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Phase I study of transgenic B lymphocyte immunization (TLI) against telomerase in androgen-independent prostate cancer (PC).

2519 Background: Human telomerase reverse transcriptase (hTRT) is expressed in the majority of human tumor cells (>90% of PC) but is absent from most normal adult cells, identifying it as a potential immunotherapeutic target (PNAS 97:4796, 2000). We developed a new approach to induce T cell responses in vivo based on the injection of primary B lymphocytes genetically programmed to serve as antigen presenting cells with the dual function of antigen synthesis and presentation. This is done ex vivo by exploiting the phenomenon of spontaneous B cell transgenesis (Gene Therapy 11:42, 2003), using a plasmid with a modified immunoglobulin heavy chain gene incorporating 3 inserts: two HLA-A2-restricted hTRT peptides: p540 (PNAS 97:4796, 2000) in CDR 3, p572 (PNAS 99:12275, 2002) in CDR1; and a 12mer malarial peptide acting as a Th cell determinant in CDR2.


METHODS
HLA-A2(+) subjects had androgen-independent PC with (8) or without (1) overt metastases, PS<3, life expectancy >6 months, no current steroid treatment. The median pretreatment PSA value was 248. Prior treatment, except immunotherapy, was allowed. Mononuclear cells were separated from peripheral blood and incubated overnight with plasmid DNA. Nine subjects (3 in each of 3 cohorts) were reinfused once with 104, 105, or 106 autologous transgenic B cells.


RESULTS
All subjects remain alive with followup of 6 months-cohort 1, 3 months-cohort 2 and 1 month-cohort 3. No infusion-related events or dose-limiting toxicities were seen. No PSA responses were seen. Tetramer staining of hTRT-specific CD8 T lymphocytes was seen in 1/3 pts in cohort 1 and 3/3 in cohort 2. Cohort 3 is too early to assess.


CONCLUSIONS
single-dose TLI is feasible, safe and capable of inducing a T cell response against hTRT. A 4th cohort is planned with 2 infusions 1 month apart using frozen cells for the 2nd dose. [Table: see text].