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BioOncology Watch Timely Information for Practicing
Physicians |
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february 2001 Non-Hodgkin's Lymphoma
Bispecific antibody
(BsAb) therapy. CD64 (FcgRI) receptors mediate the lysis of tumor
cells by activated polymorphonuclear cells (PMNs) in the presence of
appropriate antibodies. Jamie
Honeychurch and coworkers developed a huCD64 transgenic mouse model to investigate
the potential of a panel of BsAbs to retarget granulocyte colony-stimulating
factor-activated PMNs against syngeneic B-cell lymphoma cells via their CD64
trigger molecules. The BsAbs had dual
specificity directed against both huCD64 on the effector PMN cells and an
antigen (either immunoglobulin-idiotype [Id], MHC II, or CD19) on the
lymphoma cells. All 3 derivatives of
BsAbs enabled PMNs to lyse tumor cells while a mixture of anti-Id and
anti-huCD64 monospecific Abs were ineffective mediators of tumor
destruction. The (huCD64 x Id) BsAb
was the only derivative found to confer long-term survival to the mice. These long-term survivors were also
resistant to tumor rechallenge.
T-cell depletion studies showed that this additional therapeutic
activity associated with the (huCD64 x Id) BsAb was dependent on CD4 and CD8
T-cells. These experiments demonstrate that CD64-directed BsAbs can establish
T-cell immunity against B-cell lymphoma.
(Honeychurch J, et al. Blood 2000; 96:3544-3552) Malignant Glioma
Iodine-131-labeled
81C6 monoclonal antibody (mAb) therapy. Malignant gliomas are the
most common primary brain tumors in adults and the median survival with
standard therapy (surgery followed by external-beam radiation and
chemotherapy) ranges from 40 to 60 weeks.
81C6 is a murine mAb that binds to tenascin, a tumor-associated
extracellular matrix glycoprotein that is ubiquitous in gliomas. In preclinical studies iodine-131-labeled
81C6 has demonstrated significant anti-tumor activity in human glioma xenografts. Ilkcan Cokgor and colleagues at Duke
University Medical Center conducted a phase I trial of single-dose
iodine-131-81C6 administered into surgically created resection cavities
through a Rickham reservoir in newly diagnosed patients with malignant glioma. Dose-limiting toxicity was delayed
neurologic toxicity, the maximum-tolerated dose (MTD) was 120 mCi, and median
survival was 79 weeks. Phase II
studies are warranted as therapy at the MTD was well tolerated and the
survival results encouraging. (Cokgor
I, et al. J Clin Oncol 2000; 18:3862-3872) Cancer Vaccines
Anti-carcinoembryonic
antigen (CEA) immune response. Preclinical data suggests that
the combination of 2 CEA vaccinations utilizing different recombinant viral vectors,
the vaccinia virus (rV) and the non-replicating avipox virus, generate a more
vigorous T-cell response to tumor antigen than either vaccine alone. Thus, John Marshall et al conducted a
phase I study of diversified prime-and-boost regimens of rV-CEA and
avipox-CEA vaccinations to enhance T-cell responses to CEA. The generation of CEA-specific T-cell
responses was found to be greatest when rV-CEA was followed by avipox-CEA
(given up to 8 times) and further increases in CEA-specific T-cell precursors
resulted when local granulocyte-macrophage colony-stimulating factor and
low-dose interleukin-2 were given with subsequent vaccinations. The vaccinations were well tolerated,
however no objective tumor responses were observed. This study showed that although vaccines to CEA generated
CEA-specific T-cell immune responses, vaccines alone were unable to induce
objective tumor responses. Cytokines
may have a role in enhancing the clinical benefit of anti-tumor vaccination. (Marshall JL, et al. J Clin Oncol
2000; 18:3964-3973) Prostate Cancer
Antigen-loaded dendritic cells.
Eric Small and associates report the results of a phase I/II trial of
Provenge (Dendreon Corp.), a novel immunotherapy consisting of autologous
dendritic cells loaded ex vivo with
a recombinant fusion protein formed by linking prostatic acid phosphatase
(PAP) to granulocyte-macrophage colony-stimulating factor, as treatment for
patients with hormone-refractory prostate cancer (n=31). Provenge was
tolerated well without hematologic, hepatic, or renal toxicity. Fever was the
most common adverse event, occurring after 14.7% of infusions. Immune responses to the fusion protein and
to PAP alone developed in 100% and 38% of patients, respectively. Six patients had a decline in serum PSA
levels during therapy; 3 patients had a >50% decline and 3 patients had a
25%-49% decline in serum PSA concentration compared to baseline. Patients who developed an immune response
to PAP had a median time to progression (TTP) of 34 weeks compared to 13
weeks for those who did not develop an immune response to PAP (p
<0.027). In addition, the median
TTP was greater for those patients who were administered a larger dose of
Provenge (>100 x 106 cells/infusion) (31.7 vs. 12.1 weeks; p=0.013). The preliminary evidence of efficacy seen
in this trial warrants further investigation. (Small EJ, et al. J Clin
Oncol 2000; 18:3894-3903) |
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