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Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Cancer vaccine strategies: translation from mice to human clinical trials
Jay A Berzofsky1,2, Masaki Terabe3, Jane B Trepel4
1Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. berzofsj@mail.nih.gov.
Abstract:
We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped 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 ("epitope enhancement"). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is 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 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.
Insights
Cancer vaccines developed in mice show promise in human trials. Prostate cancer patients receiving TARP peptide vaccines demonstrated decreased Prostate-Specific Antigen slopes, while HER2-targeted vaccines showed clinical benefit in advanced cancer patients.
Area of Science:
- Oncology
- Immunology
- Vaccinology
Background:
- Preclinical cancer vaccine strategies require translation to human clinical trials.
- Prostate-Specific Antigen (PSA) and HER2 are key targets in cancer vaccine development.
- Mouse models are crucial for evaluating cancer vaccine efficacy and mechanisms.
Purpose of the Study:
- To translate two distinct cancer vaccine strategies from preclinical mouse studies to human clinical trials.
- To evaluate the safety and efficacy of a TARP peptide vaccine in prostate cancer patients.
- To assess the clinical benefit of an adenoviral HER2 vaccine in patients with advanced metastatic cancer.
Main Methods:
- TARP peptide vaccine development involved epitope mapping, enhancement for immunogenicity, and vaccination of HLA-A2+ prostate cancer patients with peptides in Montanide-ISA51 or on autologous dendritic cells (DCs).
- An adenoviral vector vaccine expressing HER2 domains was developed and tested in advanced metastatic cancer patients.
- Patient responses were assessed by Prostate-Specific Antigen slope changes, clinical benefit, and circulating tumor cell counts.
Main Results:
- 74% of prostate cancer patients receiving the TARP vaccine showed a decreased PSA slope at one year.
- For DC-vaccinated patients, response inversely correlated with a tolerogenic DC signature.
- 45% of evaluable patients with advanced metastatic cancer showed clinical benefit from the HER2 vaccine, with some experiencing a decline in circulating tumor cells.
Conclusions:
- Cancer vaccines developed and tested in mice can be successfully translated to human clinical trials.
- Both TARP peptide and HER2 vaccines demonstrated promising early results in human patients.
- Further clinical trials, including a randomized placebo-controlled phase II trial for the TARP vaccine, are warranted.
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