Translation of cancer vaccines from mice to human clinical trials
Lauren V. Wood1, Masaki Terabe1, Jane Trepel2, Ira Pastan3, John C. Morris4, and Jay A. Berzofsky1
1Vaccine Br., 2Developmental Therapeutics Br., 3Lab of Molecular Biology, CCR, NCI. 4U of Cincinnati
We translated 2 cancer vaccines from mice to human clinical trials with promising early results. 1) TARP is a cancer antigen expressed in ~95% of prostate cancers. We mapped TARP epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells expressing TARP & HLA-A2 (“epitope enhancement”). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence after definitive surgery or radiotherapy (Stage D0) were vaccinated with 2 peptides either in Montanide ISA51 plus GM-CSF or pulsed on autologous dendritic cells (DCs). In PSA biochemical recurrence no tumor can be detected radiographically, but the slope of PSA rise has been validated as prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 yr compared to their own baseline slopes (p = 0.0004). A randomized placebo-controlled phase II trial is underway. 2) HER2 is a driver surface oncogene product expressed in ~25% of breast cancers and less frequently in several other tumors. Although monoclonal antibodies to HER2 have shown efficacy, no vaccine to induce anti-HER2 antibodies is available. We made an adenoviral vector vaccine expressing the extracellular & transmembrane domains of HER2 and could cure mice with very large established mammary tumors expressing HER2. The protection was dependent on antibodies to HER2, not T cells, but the mechanism was different from that of trastuzumab. We tested a human version in advanced metastatic cancer patients with any HER2+ tumor, who were naïve to HER2-directed therapies, using the HER2 adenovirus to transduce autologous DCs to express HER2. At the 2nd and 3rd dose levels, 45% of evaluable patients showed some clinical benefit (CR, PR or SD ≥ 6 months). Circulating tumor cells also declined in some vaccinated patients. Both a 4th dose level and treatment of breast cancer patients who failed HER2-targeted therapies are in progress. Thus cancer vaccines developed in mice were translated to humans with promising early results.
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