User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors

Primary tabs

Limentani, Steven A Campone, Mario Dorval, Thierry Curigliano, Giuseppe de Boer, Richard Berlière, Martine [UCL] Lehmann, Frédéric F

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2016
Language Anglais
Journal information "Breast Cancer Research and Treatment" - Vol. 156, no.2, p. 319-330 (2016)
Peer reviewed yes
Publisher Kluwer Academic ((Netherlands) Dordrecht )
issn 0167-6806
e-issn 1573-7217
Publication status Publié
Affiliations UCL - SSS/IREC/GYNE - Pôle de Gynécologie
UCL - (SLuc) Service de gynécologie et d'andrologie
MESH Subject Adult ; Immunologic Factors ; Immunotherapy ; Middle Aged ; Receptor, ErbB-2 ; Recombinant Proteins ; Survival Analysis ; Treatment Outcome ; Up-Regulation ; Aged ; Breast Neoplasms ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Dosage Calculations ; Female ; Gene Expression Regulation, Neoplastic ; Humans
Keywords Cancer immunotherapeutic ; HER2-overexpressing breast cancer ; Vaccine ; dHER2 protein
Links
  1. Moasser M M, The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis, 10.1038/sj.onc.1210477
  2. Ross J. S., Slodkowska E. A., Symmans W. F., Pusztai L., Ravdin P. M., Hortobagyi G. N., The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine, 10.1634/theoncologist.2008-0230
  3. Miller JL (1998) Progress in breast cancer treatment: prevention, new therapies come to forefront. Am J Health Syst Pharm 55:2326–2330
  4. Ahn ER, Wang E, Glück S (2012) Is the improved efficacy of trastuzumab and lapatinib combination worth the added toxicity? A discussion of current evidence, recommendations and ethical issues regarding dual HER2-targeted therapy. Breast Cancer 6:191–207
  5. Higgins Michaela J., Baselga José, Targeted therapies for breast cancer, 10.1172/jci57152
  6. Nahta R (2012) Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer. ISRN Oncol. doi: 10.5402/2012/428062
  7. Swain Sandra M, Kim Sung-Bae, Cortés Javier, Ro Jungsil, Semiglazov Vladimir, Campone Mario, Ciruelos Eva, Ferrero Jean-Marc, Schneeweiss Andreas, Knott Adam, Clark Emma, Ross Graham, Benyunes Mark C, Baselga José, Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study, 10.1016/s1470-2045(13)70130-x
  8. Gwin W. R., Spector N. L., Pertuzumab Protects the Achilles' Heel of Trastuzumab--Emtansine, 10.1158/1078-0432.ccr-13-2626
  9. Goldhirsch Aron, Gelber Richard D, Piccart-Gebhart Martine J, de Azambuja Evandro, Procter Marion, Suter Thomas M, Jackisch Christian, Cameron David, Weber Harald A, Heinzmann Dominik, Lago Lissandra Dal, McFadden Eleanor, Dowsett Mitch, Untch Michael, Gianni Luca, Bell Richard, Köhne Claus-Henning, Vindevoghel Anita, Andersson Michael, Brunt A Murray, Otero-Reyes Douglas, Song Santai, Smith Ian, Leyland-Jones Brian, Baselga Jose, 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial, 10.1016/s0140-6736(13)61094-6
  10. Disis M L, Pupa S M, Gralow J R, Dittadi R, Menard S, Cheever M A, High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer., 10.1200/jco.1997.15.11.3363
  11. Disis Mary L., Gooley Theodore A., Rinn Kristine, Davis Donna, Piepkorn Michael, Cheever Martin A., Knutson Keith L., Schiffman Kathy, Generation of T-Cell Immunity to the HER-2/neu Protein After Active Immunization With HER-2/neu Peptide–Based Vaccines, 10.1200/jco.2002.06.171
  12. Disis Mary L., Schiffman Kathy, Guthrie Katherine, Salazar Lupe G., Knutson Keith L., Goodell Vivian, dela Rosa Corazon, Cheever Martin A., Effect of Dose on Immune Response in Patients Vaccinated With an HER-2/neu Intracellular Domain Protein—Based Vaccine, 10.1200/jco.2004.09.005
  13. Emens L A, Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity, 10.1677/erc.1.00671
  14. Morse Michael A, Hobeika Amy, Osada Takuya, Niedzwiecki Donna, Marcom Paul, Blackwell Kimberly L, Anders Carey, Devi Gayathri R, Lyerly H Kim, Clay Timothy M, Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2, 10.1186/1479-5876-5-42
  15. Murray JL, Gillogly ME, Przepiorka D et al (2002) Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2 + in patients with metastatic breast and ovarian cancer. Clin Can Res 8:3407–3418
  16. Peoples George E., Gurney Jennifer M., Hueman Matthew T., Woll Mike M., Ryan Gayle B., Storrer Catherine E., Fisher Christine, Shriver Craig D., Ioannides Constantin G., Ponniah Sathibalan, Clinical Trial Results of a HER2/neu (E75) Vaccine to Prevent Recurrence in High-Risk Breast Cancer Patients, 10.1200/jco.2005.03.047
  17. Salazar LG, Fikes J, Southwood S et al (2003) Immunization of cancer patients with HER2/neu-derived peptides demonstrating high-affinity binding to multiple class II alleles. Clin Can Res 9:5559–5565
  18. Qin Tao, Yuan, Peng, Bai, Shi, Teng, Liu, Wang, HER2-positive breast cancer patients receiving trastuzumab treatment obtain prognosis comparable with that of HER2-negative breast cancer patients, 10.2147/ott.s40851
  19. Valabrega G, Montemurro F, Aglietta M, Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer, 10.1093/annonc/mdl475
  20. Stagg J., Loi S., Divisekera U., Ngiow S. F., Duret H., Yagita H., Teng M. W., Smyth M. J., Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy, 10.1073/pnas.1016569108
  21. Vu T, Claret FX (2012) Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2:62
  22. Shi Yun, Fan Xuejun, Meng Weixu, Deng Hui, Zhang Ningyan, An Zhiqiang, Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation, 10.1186/bcr3637
  23. Foy Teresa M., Fanger Gary R., Hand Susan, Gerard Catherine, Bruck Claudine, Cheever Martin A., Designing HER2 vaccines, 10.1053/sonc.2002.34056
  24. Disis Mary L., Wallace Danelle R., Gooley Theodore A., Dang Yushe, Slota Meredith, Lu Hailing, Coveler Andrew L., Childs Jennifer S., Higgins Doreen M., Fintak Patricia A., dela Rosa Corazon, Tietje Kathleen, Link John, Waisman James, Salazar Lupe G., Concurrent Trastuzumab and HER2/neu-Specific Vaccination in Patients With Metastatic Breast Cancer, 10.1200/jco.2008.20.6789
  25. Rubin I., Yarden Y., The Basic Biology of HER2, 10.1093/annonc/12.suppl_1.s3
  26. Hamilton Erika, Blackwell Kimberly, Hobeika Amy C, Clay Timothy M, Broadwater Gloria, Ren Xiu-Rong, Chen Wei, Castro Henry, Lehmann Frederic, Spector Neil, Wei Junping, Osada Takuya, Lyerly H Kim, Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion, 10.1186/1479-5876-10-28
  27. Emens Leisha A, Cancer vaccines: on the threshold of success, 10.1517/14728214.13.2.295
  28. Curigliano G, Romieu G, Campone M et al (manuscript submitted in parallel) A Phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer. Breast Cancer Res Treat
  29. Reinartz S., Vaccination of Patients with Advanced Ovarian Carcinoma with the Anti-Idiotype ACA125: Immunological Response and Survival (Phase Ib/II), 10.1158/1078-0432.ccr-03-0056
  30. Garcia B., Neninger E., de la Torre A., Leonard I., Martinez R., Viada C., Gonzalez G., Mazorra Z., Lage A., Crombet T., Effective Inhibition of the Epidermal Growth Factor/Epidermal Growth Factor Receptor Binding by Anti-Epidermal Growth Factor Antibodies Is Related to Better Survival in Advanced Non-Small-Cell Lung Cancer Patients Treated with the Epidermal Growth Factor Cancer Vaccine, 10.1158/1078-0432.ccr-07-1050
  31. Harrop Richard, Shingler William, Kelleher Michelle, de Belin Jackie, Treasure Peter, Cross-trial Analysis of Immunologic and Clinical Data Resulting From Phase I and II Trials of MVA-5T4 (TroVax) in Colorectal, Renal, and Prostate Cancer Patients : , 10.1097/cji.0b013e3181f5dac7
  32. Harrop Richard, Shingler William H., McDonald Mike, Treasure Peter, Amato Robert J., Hawkins Robert E., Kaufman Howard L., de Belin Jackie, Kelleher Michelle, Goonewardena Madusha, Naylor Stuart, MVA–5T4-induced immune responses are an early marker of efficacy in renal cancer patients, 10.1007/s00262-011-0993-7
  33. Campbell C. T., Gulley J. L., Oyelaran O., Hodge J. W., Schlom J., Gildersleeve J. C., Humoral response to a viral glycan correlates with survival on PROSTVAC-VF, 10.1073/pnas.1314722111
Bibliographic reference Limentani, Steven A ; Campone, Mario ; Dorval, Thierry ; Curigliano, Giuseppe ; de Boer, Richard ; et. al. A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors. In: Breast Cancer Research and Treatment, Vol. 156, no.2, p. 319-330 (2016)
Permanent URL http://hdl.handle.net/2078.1/184143