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Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].

Hamilton E, Blackwell K, Hobeika AC, Clay TM, Broadwater G, Ren XR, Chen W, Castro H, Lehmann F, Spector N, Wei J, Osada T, Lyerly HK, Morse MA - J Transl Med (2012)

Bottom Line: We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.This regimen was well tolerated, with no cardiotoxicity.Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Division of General Surgery, Duke University Medical Center, Durham, NC, USA. lyerl001@mc.duke.edu

ABSTRACT

Background: Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.

Methods: We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.

Results: This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).

Conclusions: dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway.

Trial registry: ClinicalTrials.gov NCT00952692.

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Related in: MedlinePlus

Outcomes for patients treated with dHER2 ASCI vaccination and lapatinib. a) Kaplan Meier Plot Progression Free Survival b) Overall Survival.
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Figure 4: Outcomes for patients treated with dHER2 ASCI vaccination and lapatinib. a) Kaplan Meier Plot Progression Free Survival b) Overall Survival.

Mentions: There were no objective clinical responses. One patient remained progression free on trial for 6 months. Median time to progression was 55 days (range: 41-188) (Figure 4a). Ten of 12 patients remain alive in follow-up. Overall survival at 300 days was 92% (95% CI: 77-100%) (Figure 4b). Because of the small numbers of patients, we could not statistically compare TTP or overall survival with immune responses; however, there were no obvious correlations.


Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].

Hamilton E, Blackwell K, Hobeika AC, Clay TM, Broadwater G, Ren XR, Chen W, Castro H, Lehmann F, Spector N, Wei J, Osada T, Lyerly HK, Morse MA - J Transl Med (2012)

Outcomes for patients treated with dHER2 ASCI vaccination and lapatinib. a) Kaplan Meier Plot Progression Free Survival b) Overall Survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306270&req=5

Figure 4: Outcomes for patients treated with dHER2 ASCI vaccination and lapatinib. a) Kaplan Meier Plot Progression Free Survival b) Overall Survival.
Mentions: There were no objective clinical responses. One patient remained progression free on trial for 6 months. Median time to progression was 55 days (range: 41-188) (Figure 4a). Ten of 12 patients remain alive in follow-up. Overall survival at 300 days was 92% (95% CI: 77-100%) (Figure 4b). Because of the small numbers of patients, we could not statistically compare TTP or overall survival with immune responses; however, there were no obvious correlations.

Bottom Line: We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.This regimen was well tolerated, with no cardiotoxicity.Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Division of General Surgery, Duke University Medical Center, Durham, NC, USA. lyerl001@mc.duke.edu

ABSTRACT

Background: Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.

Methods: We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.

Results: This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).

Conclusions: dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway.

Trial registry: ClinicalTrials.gov NCT00952692.

Show MeSH
Related in: MedlinePlus