Despite recent advances in targeted therapies, the outlook for patients with many cancers, such as pancreatic and ovarian, remains bleak. Hence new treatments such as immunotherapy are being actively pursued. The p53 protein is a well-characterized suppressor of uncontrolled cell division. Mutations in the gene occur in ≥50% of all solid tumors, whereby it acquires oncogenic properties and leads to high levels of dysfunctional p53 protein within the malignant cells. The concentration of normal, non-mutant p53 in healthy cells is low, making p53 an attractive target for selective killing of tumor cells. We have chosen a viral based vaccine approach, using Modified Vaccinia Ankara (MVA) as the delivery vehicle for the p53 target antigen to patients. Recombinant MVA vaccines have an impressive safety record, being administered in numerous clinical trials with only mild side-effects.
Our preclinical studies showed that immunization of mice with a p53MVA vaccine caused rejection of established tumors and generation of systemic tumor immunity. In addition, when p53MVA was used to generate cytotoxic T cells from the blood of cancer patients, these were capable of killing tumor cells in vitro.
Together with Vincent Chung M.D., we completed a first in human, Phase I study evaluating the safety and immunogenicity of clinical grade p53MVA vaccine in patients with colon and pancreatic cancers. The vaccine was well tolerated, with no severe toxicities observed. CT scans were used to evaluate progression of disease and blood draws were taken for safety and immunological assessments throughout the vaccination phase. Anti-p53 immune responses were detectable in the majority of patients after vaccination, but responses were generally transient in these heavily immunosuppressed patients with advanced disease. Therefore we have initiated two new clinical trials, using the p53MVA vaccine in combination with two different immunomodulatory agents:
Trial 1: p53MVA in combination with gemcitabine chemotherapy in platinum resistant ovarian cancer patients (NCT02275039).
This phase I trial studies the side effects and recommended dose of the combination of p53MVA vaccine (modified vaccinia virus ankara vaccine expressing tumor protein p53 [p53]) and gemcitabine hydrochloride in treating patients with ovarian epithelial cancer that has come back. Vaccines made from inserting a laboratory-treated gene into a person's tumor cells may help the body build an effective immune response to kill tumor cells that express p53. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving modified vaccinia virus ankara vaccine expressing p53 together with gemcitabine hydrochloride may work better in treating patients with ovarian epithelial cancer.
Trial 2: p53MVA in combination with pembrolizumab in patients with p53 over-expressing solid tumors which are refractory to standard therapy (NCT02432963).
This phase I trial studies the side effects of vaccine therapy and pembrolizumab in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment and that have failed prior therapy. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving vaccine therapy together with pembrolizumab may be a better treatment in patients with solid tumors.
Gemcitabine is a standard of care chemotherapy agent which can have stimulatory effects on the immune system, and has shown promising results when coupled with cancer vaccines in pancreatic cancer patients. Pembrolizumab is one of the newly licensed anti PD-1 blocking antibodies which has shown exciting results in several malignancies. The aim of combining the p53MVA vaccine with these agents is to combat the prevalent immunosuppression of heavily pretreated patients with advanced disease and boost the vaccine response to clinically beneficial levels.
1. Hardwick N, Chung V, Cristea M, Ellenhorn JDI, Diamond DJ. Overcoming Immuno-suppression to enhance a p53MVA vaccine: OncoImmunology. 3(10):e958949, 2014. PMC4292557
2. Hardwick N, Carrol M, Kaltcheva T, Qian D, Lim D, Leong L, Chu P, Kim J, Chao J, Fakih M, Yen Y, Espenschied J, Ellenhorn DI, Diamond DJ, Chung V. p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T cell responses. Clinical Cancer Research, 20:4459-4470, 2014. PMC4155000
3. Song GY, Srivastava T, Ishizaki H, Lacey SF, Diamond DJ, and Ellenhorn JDI. Recombinant Modified Vaccinia Virus Ankara (MVA) Expressing Wild Type Human p53 Induces Specific Anti-tumor CTL Expansion. Cancer Investigation, 29:501-510 2011. PMC3260009
4. Ishizaki H, Manuel E, Song G-Y, Srivastava T, Diamond DJ, Ellenhorn JDI. Modified vaccinia Ankara (MVA) expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model. Cancer Immunology & Immunotherapy, 60(1):99 -109, 2011. PMC3289969
5. Ishizaki H, Song G-Y, Srivastava S, Carroll KD, Shahabi V, Diamond DJ, Ellenhorn JDI. Heterologous prime/boost immunization with p53-based vaccines combined with toll-like receptor stimulation enhances tumor regression. JIT, 33(6):609-617, 2010. PMC3523364
6. Margolin K, Synold, TW, Lara P, Frankel P, Lacey SF, Quinn DI, Baratta T, Dutcher JP, Xi B, Diamond DJ, and Gandara DR. Oblimersen and -interferon in metastatic renal cancer: a phase II study of the California Cancer Consortium. J. Cancer Res. Clin. Oncol., 133(10):705-711, 2007. PM: 17508219
7. Song G-Y, Gibson G, Haq W, Huang EC, Srivastava T, Hollstein M, Daftarian P, Wang Z, Diamond DJ, and Ellenhorn J. An MVA vaccine overcomes tolerance to human p53 in mouse and humans. Cancer Immunology & Immunotherapy, 56(8): 1193-1205, 2007. PM:17219151
8. Daftarian P, Ali S, Song G-Y, Diamond DJ, and Ellenhorn JDI. Two Distinct Pathways of Immuno-modulation Improve Potency of p53 Immunization in Rejecting Established Tumors. Cancer Research, 64 (15):5407-5414, 2004. PM:15289349
9. Espenschied J, Lamont J, Longmate J, Pendas S, Wang Z, Diamond DJ, and Ellenhorn JDI. CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in a established murine tumor model. J. Immunol. 170: 3401-3407, 2003. PM:12626601
10. Epel M, Ellenhorn JDI, Diamond DJ, and Reiter Y. A Functional Recombinant Single-Chain T Cell Receptor Fragment Capable of Selectively Targeting Antigen-Presenting Cells. Cancer Immunol Immunother 51: 565-573, 2002. PM:12384808
11. Liu X, Peralta E, Ellenhorn J and Diamond DJ. Targeting of Human p53- overexpessing Tumor Cells by an HLA A*0201-restricted Murine T-Cell Receptor Expressed in Jurkat T cells. Cancer Research, 60:693-701, 2000. PM:10676655
12. Peralta E, McCarty TM, Doerr A, Jones PA, Markl I, Diamond DJ, and Ellenhorn JDI. Immunotherapy of bladder cancer by targeting p53. Journal of Urology, 162(5):1806-11, 1999. PM:10524939
13. Schwarz RE, McCarty TM, Peralta EA, Diamond DJ, and Ellenhorn JDI. An orthotopic in vivo model of human pancreatic cancer. Surgery, 126 (3): 562-567, 1999. PM:10486610
14. McCarty TM, Yu Z, Liu X, Diamond DJ, and Ellenhorn JD. An HLA-restricted p53 specific immune response from HLA transgenic p53 knockout mice. Ann. Surg. Oncol. 5(1):93-99, 1998. PM:9524714
15. McCarty TM, Liu X, Sun J, Peralta EA, Diamond DJ, and Ellenhorn JDI: Targeting p53 for adoptive T Cell immunotherapy.Cancer Research, 58: 2601-2605, 1998. PM:9635585
16. McCarty TM, Liu X, Schwarz RE, Diamond DJ, and Ellenhorn JDI. Targeting p53 for adoptive T cell immunotherapy. Owen H. Wangensteen Surgical Forum, 48,783 785, 1997
17. Yu Z, Liu X, McCarty TM, Diamond DJ, Ellenhorn JDI: The use of transgenic mice to generate p53 specific and HLA restricted cytolytic T cells (CTL). Journal of Surgical Research, 69: 337-343, 1997
18. Ellenhorn JDI, Yu Z, Diamond DJ. Generation of p53 specific and HLA restricted cytolytic T lymphocytes using recombinant vaccinia virus and HLA transgenic mice. Owen H. Wangensteen Surgical Forum, 47: 503 505, (1996).
This work has been supported by funds from the National Cancer Institute (R29CA070819 and R21CA114889), a contract from SAIC (25X5061), FAMRI, Champion Power Equipment, the City of Hope Phase I program, and the City of Hope Cancer Center (P30-CA033572).
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John A. Zaia, M.D.: PI of the Phase Ib Trial in healthy adults
Ryotaro Nakamura, M.D.: PI of the Phase Ib and II Trial in HCT recipients; Clinical Staff of Department of Hematology and HCT
Stephen J. Forman, M.D.: Chair, Hem/HCT (City of Hope National Medical Center)
Corinna LaRosa, Ph.D.: Director of the laboratory correlative studies for vaccine clinical trials
Michael Verneris, M.D.: PI of the Phase II trial in HCT recipients
Jeffrey S. Miller, M.D.: co-PI (University of Minnesota Medical Center).
Pfizer, Inc.: Vaccine Research, supplier of PF-03512676 adjuvant.
Dr. Nicola Hardwick, Mary Carrol R.N., Mario DiMacali, C.R.A., Dr. Teodora Kaltcheva, Dr. Dajun Qian, Dr. Dean Lim, Dr. Lucille Leong, Dr. Peiguo Chu, Dr. Joseph Kim, Dr. Joseph Chao, Dr. Marwan Fakih, Dr. Yun Yen, Dr. Jonathan Espenschied, Dr. Joshua D I Ellenhorn, Dr. Don J. Diamond and Dr. Vincent Chung