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BioOncology Watch Timely Information for Practicing
Physicians |
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march 2003 RITUXIMAB Complement-dependent cytotoxicity (CDC). Rituximab activates complement
when it binds to CD20+ B-cells and the resulting cell-surface deposition of
complement fragment protein (C3b and its breakdown products (C3b[i]) may
opsonize cells for destruction. Adam
Kennedy and colleagues at the University of Virginia Health Sciences Center
(Charlottesville) found that the incubation of CD20+ cells with an
anti-C3b[i] monoclonal antibody (mAb 3E7) in addition to rituximab in normal
human serum enhanced C3b[i] deposition.
Furthermore, rituximab-mediated killing of both Raji and DB cells was
enhanced by mAb 3E7. A second set of
experiments by Olivier Manches et al.
( ADOPTIVE IMMUNOTHERAPY Antileukemic activity of allorestricted cytotoxic T
lymphocytes (CTLs). Allorestricted
CTLs directed against CD45 can recognize host leukemia cells but not donor
cells from a marrow graft or host non-hematopoietic tissues. Persis Amrolia and associates identified
four CD45-derived peptides that showed binding to HLA-A0201. Only one of these peptides, P1218, was able
to generate peptide-specific CTL lines (from 3 of 7 donors). The P1218-specific CTL lines recognized
leukemic blasts obtained from patients with chronic or acute myeloid
leukemias and were active against hematopoietic cell lines expressing both
HLA-A2 and CD45, but were not cytotoxic to CD45-negative or HLA-A2-negative
cells. P1218-specific CTLs have potent
activity against leukemic progenitor cells and may contribute to host
myeloablation, thus enhancing donor cell engraftment. P1218-specific CTL lines can be easily
expanded for clinical protocols. (Amrolia PJ, et al. Blood 2003;101:1007-1014) PHASE I AND II TRIALS Phase I study of cantuzumab mertansine. Anthony Tolcher and colleagues
conducted a phase I study of escalating doses (22 to 295 mg/m2) of
cantuzumab mertansine administered intravenously (i.v.) every 3 weeks to
chemotherapy-refractory patients with CanAg-expressing solid malignancies (N
= 37). Cantuzumab mertansine
(GlaxoSmithKline and ImmunoGen Inc.) is a novel tumor-activated
immunoconjugate made up of the maytansine derivative DM1 (an antimicrotubule
agent) linked to the humanized monoclonal antibody huC242 that is directed
against the extracellular epitope of CanAg (a glycoform of MUC1). CanAg is strongly expressed in most pancreatic,
biliary, and colorectal cancers as well as a number of non-small cell lung,
gastric, uterine, and bladder cancers.
The immunoconjugate complex is internalized following the binding of
cantuzumab mertansine to the external domain of CanAg and the DM1-huC242
disulfide linkage is then cleaved releasing DM1 molecules
intracellularly. The maximum tolerated
dose (MTD) was determined to be 235 mg/m2 i.v. every 3 weeks and
dose-limiting toxicities (DLTs) were grade 3 liver transaminase elevations
and grade 3 fatigue. Dose, peak
concentration, and area under the concentration-time curve correlated with
the severity of transaminase elevation.
Shed CanAg plasma levels decreased to undetectable levels in 25 of 30
patients after the first dose of cantuzumab mertansine. Minor tumor responses were observed in 2
colorectal carcinoma patients and 4 patients had stable disease for >6
courses. These encouraging results
warrant further investigation of this agent in CanAg-expressing tumors. (Tolcher AW, et al. J Clin Oncol 2003;21:211-222) Phase II study of trastuzumab in gynecologic tumors. Michael Bookman and associates
of the Gynecologic Oncology Group (GOG) performed a phase II trial that
evaluated trastuzumab (HerceptinÒ; Genentech Inc) monotherapy in previously treated
patients with ovarian or primary peritoneal carcinoma that had HER2
overexpression (2+ or 3+). Only 95
patients (11.4%) out of 837 patients screened exhibited the requisite level
of HER2 overexpression. Of these, 45
patients were enrolled into the study.
Among 41 evaluable patients, a response rate of 7.3% (1 complete and 2
partial responses) was achieved with i.v. trastuzumab treatments (induction
dose of 4 mg/kg followed by 2 mg/kg weekly).
Trastuzumab-related toxicities were mild in severity. These findings demonstrate that HER2
overexpression is infrequent in ovarian and primary peritoneal carcinomas and
that trastuzumab has limited activity in these gynecologic tumors. (Bookman MA, et al. J Clin Oncol 2003;21:283-290) PROTEASOME INHIBITOR Molecular mechanisms of activity. The ubiquitin-proteasome pathway
regulates cell-cycle progression by regulating cyclins and cyclin-dependent
kinase inhibitor proteins. The
recently developed proteasome inhibitor, PS-341, has been previously shown to
induce apoptosis in resistant multiple myeloma (MM) cells, inhibit adhesion
of MM cells, and inhibit MM growth-promoting cytokines. Teru Hideshima and coworkers from the Dana
Farber Cancer Institute (Boston, MA) now report that studies utilizing MM-derived
cell lines and fresh patient-derived MM cells demonstrate that PS-341 induces
caspase-8 and -3 activity through the activation of JNK, inhibits DNA repair,
and activates p53 by phosphorylation and degradation of MDM2 protein. These studies provide a framework for
further evaluation of PS-341. (Blood 2003;101:1530-1534) |
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