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Biomedical subjects

K A Foon

Publications and source records attributed to K A Foon.

At least 109 records · Page 6Linked to original sources
PubMed1987

Monoclonal antibody therapy in malignant melanoma: factors effecting in vivo localization.

Thirteen patients with metastatic malignant melanoma received intravenous therapy with the murine antimelanoma monoclonal antibody 9.2.27. Five patients were entered on a dose escalation protocol with twice weekly escalating doses of 10-500 mg, in an extension of a previously reported trial. These patients demonstrated near saturation of available antibody binding sites in vivo following the 500 mg dose, with minimal toxicity. The remaining patients were entered onto a dose schedule comparison study, with a 500 mg dose administered either in a single 2 h infusion or as five daily 2 h infusions of 100 mg to examine the effects of different dose schedules and of an interrupted schedule on subsequent therapy with the same antibody. Intratumor localization of the monoclonal antibody did not appear to vary with respect to the dose schedule; however, interruption in therapy for 4 weeks was accompanied by somewhat poorer localization of antibody. This effect appeared to be primarily attributable to development of human antimurine antiglobulin in 25-30% of patients with resultant decrease in intratumor localization of antibody and more rapid clearance of the 9.2.27 antibody from the circulation. Earlier reports with other antibodies notwithstanding, initial infusions of 500 mg of 9.2.27 did not induce tolerance to the murine immunoglobulin. This study confirms and extends the findings of our initial trial of the 9.2.27 antibody by demonstrating that, although clinical responses were not observed, the antibody can be safely administered at doses up to 500 mg, with good intratumor localization of antibody. The diminished localization of antibody associated with antiglobulin responses indicates the importance of monitoring antiglobulin levels during therapy, and the necessity of controlling or preventing this phenomenon when monoclonal antibodies are administered in multiple doses as drug, toxin, or radionuclide immunoconjugates.

Adult↗
PubMed1986

Radioimmunodetection of cutaneous T-cell lymphoma with 111In-labeled T101 monoclonal antibody.

T101 monoclonal antibody recognizes a pan-T-cell antigen present on normal T cells and also found in high concentrations in cutaneous T-cell lymphoma. We used this antibody, radiolabeled with 111In, in gamma-camera imaging to detect sites of metastatic cutaneous T-cell lymphoma in 11 patients with advanced disease. In all patients, [111In]T101 concentrated in pathologically or clinically detected nodes, including those in several previously unsuspected nodal regions. Concentrations (per gram of tissue) ranged from 0.01 to 0.03 percent of the injected dose and were consistently 10 to 100 times higher than previously reported on radioimmunodetection. Focal uptake was seen in skin tumors and heavily infiltrated erythroderma but not in skin plaques. The specificity of tumor targeting was documented by control studies with [111In]chloride or [111In]9.2.27 (anti-melanoma) monoclonal antibody. Increasing the T101 dose (1 to 50 mg) altered distribution in nontumor tissues. These studies suggest that imaging with [111In]T101 may be of value in identifying sites of cutaneous T-cell lymphoma. In contrast to the targeting of solid tumors, the mechanism of localization appears to be related to binding to T cells, which can then carry the radioactivity to involved sites.

Adult↗
PubMed1986

Evaluation of alternative methodologies for the generation of murine monoclonal anti-idiotypic antibodies to human B cell leukemias and lymphomas.

The standard immunization procedure for the development of monoclonal antibodies to human malignant B cell idiotype immunoglobulin in our laboratory consists of intraperitoneal immunization with 50-100 micrograms of purified immunoglobulin followed 7 days later by intravenous immunization with an equal quantity of protein. In order to shorten the process and decrease the amount of idiotypic immunoglobulin necessary for successful immunization, we have evaluated 2 alternative immunization procedures. When immunized by the standard method, the percentage of hybridomas demonstrating anti-idiotype activity was 0.3-1.0%. In order to increase the proportion of anti-idiotype hybrids tolerance to the constant regions of human IgM was established by intraperitoneal administration of disaggregated human gamma globulin 14 days prior to immunization of both male and female mice. The percentage of wells with anti-idiotype activity rose to 16-52% in tolerant male mice. The percentage of anti-idiotype hybrids generated was significantly lower in tolerant female mice. To accelerate the process of anti-idiotype development, a single intrasplenic immunization with soluble idiotype IgM was also evaluated. No anti-idiotype or anti-IgM secreting heterohybrids were formed out of nearly 1400 wells seeded in 3 separate fusions using soluble IgM. When the idiotype IgM was immobilized onto protein A-Sepharose, and then injected intrasplenically, approximately 1% of the wells seeded showed anti-idiotype activity. Thus, a single intrasplenic immunization with immobilized immunoglobulin resulted in significant time saving, while prior tolerization may greatly increase the percentage of anti-idiotype hybrids.

Antibodies, Anti-Idiotypic↗
PubMed1986

The role of recombinant interferon alfa-2a in the therapy of cutaneous T-cell lymphomas.

Maximally tolerated doses of interferon alfa-2a, 50 X 10(6) U/m2 administered intramuscularly (IM) 3 times weekly, were given to 20 patients with advanced stages of cutaneous T-cell lymphoma (CTCL) to determine the efficacy and toxicity of this therapy. All patients were heavily pretreated and had failed standard therapies. Objective remissions were noted in 45% of the patients, including two patients who achieved complete remissions and seven patients who had partial remissions. The median duration of response was 5.5 months, with responses lasting a minimum of 3 months and a maximum of more than 3 years. Responses in excess of 2 years occurred in three of the nine responding patients. These results were achieved with moderate toxicities. The dose-limiting toxicity was a flu-like syndrome consisting of malaise, anorexia, weight loss, and falling performance status. Toxicity was observed in all patients but was always alleviated by dose reduction. Patients with indolent B-cell non-Hodgkin's lymphoma who received the same therapy had a similar objective response rate (54%) and showed the same toxicities. These trials were followed by an ongoing trial using the same dose of interferon in a different schedule given for 12 weeks followed by a dose escalation to 100 X 10(6) U/m2. Three partial responses were observed in the first 13 patients on this trial treatment. Other studies examining lower dose interferon compared to the 50 X 10(6) U/m2 are in progress. This study establishes interferon alfa-2a as a treatment of choice for patients with advanced cutaneous T-cell lymphomas refractory to chemotherapy and other standard therapies. Trials combining interferon with other standard treatments and the use of interferon in earlier stages of disease are needed.

B-Lymphocytes↗
PubMed1986

Biological therapy of cancer.

Interferons and monoclonal antibodies are among the most promising biological approaches to cancer treatment which have so far been investigated. Both natural and recombinant interferon-alpha preparations have shown activity in a number of trials in hematologic malignancies, even in previously treated patients; activity in solid tumors, however, has been limited. Unconjugated monoclonal antibodies have been safely administered in several small trials and have had therapeutic value on occasion. In spite of a number of remaining problems and questions, monoclonal antibodies and their conjugates seem likely to find a number of distinct roles in cancer treatment; elimination of micrometastases and purging of bone marrow for grafting may be among these roles.

Antibodies, Anti-Idiotypic↗
PubMed1986

Alpha interferon in the treatment of hematologic malignancies.

The interferons are an important first member of a family of biologic response-modifiers used in treating human malignancies. Activities associated with the interferons include inhibition of viral replication, influence on cellular protein production, direct antiproliferative effects, and a variety of modulatory effects on the immune response. These regulatory functions of interferon underlie the interest in its use as an anticancer agent. Alpha interferon is the most extensively studied interferon species. Although antitumor activity has been seen both in vitro and in vivo in some solid malignancies, the most impressive responses have occurred in the hematologic malignancies. More than 90 percent of patients with hairy cell leukemia have a sustained recovery of their peripheral blood cell counts with alpha interferon therapy. Approximately 50 percent of patients with low-grade non-Hodgkin's lymphoma and cutaneous T cell lymphoma demonstrate a response to alpha interferon. More than 80 percent of patients with chronic myelogenous leukemia have a response to alpha interferon, and in one study, nearly half of the patients with response had complete suppression of the Philadelphia chromosome clone on at least one examination. Ongoing clinical trials are addressing such issues as optimal dosage, duration of alpha interferon therapy, and combinations of alpha interferon with other biologic agents, chemotherapy drugs, and radiation.

Humans↗
PubMed1986

Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Therapeutic and immunologic results.

Hairy cell leukemia is a lymphoproliferative disorder characterized clinically by cytopenias. Standard therapy following variable periods of disease stability consists of splenectomy that often restores normal hematologic parameters for periods ranging from weeks to years. Fifteen patients (five without prior splenectomy or chemotherapy) were treated with 3 X 10(6) units per day of recombinant leukocyte A interferon and 14 of 15 patients completed eight weeks of therapy and were evaluated for response. There was one complete and 12 partial responses for an overall response rate of 93 percent. All of these patients' conditions have remained in complete or partial remissions and they continue to receive interferon with a median follow-up of six months. Coincident with the normalization of peripheral blood counts was a return of natural killer activity and normalization of immunologic surface markers as determined by monoclonal antibodies. This study confirms and extends earlier observations with natural alpha-interferon and indicates that recombinant leukocyte A interferon in low daily doses is also very effective treatment for hairy cell leukemia. In fact, it may be the best single modality of therapy for inducing both hematologic and immunologic recovery of these patients and deserves consideration as initial therapy.

Adult↗
PubMed1986

Optimal strategies for developing human-human monoclonal antibodies.

Human monoclonal antibodies are desirable, especially as therapeutic agents, but the best means of producing them is still a matter of investigation. It is clear that human antibodies of predicted specificity from patients with autoimmune disease can be derived, and this may help unlock some of the mysteries of these illnesses. Human monoclonal antibodies against tumor-specific antigens for use in in vivo diagnosis and therapy remain desirable goals. Problems involved in their routine development include the lack of available, adequately immunized, and differentiated lymphocytes and the nature and paucity of the available human "myeloma" cell lines. These lines have been compared now by a number of authors who have reached similar conclusions. Our study directly compared the greatest number of cell lines and found UC729-6 and HF2 to be the best; on the other hand, our success in developing IgG-secreting hybridomas from U-266, using hyperimmunized lymphocytes, suggests that this line may only be capable of secretion with the more differentiated cell, the human equivalent of those hyperimmunized murine spleens. Hence both sides of the fusion equation must be made optimal. Two new approaches to circumvent this problem involve the use of either a human-murine myeloma chimera as the parental myeloma line or, more recently, genetic engineering techniques to substitute human constant regions for the murine while retaining the murine hypervariable region, preserving the binding specificity of the murine antibody.

Antibodies, Monoclonal↗
PubMed1986

Relationship of the clinical response and binding of recombinant interferon alpha in patients with lymphoproliferative diseases.

Patients with hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL) were treated with recombinant interferon alpha A (rIFN-alpha A). The binding of iodinated recombinant interferon-alpha to baseline samples of peripheral blood mononuclear cells (PBMCs) from the leukemia patients was compared with clinical responsiveness to rIFN-alpha A. HCL patients (8/10) responded to rIFN-alpha A therapy, whereas none (0/10) of the CLL patients studied responded. The PBMCs from the eight responsive HCL patients bound approximately twice as much iodinated interferon as the PBMCs from nonresponsive CLL patients. This difference was due to more high-affinity receptors per cell with no difference in the affinity of the interferon-receptor interaction. However, because PBMCs from HCL patients were larger than PBMCs from CLL patients, the cell surface receptor density was similar. The leukemic cells from one of the two nonresponsive HCL patients bound iodinated interferon similarly to the cells from the responsive HCL patients, whereas the leukemic cells from the other nonresponsive HCL patient bound considerably less. The rapidity of response of the HCL patients did not correlate with the level of binding of iodinated interferon. Our results suggest that the absolute number of interferon receptors per cell may be only one of several important parameters in the response to rIFN-alpha A therapy, and that the responsiveness of a particular lymphoproliferative disease or a particular patient to rIFN-alpha A therapy cannot be predicted or explained solely by the degree of interaction between IFN and its cell surface receptor.

Cell Separation↗
PubMed1986

Immunologic classification of leukemia and lymphoma.

Important insights into leukocyte differentiation and the cellular origins of leukemia and lymphoma have been gained through the use of monoclonal antibodies that define cell surface antigens and molecular probes that identify immunoglobulin and T cell receptor genes. Results of these studies have been combined with markers such as surface membrane and cytoplasmic immunoglobulin on B lymphocytes, sheep erythrocyte receptors on T lymphocytes, and cytochemical stains. Using all of the above markers, it is now clear that acute lymphoblastic leukemia (ALL) is heterogeneous. Furthermore, monoclonal antibodies that identify B cells, such as the anti-B1 and anti-B4 antibodies in combination with studies of immunoglobulin gene rearrangement, have demonstrated that virtually all cases of non-T-ALL are malignancies of B cell origin. At least six distinct subgroups of non-T-ALL can now be identified. T-ALL is subdivided by the anti-Leu-9, anti-Leu-1, and antibodies that separate T lymphocyte subsets into three primary subgroups. Monoclonal antibodies are also useful in the subclassification of non-Hodgkin's lymphoma, and certain distinct markers can be correlated with morphologic classification. The cellular origin of the malignant Reed-Sternberg cell in Hodgkin's disease remains uncertain. A substantial number of investigators favor a myelocyte/macrophage origin based on cytochemical staining; however, consistent reactivity with antimonocyte reagents has not been demonstrated. Although monoclonal antibodies are useful in distinguishing acute myeloid from acute lymphoid leukemias, they have less certain utility in the subclassification of acute myelogenous leukemia (AML). Attempts to subclassify AML by differentiation-associated antigens rather than by the French-American-British (FAB) classification are underway in order to document the potential prognostic utility of surface markers. Therapeutic trials using monoclonal antibodies in leukemia and lymphoma have been reported. Intravenous (IV) infusion of unlabeled antibodies is the most widely used method; transient responses have been demonstrated. Antibodies conjugated to radionuclides have been quite successful in localizing tumors of less than 1 cm in some studies. Therapy trials with antibodies conjugated to isotopes, toxins, and drugs are currently planned. Purging of autologous bone marrow with monoclonal antibodies and complement in vitro has been used in ALL and non-Hodgkin's lymphoma; preliminary data suggest that this approach may be an effective therapy and may circumvent many of the obstacles and toxicities associated with in vivo monoclonal antibody infusion.

Antibodies, Monoclonal↗
PubMed1986

Recent advances in the immunologic classification of leukemia.

Important insights into leukocyte differentiation and the cellular origins of leukemia have been gained through the use of monoclonal antibodies that define cell surface antigens and molecular probes that identify immunoglobulin and T cell receptor genes. Results of these studies have been combined with markers such as surface membrane and cytoplasmic immunoglobulin on B lymphocytes, sheep erythrocyte receptors on T lymphocytes, and cytochemical stains. Using all of the above markers, it is now clear that acute lymphoblastic leukemia (ALL) is heterogeneous. Although monoclonal antibodies are useful in distinguishing acute myeloid from acute lymphoid leukemias, they have less certain usefulness in the subclassification of acute myelogenous leukemia (AML). Attempts to subclassify AML by differentiation-associated antigens rather than by the French-American-British (FAB) classification are underway in order to document the potential prognostic usefulness of surface markers.

Antibodies, Monoclonal↗
PubMed1986

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia.

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN-alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.

Adult↗
PubMed1986

Alpha interferon treatment of low-grade B-cell non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, and chronic lymphocytic leukemia.

The interferons represent an important first member of a family of biologic response modifiers used in treating human malignancies. Activities associated with the interferons include inhibition of viral replication, influence on cellular protein production, direct antiproliferative effects, and a variety of modulatory effects on the immune response. These regulatory functions of interferon underlie the interest in its use as an anticancer agent. Interferon alpha is the most extensively studied interferon species. Although antitumor activity has been seen both in vivo and in vitro in some solid malignancies, the most impressive responses have occurred in the hematologic malignancies. For the low-grade non-Hodgkin's lymphomas, response rates of 50%, with 10% to 15% complete responses, have been reported. A response rate of 15% has been reported for chronic lymphocytic leukemia in studies outside of the National Cancer Institute (NCI); in our phase II trials at the NCI, only two (11%) of 18 patients had brief partial responses to recombinant interferon alpha. For patients with cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome), a response rate of 45%, with 10% complete responses, was seen in patients treated with recombinant interferon alpha. Based on such findings, interferon appears to be one of the most effective single agents for cutaneous T-cell lymphomas. Further phase II trials are being conducted to determine whether lower doses of interferon alpha are as effective as the high doses used in the previously reported studies. Phase III trials will involve the use of interferons in combination with chemotherapeutic agents as well as in the adjuvant setting.

Humans↗
PubMed1986

Acute myeloid leukaemia: recent advances in therapy.

Over the past ten years, there have been substantial advances in the treatment of AML. Intensive induction chemotherapy using seven-day courses of cytarabine and daunorubicin or amsacrine produce remission in 60-85% of patients. Median remission duration is 9-16 months. In some series, 20-40% of patients are in continuous remission for two years or more; many of these patients remain in remission for five years or longer and some may be cured. Bone marrow transplantation has evolved as a useful therapeutic modality capable of achieving long-term survival in some circumstances in which chemotherapy is relatively ineffective. Its precise role in the initial therapy of AML remains to be defined but it is likely to be beneficial in selected patients. These data indicate substantial recent progress in the treatment of this disease which was almost uniformly fatal 30 years ago. The fact that most patients relapse within 1-2 years reflects a lack of progress in developing effective postremission therapy. Maintenance chemotherapy, immunotherapy and CNS prophylaxis have little role in AML. It is unclear whether consolidation or intensification extend remissions or increase the proportion of long-term survivors; controlled randomized trials should answer this question within the next few years. Future progress in the treatment of AML awaits the development of more sensitive methods for detecting residual leukaemia, more effective use of current therapeutic modalities and the introduction of new effective drugs. Most data suggest that early intensive treatment is of key importance for achieving cures. We cannot presently distinguish, however, between patients cured by initial treatment and those who require further chemotherapy.

Antineoplastic Agents↗