A poxviral-based cancer vaccine the transcription factor twist inhibits primary tumor growth and metastases in a model of metastatic breast cancer and improves survival in a spontaneous prostate cancer model.

Several transcription factors play a role in the alteration of gene expression that occurs during cancer metastasis. Twist expression has been shown to be associated with the hallmarks of the metastatic process, as well as poor prognosis and drug resistance in many tumor types. However, primarily due to their location within the cell and the lack of a hydrophobic groove required for drug attachment, transcription factors such as Twist are difficult to target with conventional therapies. An alternative therapeutic strategy is a vaccine comprised of a Modified vaccinia Ankara (MVA), incorporating the Twist transgene and a TRIad of COstimulatory Molecules (B7-1, ICAM-1, LFA-3; TRICOM). Here we characterize an MVA-TWIST/TRICOM vaccine that induced both CD4+ and CD8+ Twist-specific T-cell responses in vivo. In addition, administration of this vaccine reduced both the primary tumor growth and metastasis in the 4T1 model of metastatic breast cancer. In the TRAMP transgenic model of spontaneous prostate cancer, MVA-TWIST/TRICOM alone significantly improved survival, and when combined with the androgen receptor antagonist enzalutamide, the vaccine further improved survival. These studies thus provide a rationale for the use of active immunotherapy targeting transcription factors involved in the metastatic process and for the combination of cancer vaccines with androgen deprivation.

Population pharmacokinetics of humanized monoclonal antibody HuCC49deltaCH2 and murine antibody CC49 in colorectal cancer patients.

To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of (125)I-HuCC49deltaCH2 and (125)I-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was used to fit the pharmacokinetic data. Model stability and performance were assessed using a visual predictive check procedure. Different clinical trial designs were evaluated by simulation in combination with Bayesian estimation method to predict the optimal time for surgery. The results showed that HuCC49deltaCH2 had 65% faster clearance from blood circulation and 24% shorter mean residence time than CC49. Population pharmacokinetic analysis identified body weight as the only covariate to explain between-subject variability in clearance, intercompartmental flow rate, and volume of distribution. Model predictions indicated a wide interval for the optimal time of surgery, suggesting that it would be beneficial to individualize the time of surgery for each patient by measurement of antibody disposition. Clinical trial designs with at least 3 measurements of antibody disposition were found to be better than an empirical direct observation method for the optimal prediction of surgery time.

Rationales, evidence, and design considerations for fractionated radioimmunotherapy.

Although fractionation can be used in a discrete radiobiologic sense, herein it is generally used in the broader context of administration of multiple, rather than single, doses of radionuclide for radioimmunotherapy (RIT) or other targeted radionuclide therapies. Fractionation is a strategy for overcoming heterogeneity of monoclonal antibody (MAb) distribution in the tumor and the consequent nonuniformity of tumor radiation doses. Additional advantages of fractionated RIT are the ability to 1) provide patient-specific radionuclide and radiation dosing, 2) control toxicity by titration of the individual patient, 3) reduce toxicity, 4) increase the maximum tolerated dose (MTD) for many patients, 5) increase tumor radiation dose and efficacy, and 6) prolong tumor response by permitting treatment over time. However, fractionated RIT has logistic and economic implications. Preclinical and clinical data substantiate the advantages of fractionated RIT, although the radiobiology for conventional external beam radiotherapy does not provide a straightforward rationale for RIT unless fractionation leads to more uniform distribution of radiation dose throughout the tumor. Preclinical data have shown that toxicity and mortality can be reduced while efficacy is increased, thereby providing inferential evidence of greater uniformity of radiation dose. Direct evidence of superior dosimetry and tumor activity distribution has also been found. Clinical data have shown that toxicity can be better controlled and reduced and the MTD extended for many patients. It is clear that fractionated RIT can only fulfill its potential if the effects of critical issues, such as the number and amount of radionuclide doses, the radionuclide physical and effective half-life, and the dose interval, are better characterized.