|
|
BioOncology Watch Timely Information for Practicing
Physicians |
|
|
APRIL 2000 Non-Hodgkin’s Lymphoma (NHL) Posttransplant lymphoproliferative disorders (PTLDs). Immunosuppression associated with organ
and marrow transplantation puts recipients at increased risk of developing
PTLDs that are most often B-cell. In
addition, increases in Ebstein-Barr virus (EBV)-DNA titers above normal
levels by > 3 to 4 logs are shown to be highly predictive of PTLD
development. Asa Gustafsson et al.
observed that 4 patients receiving T-cell-depleted (TCD) grafts and 1
Wiskott-Aldrich syndrome patient receiving an unmanipulated graft had rapid
rises in EBV-DNA load following bone marrow transplantation (BMT). Administration of EBV-specific cytotoxic
T-lymphocytes (CTLs) resulted in 2- to 4 log decreases of EBV-DNA titers in 4
out 5 patients with high titers; early treatment of an additional high-risk
patient with EBV-CTLs returned virus titers to within 2 to 3 logs of
normal. In one recipient of
donor-derived CTLs, EBV-DNA titers did not decrease, PTLD developed and the
patient expired. A second study by
Ingrid Kuehnle et al. reported successful treatment of 3 patients with
posttransplant EBV-associated lymphoma with rituximab. These patients remain
disease free 7, 8, and 9 months after therapy. In a third study by N. Milpied et al., rituximab therapy in 32
PTLD patients produced a response rate of 69% (20 CRs and 2 PRs). (Gustafsson A, et al. Blood 2000;
95:807-814, Kuehnle I, et al. Blood
2000; 95:1502-1505, and Milpied N, et al.
Blood 1999; 94 (Suppl 1): abstract 2803) Oral CD40 ligand (CD40L) gene therapy. CD40 ligation upregulates the expression
of tumor antigens on malignant B cells and induces Fas expression, which
facilitates apoptosis through the FasL/Fas pathway. Mitsuyoshi Urashima and colleagues transfected the human CD40L
gene into attenuated salmonella typhimurium bacterium (ST40L) and gave
it orally to mice that had been subcutaneously injected with A20 cells, a
CD40+ B cell lymphoma (BCL) cell line, to induce CD40L expression in the
intestinal immune system. The
survival of mice given ST40L simultaneously with the BCL injection was
greater than those treated with either bacteria or saline alone (P<
.0001). ST40L did not provide
protection against a CD40- tumor (wehi3 leukemia cells) and administration of
ST40L before or after tumor challenge decreased its effectiveness. This preclinical study suggests that oral
CD40L gene therapy may be a simple effective treatment against CD40+
BCL. (Urashima M, et al. Blood 2000; 95:1258-1263) Use of dendritic cells (DCs) to induce idiotype-specific CTLs. Frank Osterroth and coworkers describe a
protocol for the induction of anti-idiotype CTLs from patients with
lymphoma. Individual patient tumor
samples were obtained from frozen biopsies or blood samples, recombinant
tumor specific idiotype antigen for DC uptake was obtained by a periplasmic
expression system in E. coli, and idiotype-expressing DCs were generated by
transduction with recombinant Semliki forest virus vectors. These idiotype-loaded DCs stimulated a
strong specific CTL cytotoxicity while idiotype-transduced DCs only resulted
in moderate natural killer cell activity.
This technique represents a potential individualized anti-lymphoma
therapy. (Osterroth F, et al. Blood 2000; 95: 1342-1349) HER-2/neu Gene
Anti-HER-2/neu treatments. Overexpression of the HER-2/neu gene is associated with many
types of cancer. Xiangming Xing et
al. identified a DNA-binding protein, PEA3, that specifically binds to the
HER-2/neu gene promoter region and downregulates its activity. Cotransfection of PEA3 cDNA with the
oncogene in NIH3T3 cells suppressed malignant transformation and PEA3 was
shown to inhibit the growth of HER-2/neu overexpressing tumors in vitro and
in xenograft models. In a second
study, H. Kunisue et al. investigated the combination of anti-HER-2
monoclonal antibody therapy (trastuzumab) with anti-estrogen therapy (ICI
182, 780) in 3 human breast cancer cell lines. Combination therapy enhanced growth inhibition in the cell line
expressing both estrogen receptors (ER) and HER-2 (ML-20 cells) while no
additive effects were observed in those cell lines that are ER-/HER-2+. These preclinical studies provide a
rationale for further investigations of a novel suppressor of HER-2/neu
activity (PEA3) and combined anti-HER-2 monoclonal antibody and anti-estrogen
therapy. (Xing X, et al. Nature 2000; 6: 189-195 and Kunisue
H, et al. Br J Cancer 2000;
82: 46-51) Leukemia
Immunostimulation of chronic lymphocytic leukemia (CLL) B cells. Because evidence exists that
CpG-oligodeoxynucleotides (ODNs) are potent stimulators of B cells, Thomas
Decker and associates studied the effects of adding CpG-ODN to cultures of
purified B-CLL cells and normal peripheral blood B cells. CpG-ODN triggered a strong and consistent
up-regulation of CD40, MHC class I and other surface molecules important for
antigen presenting cell (APC) function.
The up-regulation of CD40 was stronger in B-CLL cells than in normal B
cells. Moreover, coculture with
CpG-ODN overcame the reduced potential of B-CLL cells to produce IL-6 and
proliferate in response to CD40 ligation.
These data suggest the potential use of CpG-ODN as a component of an
immunotherapy strategy for B-CLL patients.
(Decker T, et al. Blood
2000; 95: 999-1006) Treatment of relapsed leukemia with unrelated donor leukocyte
infusions (DLIs). David
Porter and colleagues retrospectively analyzed 58 patients from the National
Marrow Donor Program database who received unrelated DLI for treatment of
relapsed leukemia following unrelated donor BMT. This population included patients with chronic myelogenous
leukemia (CML; n=25), acute myelogenous leukemia (AML; n=23), acute
lymphoblastic leukemia (ALL; n=7), and other diseases (n=3). The overall CR rate was 42% (95% CI,
28%-56%). The estimated probability
of disease free survival at 1 year after CR was 65% for CML, 23% for AML, and
30% for ALL. Nineteen patients (33%)
remain alive with a median follow-up of 66 weeks (range, 9-180+ weeks). Acute and chronic GVHD occurred in 37% and
41% of patients, respectively. This
analysis demonstrates that unrelated DLI induces a graft versus tumor effect
in patients with relapsed leukemia with acceptable toxicity compared to other
treatment options. (Porter DL, et al. Blood 2000; 95: 1214-1221) |
||
|
Produced by Market Development Group through an
educational grant from Genentech, Inc. and IDEC
Pharmaceuticals. Comments and inquiries can be e-mailed to webmaster@biooncologywatch.org |
||