Abstract OT3-1-02: Phase II randomized study of combination immunotherapy with or without Polysaccharide Krestin (PSK®) concurrently with a HER2 ICD peptide-based vaccine and trastuzumab in patients with stage IV breast cancer
Authors: Childs JS , Higgins DM , Parker S , Reichow J , Lu H , Standish L , Disis ML , Salazar LG 
Published: August 2014

Abstract
Background: Endogenous immunity in patients with HER2+ metastatic breast cancer (MBC) is likely dampened by an immune-suppressive tumor microenvironment and not sufficient to control tumor growth. Thus, most patients have disease relapse after achieving complete remission with standard therapies. Immunomodulation directed at enhanced stimulation of tumor specific immunity could result in immunologic eradication of residual HER2+ tumor cells and prevent BC relapse. We have shown PSK to be a potent TLR-2 agonist that stimulates both innate and adaptive immunity in a BC mouse model. Additionally, we have shown combination immunotherapy with HER2 peptide vaccines and trastuzumab (TRAZ) to be safe and able to elicit HER2 specific Th1 immunity and epitope spreading (ES) which has been associated with survival in vaccinated patients. Lastly, decreased serum TGF-β elicited by HER2 vaccination correlates with Th1 ES and may serve as a biomarker to predict cancer vaccine efficacy. We hypothesize that PSK, when given with TRAZ can augment vaccine induced HER2 specific TH1 immunity and prevent disease relapse in patients with optimally treated HER2+ MBC.
Trial design: Phase II randomized two-arm clinical trial. Patients will be enrolled and randomly assigned in equal numbers to 1 of 2 arms (15 patients/arm) as follows: Arm 1:HER2 ICD vaccine, TRAZ and placebo or Arm 2:HER2 ICD vaccine, TRAZ and PSK. All patients will receive 3 monthly HER2 ICD vaccines plus TRAZ and 4 months of concomitant PSK or placebo. Serial blood draws for immunologic monitoring will be done.
Eligibility criteria: Patients with Stage IV HER2+ BC who have been treated with definitive therapy and are: (1) without evidence of disease or have stable-bone only disease, (2) receiving TRAZ monotherapy, and (3) without clinically significant autoimmune disease. Patients must have normal LVEF per MUGA scan or echocardiogram.
Aims: (1) Evaluate safety of PSK when given with a HER2 vaccine and TRAZ (2) Evaluate the effect of PSK on serum TGF-β levels when given with a HER2 vaccine and TRAZ and (3) Evaluate the effect of PSK on intermolecular ES when given with a HER2 vaccine and TRAZ. A secondary objective is to evaluate progression free survival (PFS) and overall survival (OS).
Statistical methods: (1) Toxicity will be determined by clinical and chemical parameters and grading will be done per CTEP CTCAE 4.0.; (2) Evaluation of TGF-β levels, pre and post-PSK treatment will be assessed with linear regression models; and analysis of multiple post-baseline measurements will be performed using generalized estimating equations; (3) A positive antigen-specific immune response will be defined as a precursor frequency &gt;1:20,000 antigen-specific peripheral blood mononuclear cells. Differences in the levels of HER2 immunity will be evaluated between arms using a two-tailed T test. The degree of ES in each arm will be evaluated with generalized linear modeling; (4) Large differences in PFS and OS observed between groups will be noted and described.
Target accrual: 30 patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-1-02.