Despite active chemotherapy, virtually no improvement has been observed in the survival of patients with low grade B cell NHL. Rituximab, a anti-CD20 mAb induces remissions in 50-60% of patients with follicular NHL. The mechanism of action is not known but likely includes augmented immune effector mechanisms through antibody dependent cell mediated cytotoxicity (ADCC) conferred by the human IgG1 constant region. However, we have observed 1) only 50% of patients respond, and 2) only 40% of initially responding patients respond to re-treatment, and 3) there are no correlates of immune function that predict response, and 4) preliminary data demonstrates direct anti- proliferative effects of the antibody in vitro on some human tumor cell lines, and 5) these direct effects are greater than that observed with other anti-CD20 mAbs. We hypothesize that these direct effects on this mAb (block of proliferation and induction of apoptosis) are responsible for the therapeutic effects and that the loss of these direct effects contributes to acquired resistance. We will therefore test our hypothesis by developing methods for testing the anti-proliferative effects of anti-CD20 antibody on primary human lymphoma cells and then determine whether the presence or absence of these effects predict clinical activity.
The Aims of this proposal are to: I. Develop surrogate measures of early events in cell signaling induced in B cell lymphoma lines that are sensitive or resistant to in vitro anti-CD20 mediated effects by evaluating effect on (a) cell proliferation and apoptosis; (b) re-distribution of the CD20 antigen into a insoluble membrane fraction; (c) tyrosine phosphorylation through Src family kinases; (d) calcium mobilization; (e) expression/regulation of bcl-2 family proteins. II. Evaluate primary NHL cells from patients treated with Rituximab for these cell signaling events and correlate with observed clinical sensitivity or development of resistance. (a) analysis of cryopreserved NHL cells from earlier Rituximab clinical trials; (b) prospective analysis of tumor biopsies from patients on FHCRC protocol #1344. III. Determine the role of the mAb FC region in mediating anti- proliferative effects of anti-CD20 mAbs in xenografts of B cell NHL lines in NOD/SCID mice.
| Rose, Andrea L; Smith, Barbara E; Maloney, David G (2002) Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects. Blood 100:1765-73 |
| Maloney, David G; Smith, Barbara; Rose, Andrea (2002) Rituximab: mechanism of action and resistance. Semin Oncol 29:2-9 |
