Vaccines

Renal cell carcinoma (RCC). Alexander Kugler and colleagues vaccinated 17 metastatic RCC patients subcutaneously with hybrid cells formed by the fusion of autologous tumor cells and allogeneic monocyte-derived dendritic cells. The vaccine was injected immediately after electrofusion and irradiation (200 Gy) of the cells. Booster vaccinations were administered after 6 weeks and then every 3 months until disease progression. The induction of cytotoxic T cells reactive with the Muc1 tumor-associated antigen was demonstrated and recruitment of CD8+ lymphocytes into tumor sites was observed. Four patients achieved CRs, 2 patients had PRs, and an additional patient had a mixed response (41% response rate). The vaccinations were well tolerated by all patients with no reported serious adverse events. These data indicate that hybrid cell vaccination is safe and may provide effective therapy for patients with RCC. However, RCCs are unpredictable and further prospective trials are needed to confirm these findings. (Kugler A, et al. Nature Medicine 2000;6:332-336)

Chronic myelogenous leukemia (CML). CML is characterized by the formation of the chimeric bcr-abl gene resulting in the expression of a chimeric protein product (p210). This chimeric fusion protein is a tumor-specific antigen because the junctional regions of p210 contain a unique sequence of amino acids. These peptides have previously been shown to induce HLA-restricted cytotoxicity in vitro. J. Pinilla-Ibarz et al. conducted a phase I study to evaluate the safety and immunogenicity of a bcr-abl breakpoint peptide vaccine (Aquilla Biopharmaceuticals). Four cohorts of 3 patients each received one of the following: 50 ug; 150 ug; 500 ug; or 1500 ug total peptide mixed with 100 ug of the QS-21 adjuvant (n=12). Toxicities were minimal and mainly related to injection site adverse reactions. T cell proliferative and/or delayed-type hypersensitivity responses were generated in 3 of the 6 patients treated at the 500 ug and 1500 ug dose levels. The induction of cytotoxic T lymphocytes was not demonstrated. These findings show that vaccination with bcr-abl-derived peptide is feasible and safe and capable of eliciting an immune response. Future trials will determine if this strategy will be effective. (Pinilla-Ibarz J, et al. Blood 2000;95:1781-1787)

Non-Hodgkin's Lymphoma (NHL)

Radioimmunoconjugate therapy. Iodine-131 tositumomab (Coulter Pharmaceutical) is a radiolabeled monoclonal antibody that is specific to the CD20 antigen and delivers radiation to antigen-positive cells as well as neighboring malignant cells. Julie Vose and coworkers conducted a phase II trial (n=47) in which patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade NHL received both a single I.V. dosimetric dose (450 mg unlabeled tositumomab followed by 5mCi of iodine-131 tositumomab) and a single I.V. therapeutic dose (75 cGy total body dose of iodine-131 tositumomab 7 to 14 days after the dosimetric dose). Twenty-seven patients (57%) had a response and 15 patients (32%) achieved a CR. The median duration of CR was 19.9 months (95% CI, 14.3 months to upper limit not reached). The principal toxicity was hematologic (5 patients had a platelet count <10,000 cells/mm³ and 2 patients had an ANC <100 cells/mm³). These findings show that iodine-131 tositumomab therapy was well tolerated and was associated with a high response rate in an advanced low-grade lymphoma population. (Vose J, et al. J Clin Oncol 2000;18:1316-1323)

Mantle cell lymphoma (MCL)

Graft vs. lymphoma (GVL). I. F. Khouri and associates report the first results suggestive of a GVL effect in patients with MCL following allogeneic hematopoietic transplantation (n=16). Fourteen patients received a high-dose chemotherapy preparative regimen and 2 patients received a nonablative preparative regimen. The most important evidence of a GVL effect comes from 2 patients. The first is a patient given nonablative therapy who had progressive disease posttransplant but achieved a CR (14+ months duration) after developing graft vs. host disease (GVHD). The second was a patient who had received high-dose chemotherapy and was positive for minimal residual disease by polymerase chain reaction (PCR) assay (bcl-1 or immunoglobulin gene rearrangement) up to 4 months posttransplantation but converted to PCR-negative when tested 3 months later. In addition, the only relapse was in a patient who failed to engraft (the other patient who received nonablative therapy). All the high-dose chemotherapy patients achieved a response (12 CRs and 2 PRs). Failure-from-progression and survival at 3 years were both 55% (95% CI: 28%-83%). These data indicate that allogeneic transplantation is a potentially effective therapy for MCL and that a GVL effect may play an important role in its therapeutic benefit. (Khouri IF, et al. Annals of Oncology 1999;10:1293-1299)

Preclinical Studies

Fc receptor modulation of antibody cytotoxicity. Raphael Clynes and associates conducted studies in a variety of syngenic and xenograft models demonstrating that Fcg receptor binding modulates antibody-dependent cell-mediated cytotoxicity (ADCC). Mouse monoclonal antibodies and the humanized therapeutic agents trastuzumab (Herceptin) and rituximab (Rituxan) were found to interact with both activation (FcgRIII) and inhibitory (FcgRIIB) receptors on cells. Mice deficient in FcgRIIB had much greater ADCC while mice deficient in FcgIII were unable to arrest tumor growth. These studies show that that Fc-receptor-dependent mechanisms contribute to the activity of antitumor antibodies and that engineering therapeutic antibodies to maximize their interaction with FcgIII and minimize their interaction with FcgRIIB may produce the most effective agents. (Clynes RA, et al. Nature Medicine 2000;6:443-446)

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