BERKELEY, CA (UroToday.com) - The combination of modified vaccinia Ankara (MVA) to deliver the tumor-associated antigen 5T4 presents itself as a novel immunotherapeutic vaccine.
The oncofetal antigen 5T4 is highly expressed in 80% of breast, kidney, colorectal, prostate, and ovarian carcinomas, making it an ideal antigen for vaccine therapy. To date, more than 3,000 doses of MVA-5T4 have been administered to colorectal, renal, and prostate cancer patients with rare occurrences of grade 3 or 4 vaccination-related adverse events being observed. Studies have demonstrated that MVA-5T4 is safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies. Although an immune response has been observed, antitumor activity has been modest or absent in clinical trials.
| With minimal side effects and the ability to produce a strong immunogenic response, MVA-5T4 is a viable addition to the cancer therapy arsenal. |
The MVA-5T4 vaccine has been developed in multiple phase I/II trials in colorectal, renal, and prostate cancer patients. The first MVA-5T4 clinical trial in humans was a dose-escalating study in colorectal cancer patients.[1] There were no treatment-related adverse events, and patients saw disease stabilization of 3-18 months. Phase II trials combining MVA-5T4 plus chemotherapy found a synergistic effect in comparison to MVA-5T4 in patients with colorectal cancer resulting in a greater magnitude of 5T4-specific antibody responses and increased clinical response.[2, 3] When MVA-5T4 was used before and after surgery for colorectal cancer, overall survival (OS) was 25.9 months.[4]
In renal cell carcinoma, MVA-5T4 was developed in combination with other immunologic agents. When combined with interferon-α, nearly all patients mounted a 5T4-spcific antibody immune response, and median progression-free survival and OS was 3.8 months and 12[1] months, respectively.[5] In combination with high-dose interleukin-2 (IL-2), MVA-5T4 resulted in all patients mounting a 5T4-specific antibody response.[6] Low-dose IL-2 plus MVA-5T4 resulted in a PFS of 3.37 months and an OS of 12.87 months.[7] These results led to the multi-center, randomized, double-blind, placebo-controlled, phase III study.[8] A phase III trial resulted in the development of an immune response surrogate that is to be applied to all future MVA-5T4 clinical trials. Data from this study helped identify an immune response surrogate for 5T4 antibody response to evaluate treatment benefit as well as confirmed the association between a high 5T4 immune response and enhanced OS.
In castration-resistant prostate cancer (CRPC), MVA-5T4 has been evaluated as a monotherapy and in combination with granulocyte macrophage-colony stimulating factor.[9] All patients mounted a 5T4-specific antibody immune response and periods of disease stabilization were observed from 2 to 10 months.
The MVA-5T4 vaccine has elicited a 5T4-specific antibody immune response in colorectal, renal cell, and prostate cancer patients. In all trials, the vaccine was safe and well tolerated, resulting only in minor flu-like symptoms and mild reactions at the injection site. In colorectal patients, MVA-5T4 in combination with chemotherapy suggests improved clinical benefit. Renal cancer patients treated with MVA-5T4 as monotherapy or in combination therapy have suggested activity. The results of MVA-5T4 in prostate cancer patients led to the current development of MVA-5T4. With minimal side effects and the ability to produce a strong immunogenic response, MVA-5T4 is a viable addition to the cancer therapy arsenal.
References
- Harrop R, Connolly N, Redchenko I, et al. Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clinical Cancer Research 2006; 12(11): 3416-24.
- Harrop R, Drury N, Shingler W, et al. Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. Cancer Immunology, Immunotherapy: CII 2008; 57(7): 977-86.
- Harrop R, Drury N, Shingler W, et al. Vaccination of colorectal cancer patients with modified vaccinia ankara encoding the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune responses. Clinical Cancer Research 2007; 13(15 Pt 1): 4487-94.
- Elkord E, Dangoor A, Burt DJ, et al. Immune evasion mechanisms in colorectal cancer liver metastasis patients vaccinated with TroVax (MVA-5T4). Cancer Immunology, Immunotherapy CII 2009; 58(10): 1657-67.
- Amato RJ, Shingler W, Goonewardena M, et al. Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial. Journal of Immunotherapy 2009; 32(7): 765-72.
- Kaufman HL, Taback B, Sherman W, et al. Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma. Journal of Translational Medicine 2009; 7: 2.
- Amato RJ, Shingler W, Naylor S, et al. Vaccination of renal cell cancer patients with modified vaccinia ankara delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II trial. Clinical Cancer Research 2008; 14(22): 7504-10.
- Amato RJ, Hawkins RE, Kaufman HL, et al. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clinical Cancer Research 2010; 16(22): 5539-47.
- Amato RJ, Drury N, Naylor S, et al. Vaccination of prostate cancer patients with modified vaccinia ankara delivering the tumor antigen 5T4 (TroVax): a phase 2 trial. Journal of Immunotherapy 2008; 31(6): 577-85.
Written by:
Robert Amato, DO and Mika Stepankiw, MS as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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Evaluation of MVA-5T4 as a novel immunotherapeutic vaccine in colorectal, renal and prostate cancer - Abstract
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