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Biomedical subjects

T J Hamblin

Publications and source records attributed to T J Hamblin.

At least 91 records · Page 5Linked to original sources
PubMed1989

Identification of normal B-cell counterparts of neoplastic cells which secrete cold agglutinins of anti-I and anti-i specificity.

A monoclonal antibody, which recognizes a cross-reacting idiotypic determinant present on human cold-reactive autoantibodies with anti-I or anti-i binding activity, has been found to specifically inhibit the cold agglutination of red cells. This suggests that an epitope close to the binding site of such autoantibodies is being recognized. The antibody has been used to identify tumour cells in the blood of three patients with cold haemagglutinin disease, and to analyse the heterogeneous nature of the neoplastic B-cell clone present in the bone marrow of one of the patients. Using S-phase analysis, it was found that cell proliferation was occurring in the bone marrow but not in the blood, and that the major proliferating population was that of lymphoplasmacytoid cells containing large vesicular inclusions of idiotypic IgM. It has also been possible to locate normal B-cells which are recognized by the anti-idiotypic antibody. Such cells have been found throughout the normal adult lymphoid tissue where they account for 2.9-10.8% of the B lymphocyte population. They are also present in fetal spleen at 15 weeks gestation, indicating that immunoglobulins bearing this sequence form part of the immature B-cell repertoire.

Agglutinins↗
PubMed1989

Clinical parameters for evaluating biological response modifier therapy.

Evaluating response in cancer is a well established practice, depending on the recognition of complete response, partial response, stable disease and progressive disease. For chemotherapeutic drugs, only those patients achieving a complete response experience an increase in survival. Partial response merely indicates that the drug has some activity in that disease. What the patient wants is not active drugs but prolonged survival with good quality of life. It is well recognised that tumours may remain dormant for many years, and that even those patients with complete responses to chemotherapy usually have minimal residual disease. It is assumed that such minimal disease is controlled and held in check by a biological process. The principal aim of biological response modifiers is to enhance this effect so as to control an even larger tumour load. It therefore follows that removal of all tumour is not the only benefit, and that stable disease and even slower progression might translate to longer survival. Survival curves are the acid test and we should expect longer survival even for those patients failing to achieve complete response if we are to establish that life imprisonment is as effective in cancer treatment as capital punishment.

Humans↗
PubMed1988

Idiotypic vaccination as a treatment for a B cell lymphoma.

To develop a model for the active immunotherapy of human B cell malignancy we vaccinated tumor-bearing animals with a well defined tumor associated Ag, the idiotypic Ig. The tumor used was the mouse B cell lymphoma BCL1, a highly malignant tumor in which transfer of a single tumor cell to a syngeneic mouse is capable of causing disease and eventual death. Varying doses (10(2) to 10(4] of BCL1 cells were given to mice on day 0 of the experiment, and treatment by active immunization was initiated on day 3. Immunization with purified, tumor-derived, idiotypic IgM (BCL1 IgM) coupled to keyhole limpet hemacyanin (KLH) was highly effective in treating mice challenged with 10(2) or 10(3) BCL1 cells, but less effective in mice that had received 10(4) tumor cells. Immunization with unconjugated BCL1 IgM showed no signficant therapeutic benefit. Coupling of the IgM to KLH led to higher levels of anti-idiotypic antibody after immunization; however, the higher levels were probably not responsible for the control of the malignancy as there was no correlation in healthy immunized animals between the levels of anti-idiotypic antibody, measured immediately before tumor challenge, and survival. This lack of correlation is due to the emergence of variant tumors in such protected mice. A more significant factor in the therapeutic advantage of KLH conjugation could be that immunization with BCL1 IgM-KLH led to an earlier induction of the anti-idiotypic response than immunization with BCL1 IgM and, as the BCL1, lymphoma divides rapidly, the speed of induction of the immune response may be important in outstripping tumor cell growth. Mice with BCL1 tumour showed some evidence of immunosuppression as indicated by a reduced ability to mount an immune response against KLH. Although it is not possible to model spontaneous human lymphoma accurately, the generation of a functional anti-idiotypic response capable o eliminating a malignant animal lymphoma in situ opens up the possibility of a limited trial of active immunotherapy in selected human patients.

Animals↗
PubMed1988

Problems and prospects in the use of lymphoma idiotypes as therapeutic targets.

The infusion of anti-idiotypic antibody in patients with lymphoma has proved a relatively innocuous procedure, but in general had yielded only partial, short-lived remissions of disease. A major problem is that xenogeneic antibody is simply not well-fitted to destroying mammalian cells: complement and cellular effectors (K cells and phagocytes) are not efficiently recruited, and the target cells in any case present some excellent defense mechanisms. Antigenic modulation is particularly prominent among these defenses, and we present evidence here for modulation of idiotype being much more efficient in vivo than in vitro. Two broad types of antibody derivative are under development to improve the killing of neoplastic targets. One type relies on recruiting natural effectors, and is exemplified by univalent chimeric antibody. The other relies on delivering an exogenous effector such as a drug or toxin, and is exemplified by bispecific anti-Id/anti-saporin F(ab'gamma)2 antibody. Both types of derivative have been able to suppress animal lymphoma to the extent that tumor escape occurs largely through the emergence of idiotype-negative mutants.

Aged↗
PubMed1988

Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival.

We have studied the clinical and laboratory features of 53 cases of chronic myelomonocytic leukaemia (CMML) defined according to the FAB criteria. A granulocyte count of greater than 16 X 10(9)/l or a monocyte count of greater than 2.6 X 10(9)/l correlated with a poorer survival, but the best predictor of poor survival was the modified 'Bournemouth' score in which one point each was allocated for Hb less than 10 g/dl, neutrophils less than 2.5 X 10(9)/l or greater than 16 X 10(9)/l, platelets less than 100 X 10(9)/l and bone marrow blasts greater than 5%. A score of 2 or more was predictive of poor survival (Chi2 = 10.25; P less than 0.001). Those patients with low monocyte and neutrophil counts and a low modified Bournemouth score tended to have a clinical course similar to refractory anaemia (RA) with an indolent course not requiring treatment and long survival whereas those with high monocyte and neutrophil counts and a high modified 'Bournemouth' score have a clinical course resembling that of refractory anaemia with excess of blasts (RAEB).

Aged↗
PubMed1988

CD3+ CD8+ T cell lymphocytosis masking B cell leukaemia.

A patient with CD3, CD8 positive lymphocytosis presented with features consistent with T cell chronic lymphocytic leukaemia/proliferations of large granular lymphocytes. The marrow and blood lymphoid populations (19.4 x 10(9)/l) contained more than 80% CD3 and CD8 positive cells with no evidence of a monotypic B cell population. A biopsy specimen of a vasculitic rash showed a diffuse infiltrate of CD3, CD8 positive cells into the upper dermis, consistent with T cell lymphocytic disease. After follow up for two years without treatment the blood lymphocyte count was 53 x 10(9)/l and was composed of cytologically small lymphocytes. A monoclonal SIg M D k lymphoid population (more than 90%) was demonstrable in sample blood and marrow aspirate. Gene rearrangement studies carried out on DNA extracted from peripheral blood lymphocytes at presentation and at two year follow up exhibited JH and Ck immunoglobulin gene rearrangement but no rearrangement of T cell receptor TcR gamma and beta genes. It is thought that this is the first well documented case of an aggressive CD8 positive lymphocytosis preceding, or in response to, an underlying B cell neoplasm.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Lymphokine-activated killer cells from normal and lymphoma subjects are cytotoxic for cells coated with antibody derivatives displaying human Fc gamma.

Lymphokine-activated killer (LAK) cells were successfully generated in all cases from blood mononuclear cells obtained from six patients with lymphoma. The LAK cells from three of these patients and from five normal adult donors were tested for their effector abilities in antibody-dependent cellular cytotoxicity (ADCC) against guinea pig leukemic lymphocytes coated with various antiidiotype antibodies. Cells from all the donors behaved similarly. Mouse monoclonal antibodies of IgG1, IgG2a, and IgG2b isotypes invoked no ADCC. However, substantial ADCC was invoked by the chimeric antibody FabFc, in which Fab'gamma from mouse antiidiotype is thioether-bonded to human normal Fc gamma. Similar results were obtained on testing LAK cells from a normal donor against uncultured human lymphoma targets coated with native or chimeric antiidiotype. The ADCC invoked by the mouse-human chimeric antibodies appears to depend on the human Fc gamma they display and not on the univalency of the derivatives used. The findings imply that LAK technology could usefully augment serotherapy that uses antibody derivatives displaying human Fc gamma.

Adult↗
PubMed1988

Chromosomal abnormalities in B-CLL.

Amongst 141 patients with B-CLL, 53% had an abnormal karyotype. Treatment free survival was shorter in those with karyotypic abnormalities, and especially in those with multiple abnormalities. Multiple abnormalities tended to be associated with progressive disease. Trisomy 12 alone carried no worse a prognosis than a normal karyotype. 49% of patients with stage AO disease had an abnormal karyotype.

Actuarial Analysis↗
PubMed1988

Use of a cross reacting anti-idiotype to identify normal counterparts of neoplastic cells.

We have established that 9G4, a cross reacting monoclonal anti-idiotype identifies an epitope close the binding site of anti-I cold agglutinins. 9G4 positive lymphocytes comprise around 5% of B cells and are widely represented in all lymphoid tissue. They may be detected in 15 week fetal spleen at the time of the earliest appearance of B cells and thus form part of the basic B cell repertoire. Such antibodies are derived largely from CD5 positive B cells. 9G4 is thus a useful tool to investigate the normal counterpart of the CLL cell.

Adult↗
PubMed1987

Differentiation induction in myelodysplasia and acute myeloid leukaemia: use of synergistic drug combinations.

DNA synthesis inhibitors and vincristine greatly enhance the response of leukaemic and dysplastic cells to differentiation inducing agents such as retinoic acid (RET). Differentiation induction therapy is an attractive therapeutic approach in myelodysplasia (MDS) and in acute myeloid leukaemia (AML) in the elderly, since it should be possible to increase the production of mature cells, at the expense of precursor cells, without incurring the complications of intensive cytotoxic therapy. Single agent differentiation therapy has, however, not been highly successful. We have therefore investigated the use of synergistic combinations of agents. We treated nine patients (6 with MDS, 3 with AML) with 13-cis-retinoic acid (up to 100 mg/m2/day) in combination with either 6-thioguanine (20-40 mg/day in 14-57 day courses) or with vincristine (1-2 mg as a single injection during a four-day course of RET). Seven patients responded with an increase in the mature cells of at least one haemopoietic lineage. A concomitant decrease in marrow blasts was observed in 3/4 responding patients. The retention of dysplastic and karyotypic abnormalities and lack of a hypoplastic phase all suggested that differentiation induction was occurring in vivo. Prior failure to respond to therapy with single agents (RET in two and cytosine arabinoside in five patients) suggests that the synergy observed in vitro operates in vivo. In-vitro studies on marrow cells from seven patients demonstrated synergistic differentiation induction in 6/7 samples. The seventh patient was one of the two who did not respond clinically. The second of these clinically unresponsive patients had cells which were relatively refractory to RET in vitro, suggesting that in-vivo and in-vitro responses may be related.

Adult↗
PubMed1987

Long survival in B-CLL correlates with surface IgM kappa phenotype.

200 patients with B-cell chronic lymphocytic leukaemia (B-CLL) presenting to a single centre over 13 years have been studied. In 72.2% the diagnosis was made on an incidental blood count, and 70.1% were stage A at presentation. Those patients whose cells expressed surface IgM kappa were significantly more likely to be stage A at presentation and significantly less likely to have a lymphocyte count greater than 50 X 10(9)/l, to have progressive disease or to require treatment than those with other classes of surface Ig. Patients whose cells express surface IgM kappa have a significantly longer actuarial survival than others and this is also so when only patients in Binet stage A or when only patients presenting below the age of 75 are studied. By studying all of the cases presenting in a single catchment area we have attempted to avoid the bias against trivial disease likely to be seen in specialist referral centres.

Adult↗