Low Tumor Load Research Articles

Bispecific antibody treatment of murine B cell lymphoma.

This report summarizes our experimental data concerning the use of bispecific antibodies (bsAb) for the treatment of the murine BCL1 B cell lymphoma model. Initially we used a hybrid-hybridoma-derived bsAb with specificity for the TcR/CD3 complex on T cells and the idiotype of the membrane-bound IgM on the tumor cells. The bsAb used as a single agent could cure animals with a low tumor load (resembling minimal residual disease). However, in experiments aimed at increasing the therapeutic effect in animals with a higher tumor burden, we could demonstrate the importance of additional T-cell-costimulatory signals and the careful timing of the bsAb administration. Recently we have generated a bispecific single-chain Fv (bsscFv) fusion protein with the same dual specificity as the hybrid-hybridoma-derived bsAb. Immunotherapy with this smaller molecule also resulted in tumor elimination in BCL1-bearing mice. A second bsscFv (alpha-CD19 x alpha-CD3) with a broader applicability is now being characterized and tested in vivo.

Management of Chronic Lymphocytic Leukemia

Significant progress has been made in the past two decades in the understanding of immunobiology of CLL and the development of clinical staging systems and identification of other prognostic factors in CLL. A significant advance in the management of CLL has also been made. Now we know when to initiate therapy. We recommend that patients with stage 0 and patients with stages I and II associated with good prognostic features such as absence of disease-related symptoms, long lymphocyte doubling time, nondiffuse bone marrow infiltration, and low tumor load not be treated; they should be followed at 2- to 6-month intervals. We recommend initiation of therapy for patients with stages I and II, associated with poor prognostic features such as presence of disease-related symptoms, short lymphocyte doubling time, diffuse bone marrow infiltration, and high tumor load and for patients with stages III and IV. However, we still do not know what constitutes the optimal therapy for the disease. In one large randomized study, the response rate as well as survival superiority of CHOP (with low-dose Adriamycin) over COP in previously untreated patients with stage C disease was observed. In another large randomized study, only a response rate advantage of CHOP (with standard dose Adriamycin) over chlorambucil and prednisone (in previously untreated patients with stages B and C) was seen. No randomized studies have compared CHOP versus chlorambucil and prednisone in patients with stages III and IV or stage C. At present, our recommendation for the treatment of patients with advanced disease is chlorambucil and prednisone therapy. New drugs under clinical trials for CLL include (1) deoxycoformycin, (2) 2-chlorodeoxyadenosine, and (3) fludarabine monophosphate. Both deoxycoformycin and 2-chlorodeoxyadenosine have been shown to have some activity in previously treated CLL patients with advanced disease. The effectiveness of these agents, however, has not been tested yet in untreated patients with advanced disease. Fludarabine monophosphate, on the other hand, has been shown to be very effective in both previously treated and untreated patients with advanced disease. Allogeneic bone marrow transplantation recently has been found to be of benefit in some patients (37 to 46 years) in a preliminary study; this therapeutic procedure should be tested further in a larger population of younger patients (less than 50 years) with advanced CLL. New agents such as lymphokines (interferons and IL-2) and monoclonal antibodies have been investigated for their efficacy and found to be minimally effective in previously treated patients with advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Autologous bone marrow transplantation in the treatment of poor prognosis non-Hodgkin's lymphomas

Twelve patients with non-Hodgkin's lymphomas of poor prognosis were treated by TCC high-dose chemotherapy (cyclophosphamide 45 mg/kg/day × 4, cytosine arabinoside 200 mg/m 2 i.v. q 12 hr × 7,6-thioguanin 100 mg/m 2 p.o. × 7 and CCNU 200 or 250 mg/m 2 p.o., single dose) followed by autologous bone marrow transplantation (ABMI) (infused dose: 853–20000 CFU-c/kg). Patients were divided into 2 groups: those in primary therapy with high tumor load (group 1; 3 initial diagnoses, 3 relapses) and those in consolidation therapy for a low tumor load (group 2; 5 complete and 1 partial remissions). Results show that: (1) the aplasia following autologous bone marrow transplantation was short. Leukocyte (>10 9/ l) and platelet (>50 × 10 9/ l) recoveries were observed on day 12 (range, 9–19) and day 14 (range, 8–27). (2) In group 1 there were 3 complete remissions (8, 21, 45+ months and 3 failures, including 1 death to toxicity of TACC. The 3 remissions occurred in patients in primary therapy and overall survival of these patients from the time of initial diagnosis was 48+, 48+ and 60+ months. In group 2 there were 5 persisting complete remissions (12+ to 40+ months) and 1 failure. Overall survival of these patients was 23+, 24+, 27+, 42+ and 70+ months. In both groups failures were associated with contamination of the frozen marrow by tumor. The toxicity of the association TACC + ABMT was acceptable and dominated by the risk of pericardial effusion and infection. The latter was absent in group 2 and occurred in 5 6 cases in group 1. These preliminary results indicate that autologous bone marrow transplantation has a possible role in the aggressive treatment of non-Hodgkin's lymphomas of high-grade malignancy and that its use should preferentially be in the consolidation mode.

Relationships Among Tumor Load, Route of Tumor Inoculation, and Response to Immunochemotherapy in a Murine Lymphoma Model<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>

The combined effects of nonspecific immunostimulation with Candida albicans (CA) and chemotherapy were studied in (BALB/cCr X DBA/2Cr)F1 and (C57BL/6Cr X DBA/2Cr)F1 mice bearing virus-induced LSTRA lymphomas. Paradoxically, animals treated with a relatively high number of tumor cells responded better to therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than those challenged with a low number of tumor cells. However, the majority of mice subjected to low initial tumor load were cured when they were treated with chemotherapy or chemotherapy plus booster injection of CA at a relatively "late" stage of the disease, i.e., when high tumor load was present in tumor-bearing hosts. It has been shown that this phenomenon, provisionally called high tumor load protection, occurs when the animals are challenged ip but not when they are challenged iv with the tumor and is abolished by total-body gamma-irradiation. Moreover, marked host protection can be attained when immunostimulated mice, inoculated iv with lymphoma cells, are subjected to simultaneous challenge with high inocula of the same tumor ip, followed by BCNU administration. These data stress the importance of the peritoneal cavity for successful CA plus drug treatment and suggest that optimal tumor "antigen load" should be present at the time of CA and/or BCNU administration.

23 INDICATIONS AND RESULTS OF BONE MARROW TRANSPLANTATION IN CHILDHOOD ACUTE LEUKEMIA (AL)

Since 1971, 7 children with AL (5 ALL, 2 ANL) have been transplanted at the University Children's Hospital. 2 of the donors were identical twins, 4 were siblings, 1 the HLA-identical father. The ALL children were transplanted after 2 to 4 relapses, the ANL earlier. 3 were in CR, 2 in PR and 2 in relapse. All got intensive chemotherapy, and 5 total body irradiation (TBI). 3 died of early complications, all others showed a take. 1 boy (w/o TBI) relapsed after 2 months, 1 with an AML had a testicular relapse after 4 months, but is in CR again since 10+ months under chemotherapy. The most recent patient shows a normal bone marrow, and no acute GvH, after 1 month. 1 boy stays in CR since 40+ mo. Our results suggest, and those from Seattle show that bone marrow transplantation in AL is feasible. As interstitial pneumonia and relapse are the most important obstacles to success, the children should be in remission (to start with a lower tumor load) and get an intensive cytostatic pretreatment, but - to avoid pneumonitis - should not get more than 750 r to the lungs.