Targeted Therapies

Formerly BioOncology Watch

www.tgt-therapies.com

OCTOBER 2004

VACCINATION THERAPY

Vaccination with autologous melanoma cells. Studies have demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) generates specific and durable antitumor immunity in multiple murine tumor models, including B16 melanoma. These preclinical results led Robert Soiffer et al to conduct a phase I study testing the biological and clinical activities of vaccination of patients with metastatic melanoma with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer. Vaccines were composed of 1 x 10⁶ to 1 x 10⁷ tumor cells that were injected subcutaneously at weekly and biweekly intervals. Vaccines were successfully manufactured for 34 (97%) of 35 metastatic melanoma patients and were well tolerated. Dense immune cellular infiltrates were elicited at injection sites in 19 of 26 evaluable patients and delayed-type hypersensitivity reactions occurred in 17 of 25 patients. In 10 of 16 patients, metastatic lesions resected after vaccination showed tumor necrosis associated with T-lymphocyte and plasma cell infiltrates. Tumor responses were achieved in 3 patients (1 complete, 1 partial, and 1 mixed response). After a minimum follow-up of 36 months, 10 patients (29%) remain alive; 4 patients have no evidence of disease. These results indicate that antitumor immunity in patients with metastatic melanoma was increased by vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF. Further studies are warranted. (Soiffer R, et al. J Clin Oncol 2003;21:3343-3350)

Vaccination with autologous tumor-derived heat-shock protein gp96. Heat shock proteins (HSPs) derived from tumor cells contain gp96 polypeptide. The gp96 polypeptide is associated with cancer-specific antigenic peptides and preclinical studies have shown that mice immunized with HSP/peptide-complex (HSPPC) reject tumor from which the HSPs were purified. These data led Vincenzo Mazzaferro and colleagues to test autologous tumor-derived HSPPC-gp96 vaccination in 29 consecutive patients with metastatic colorectal cancer (CRC). All patients had undergone potentially curative resection of liver metastases. Patients were administered 4 weekly injections followed 8 weeks later by 4 biweekly injections of HSPPC-gp96. A class I HLA-restricted T-cell-mediated anti-CRC response was observed in 15 patients (52%). The 2-year disease-free and overall survival rates were increased in vaccine responders compared to nonresponders (51% vs. 8%, p = 0.0001 and 100% vs. 50%, p = 0.001, respectively). The vaccinations were well tolerated. These findings show that HSPPC-gp96 vaccination elicits an antitumor response and may result in improved clinical outcomes in responding CRC patients who have undergone potentially curative resection of liver metastases. Additional studies are needed to confirm these results. (Mazzaferro V, et al. Clin Cancer Res 2003;9:3235-3245)

IMATINIB MESYLATE

Combined effects with zoledronate. Junya Kuroda and coworkers investigated the effects of imatinib (Novartis Pharmaceuticals) plus the bisphosphonate zoledronate (Novartis Pharmaceuticals) on Philadelphia chromosome-positive (Ph+) leukemias because zoledronate has been shown to inhibit prenylation of Ras-related proteins downstream of Bcr/Abl. In vitro, the growth of two Ph+ leukemic cell lines and a P-glycoprotein-overexpressing leukemic cell line were inhibited by single-agent zoledronate exposure. Zoledronate also prolonged the survival of NOD/SCID mice that had been given xenografts with Ph+ BV173 leukemic cells. Subsequently the combination of zoledronate with imatinib was found to significantly increase survival in the NOD/SCID mouse xenograft model utilizing the Ph+ BV173 leukemic cells compared to either agent alone. These findings of potential synergistic anti-Ph+ leukemic activity provide a rationale for future clinical studies of combination zoledronate plus imatinib therapy in patients with Ph+ leukemias. (Kuroda J, et al. Blood 2003;102:2229-2235)

Results in chronic myeloid leukemia (CML) patients with derivative chromosome 9 deletions. Deletions of the derivative chromosome 9 in patients with Ph+ CML have been associated with a poor prognosis. Brian Huntly and others studied the effects of derivative chromosome 9 deletions on the outcomes of patients with Ph+ CML who had been treated with imatinib. Fifty-nine (15%) of 391 patients analyzed were found to have deletions of the derivative chromosome 9. The complete hematologic response, major cytogenetic response, and complete cytogenetic response rates were lower in patients who had the deletions compared to those who did not have the chromosome 9 deletion abnormalities (p = 0.04. 0.008, and 0.007, respectively). In addition, time to progression for deletion-9 patients in chronic-phase (p = 0.02) and advanced-phase CML (p = 0.02) was shorter. However, no difference in overall survival was observed between patients with or without a derivative chromosome 9 deletion. These data show that the derivative chromosome 9 deletion cytogenetic abnormality in imatinib-treated patients with Ph+ CML is a poor prognostic factor. Differences in survival may also become apparent with further follow-up. (Huntly BJP, et al. Blood 2003;102:2205-2212)

Return to Archive

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