A clinical trial is planned to evaluate a novel protein, TARP, expressed in patients with prostate and breast cancer. This 58 amino acid protein, T-cell receptor ? alternate reading frame protein (TARP), was identified with the expressed sequence database. The mRNA is initiated in the J? 1 exon of the TCR ? and the protein expressed is initiated in an alterntive reading frame than the TCR ? coding sequence. The protein is expressed both by normal and malignant prostate cancer tissue with over 90% of prostate cancer specimens positive for its expression. Two HLA A2 epitopes that produce cytolytic T cell responses were determined. Epitope enhancement of the TARP peptides was performed to increase the level of immunity that could be generated with these peptides. Amino acid substitutions in the TARP27-35 peptide did not increase binding affintity and will be tested without modification whereas amino acid substitutions in TARP29-37 did produce higher binding affinity peptides. For TARP29-37, Leu at position 9 were substituted with Val (TARP29-37-9V) and immunization with the peptide resulted in the production of T cells that recognize both the wild type and modified sequence. The study was planned as a comparison between peptide vaccine in adjuvant and pulsed on dendritic cells. The trial has not been initiated as of yet because of modifications in the dendritic cell maturation scheme under development by the Department of Transfusion Medicine. An alternative method of vaccination is also undergoing evaluation in patients with lung cancer. Through a CRADA collaboration with NewLink Genetics of Ames, IA, a clinical vaccine trial using allogeneic lung cancer cells that have been genetically altered with a Moloney murine retrovirus vector to express alpha (1,3) galactosyl transferase (alpha-GT) for patients with advanced non-small cell lung cancer. The trial has completed phase I testing and a phase II component has been initiated. In the phase I component, 15 were patients treated with no serious adverse events attributable to the vaccine with doses of up to 500 million vaccine cells administered. Although peptide immunization with epitope-enhanced peptides reproducibly generates T cell responses in patients, tumor regression is infrequent. In addition immune therapies in general produce long-lasting tumor regressions in a small minority of patients. These observations suggest that there are immune mechanisms that prevent the induced immune response from producing tumor regression. A number of checkpoint controls in immune regulation can be targeted including TGF-a, CTLA-4 and the CD4+, CD25+ T cell regulatory population. A clinical trial using an antibody that binds to and inhibits TGF-a has begun accrual. We are currently testing MDX-010, a fully human antibody that binds to CTLA-4, to eliminate this checkpoint in regulation of T cell expansion. Responses have been observed in 3 of 10 patients with follicular lymphoma and accrual continues. The protocol has been modified to permit accrual of patients with other types of lymphoma including other B cell lymphomas, T cell lymphoma and Hodgkin's disease. The antitumor activity of CTLA-4 blockade was significantly enhanced in tumor-bearing animals by eliminating CD25+ cells using the PC61 antibody in studies conducted by Sutmuller. Our observation of an increase in this regulatory T cell population following MDX-010 administration provides an additoinal rationale for eliminating these cells to improve antitumor activity. It may be required that multiple checkpoints in immune regulation be targeted for optimal antitumor activity. We are proposing to evaluate the combination of MDX-010 with daclizumab in an attempt to target CD25 expressing T regulatory cells.
| O'Mahony, Deirdre; Morris, John C; Quinn, Cate et al. (2007) A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res 13:958-64 |
| Berzofsky, Jay A; Ahlers, Jeffrey D; Janik, John et al. (2004) Progress on new vaccine strategies against chronic viral infections. J Clin Invest 114:450-62 |
| Berzofsky, Jay A; Terabe, Masaki; Oh, SangKon et al. (2004) Progress on new vaccine strategies for the immunotherapy and prevention of cancer. J Clin Invest 113:1515-25 |
