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Invited Abstract (Plenary Session): Germline Determinants of Therapeutic Efficacy and Toxicity

Individual Determinants of Vaccine Therapy

Mary Crowley Medical Research Center, Dallas, TX

Abstract

PL-14

We have previously demonstrated activity and encouraging survival response with immunotherapy composed of autologous tumor cells genetically modified to secrete GM-CSF in advanced stage NSCLC (3 complete responses in 33 treated patients). In an effort to remove the requirement and variability associated with genetic transduction of individual autologous tumors we studied a "bystander" platform composed of autologous tumor cells mixed with an allogeneic GM-CSF transfected secreting cell line. Evidence of treatment-induced immune activation was demonstrated; however, objective tumor responses were not seen. We subsequently performed a randomized dose variable phase II trial involving NSCLC patients. One of 3 doses (1.25, 2.5, 5.0 x10⁷ cells/injection 9 months x 16 months) of a non-viral TGFß2 antisense gene based allogeneic tumor cell vaccine, were administered. Seventy five patients received a total of 550 vaccinations. No significant ( grade 3) adverse events associated with administration of the vaccine were observed. A dose-related survival difference was demonstrated in patients who received 2.5 x 10⁷ cells/injection versus those who received <2.5 x 10⁷ cells/injection (p=0.0069). The estimated probabilities of surviving 1 and 2 years were 68% (95% CI: 55%, 80%) and 52% (95% CI: 35%, 68%) for the two higher-dose groups combined and was 39% (95% CI: 22%, 66%) and 20% (95% CI: 4%, 36%) for the low dose group. Immune function to potentially identify individual predictive determinants was explored in the 61 advanced stage (IIIB/IV) patients. Cytokine production (IFN-, p=0.006; IL-6, p=0.004; IL4, p=0.007) was induced and furthermore antibody mediated response to vaccine HLA antigen was observed (p=0.014). Cell mediated response showed a correlation trend (p=0.086) in patients achieving stable disease or partial response compared to those with progressive disease. Results support the justification for further phase III evaluation.In an effort to further determine individual molecular determinants predictive of response to vaccine or other targeting cancer therapy we explored the use of cDNA microarray, 2-Dimensional Difference Gel Electrophoresis, mass spectrometry (MS), and nodal mapping to perform genomic and proteomic characterization of malignant and non malignant tissue. Preliminary results are complete in 5 patients. In all we have demonstrated a minimum number ( 5) of significantly, up-regulated proteins (2 fold) in malignant compared to non-malignant tissue. Proteins were chosen based on a series of defined GO signals. Western blot analysis was used to confirm MS results and identify protein expression in selected NCI 60 cell lines, patient malignant tumor samples at 2 different time points and from different disease sites. Pathway modeling was used to determine inter- and intra-pathway connectivity. First order protein-protein interaction connectivity identified GNB2L1, STMN1, and SDCBP as highly connected and these are proposed as high priority targets of patient 1 for therapeutic modulation testing.