Animal Models for Preclinical Development of Allogeneic Hematopoietic Cell Transplantation.

Since its inception in the 1950s, hematopoietic cell transplantation (HCT) has become a highly effective clinical treatment for malignant and nonmalignant hematological disorders. This milestone in cancer therapy was only possible through decades of intensive research using murine and canine animal models that overcame what appeared in the early days to be insurmountable obstacles. Conditioning protocols for tumor ablation and immunosuppression of the recipient using irradiation and chemotherapeutic drugs were developed in mouse and dog models as well as postgrafting immunosuppression methods essential for dependable donor cell engraftment.

Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.

Adoptive immunotherapy with T cells expressing a tumor-specific chimeric T-cell receptor is a promising approach to cancer therapy that has not previously been explored for the treatment of lymphoma in human subjects. We report the results of a proof-of-concept clinical trial in which patients with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma were treated with autologous T cells genetically modified by electroporation with a vector plasmid encoding a CD20-specific chimeric T-cell receptor and neomycin resistance gene. Transfected cells were immunophenotypically similar to CD8(+) effector cells and showed CD20-specific cytotoxicity in vitro.

Rituximab: mechanism of action and resistance.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known.

Rituximab: Mechanism of action and resistance.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known.

Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

Purpose: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse.

Patients And Methods: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients.

Second allogeneic transplantation after failure of first autologous transplantation.

We evaluated the outcome of second allogeneic bone marrow transplantations (BMTs) in 59 patients aged 1-57 years who relapsed after initial autologous transplantation. Patients received a second transplantation for recurrent acute myeloid leukemia (AML) (n = 24), acute lymphoblastic leukemia (ALL) (n = 13), lymphoma (n = 18), multiple myeloma (n = 3), or chronic myelogenous leukemia (n = 1) from an HLA-matched related (n = 14), mismatched related (n = 25), or matched unrelated (n = 20) donor. The probabilities of nonrelapse mortality, relapse, and disease-free survival (DFS) 2 years after the second BMT were 51%, 26%, and 23%, respectively.