Mean ELISPOT response to GP2 increased from 4719 at baseline to 14460 (p=13) after vaccination. 14460 (p=13) after vaccination. Based on safety and immunologic data, the appropriate dose was determined to be 1000 g of GP2 + 250 g of GM-CSF. Conclusion The GP2+GM-CSF vaccine is safe and stimulates an immunologic response when given concurrently with trastuzumab. An ongoing phase II trial is evaluating the efficacy of combining a CD8 T cell-eliciting vaccine with trastuzumab in HER2-positive breast cancer patients. Synopsis Combining trastuzumab with CD8+ T cell-eliciting HER peptide vaccines may provide synergistic immunotherapeutic benefit in breast cancer. This phase I trial demonstrates the GP2 + GM-CSF vaccine given concurrently with trastuzumab is safe and stimulates an immune response. Introduction Trastuzumab, a human IgG1 monoclonal antibody that targets the Upamostat extracellular domain of the HER2 protein, is routinely administered to HER2-positive breast cancer patients. Trastuzumab functions via multiple mechanisms, including decreasing signaling by preventing HER2 dimerization, increasing endocytic destruction of the HER2 receptor, and inhibiting extracellular domain shedding. 1,2 Immune-mediated mechanisms of action have also been described including antibody dependent cellular cytotoxicity (ADCC). 3,4 ADCC leads to antigen release, triggering uptake and cross-presentation by dendritic cells, stimulating an anti-HER2 CD8+ T cell response. 5,6 Trastuzumab also stimulates endogenous anti-HER2 antibody and anti-HER2 CD4+ T cell responses. 7,8 The GP2 (HER2: 654-662) peptide vaccine is comprised of the HLA-A2- and A3-restricted, HER2-derived peptide GP2 combined with the immunoadjuvant granulocyte macrophage colony-stimulating Rabbit Polyclonal to Tip60 (phospho-Ser90) factor (GM-CSF). Early phase trials demonstrated the vaccine to be safe and capable of generating a HER2-specific CD8+ T cell response. 9,10 The phase II trial randomized Upamostat HLA-A2/A3+ breast cancer patients with any level of HER2 expression (immunohistochemistry [IHC] 1-3+) in their tumor to receive six monthly inoculations of GP2+GM-CSF or GM-CSF alone with booster inoculations every six months thereafter. An intention-to-treat analysis performed at a median follow-up of 34 months, showed an 88% estimated 5-year disease-free survival (DFS) rate in vaccinated patients versus 81% in GM-CSF only patients (p=0.43). 10 In HER2-positive patients (all received trastuzumab) DFS was 94% in the vaccinated patients compared to 89% in GM-CSF only patients (p=0.86). Per-treatment analysis, which excluded recurrences during the primary vaccination series and secondary malignancies, showed 100% DFS in vaccinated HER2-positive patients compared to 89% in GM-CSF only patients (p=0.08). Breast cancer recurrences occurred only during the primary vaccination series, which was given after completing standard therapy to include trastuzumab. Given this, we hypothesized that by administering the vaccine earlier, concurrently with trastuzumab, the stimulated immune response may prevent early recurrences. Here we describe a phase I trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT03014076″,”term_id”:”NCT03014076″NCT03014076) made to evaluate the mix of GP2+GM-CSF implemented concurrently with trastuzumab. The principal objective Upamostat was to determine basic safety from the mixture. Secondary objectives had been to determine dosing and immunologic response. Strategies and Sufferers Individual Features and Clinical Process This one middle, stage Ib dose-escalation trial was executed under an investigational brand-new drug program (BB-IND#11730). Entitled sufferers needed verified histologically, stage I-III HER2-positive breasts cancer and become receiving trastuzumab within their therapy. HER2-positive was thought as IHC 3+ or a fluorescence in situ hybridization proportion 2.0 (research enrolled ahead of guideline adjustments). Enrollment happened any moment after diagnosis, nevertheless, initiation of research treatment happened after conclusion of medical procedures, chemotherapy, and rays in a way that the vaccination series overlapped using the trastuzumab monotherapy part of the treatment program. Because GP2 is normally HLA-A3 and HLA-A2 limited, after preliminary consent for testing, each patient’s HLA-A2 and HLA-A3 position was determined. HLA-A2+ and HLA-A3+ individuals were permitted signal cure participate and consent. The analysis was a 3+3 stage dose escalation/marketing trial with three sufferers signed up for each of four dosing cohorts with an extension cohort at the utmost delivered dosage (MDD) (desk). Extension was performed on the MDD because there is no dose restricting toxicity at the lower dosages. A higher dosage could not end up being implemented because of the volume necessary to solubilize the peptide.