells than the ASGPR+selection(P s<0.05).The expression rates of either ASGPR or CPS1were different in various liver cancer cell lines,ranging between 18%and 99%for ASGPR and between 9%and 98%for CPS1.In both human HCC tissues and liver cancer cell lines,there were a few HCC cells that did not stain positive for ASGPR or CPS1.The mixture of monoclonal antibodies against ASGPR and CPS1identified more HCC cells than either antibody alone.However,these antibodies did not detect any tumor cells in blood samples spiked with the human breastcancer cell line MCF-7 and the human renal cancer cell line A498.ASGPR+or/and CPS1+CTCs were detected in 29/32(91%)patients with HCC,but not in patients with any other kind of cancer or any of the other test subjects.Furthermore,the improved method detected a higher CTC count in all patients examined than did the previous method(P=0.001),and consistently achieved 12%-21%higher sensitivity of CTC detection in all seven HCC patients with more than 40 CTCs.CONCLUSION:Negative depletion enrichment combined with identification using a mixture of antibodies against ASGPR and CPS1 improves sensitivity and specificity for detecting circulating HCC cells.     

Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth.

The ERBB2 (also called HER2, neu, and c-erbB-2) gene product, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. An antibody directed to the rat oncogenic receptor has been previously shown to have an antitumor effect in model systems. In an attempt to extend this observation to the protooncogenic human receptor and also to understand the underlying mechanism, we generated a panel of monoclonal antibodies specific to the extracellular portion of the ERBB2 protein. The effects of the antibodies on tumor growth were compared with their cellular and biochemical actions in vitro. Surprisingly, opposing in vivo effects were observed: although some antibodies almost completely inhibited the growth in athymic mice of transfected murine fibroblasts that overexpress Erbb-2, other antibodies either accelerated tumor growth or resulted in intermediate responses. When tested on cultured human breast carcinoma cells or ERBB2 transfectants, the tumor-stimulatory antibody was found to induce significant elevation of tyrosine phosphorylation of the ERBB2 protein. In contrast, only partial correlation was observed between the capacity to restrict tumor growth and the effects of the antibodies on receptor degradation and cellular proliferation in vitro. This suggests that the antitumor antibodies affect both receptor function and host-tumor interactions. Our results may help establish experimental criteria for the selection of specific antibodies for use either alone or in conjunction with other molecules as pharmacological antitumor agents.     

Autologous bone marrow transplantation. Current status and future directions

PURPOSE: To assess the current status of high-dose chemotherapy with autologous marrow transplantation in hematologic malignancies and solid tumors. DATA IDENTIFICATION: Studies reported between 1978 and May 1988 were identified through computer searches using Medline and Cancerline and through extensive manual searching of bibliographies of identified books and articles. STUDY SELECTION: More than 160 studies that contained adequate response, toxicity, or survival data were selected for analysis, including peer-reviewed articles, book chapters, and proceedings of meetings. The most current or complete references were used for series reported more than once. DATA ANALYSIS: Information abstracted included regimen used, number of patients, response rates, disease-free and overall survival, and toxicities. A meta-analysis of the pooled data was done. RESULTS OF DATA ANALYSIS: For many tumor types, autologous marrow transplantation offers higher response rates than standard approaches. For leukemias and lymphomas, response rates of 60% to 80% may be achieved with the potential for cure. With solid tumors, response rates range from 30% in gliomas, 50% in melanomas and colon cancer, more than 60% in lung cancer, and 80% in breast cancer. Although responses tend to be short-lived, long-term survival can occasionally be seen. CONCLUSIONS: Results with autologous marrow transplantation can be improved through systematically developed, carefully designed clinical trials that may be facilitated by collaborative research. Studies should focus on disease-directed drug combinations, several courses of high-dose therapy, treatment at a time of lower tumor burden, and reducing toxicity with hematopoietic growth factors.