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The HER2 Peptide Nelipepimut-S (E75) Vaccine (Neuvax™) in Breast Cancer Patients at Risk for Recurrence: Correlation of Immunologic Data with Clinical Response

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The HER2 Peptide Nelipepimut-S (E75) Vaccine (Neuvax™) in Breast Cancer Patients at Risk for Recurrence: Correlation of Immunologic Data with Clinical Response Drug Evaluation For reprint orders, please contact: [email protected] HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response Nelipepimut-S (formerly known as E75) is an immunogenic peptide from the HER2 Erika J Schneble1, John S protein that is highly expressed in breast cancer. The NeuVax™ (Galena, OR, USA) Berry1, Francois A Trappey1, vaccine, nelipepimut-S plus granulocyte–macrophage colony-stimulating factor, is Guy T Clifton1, Sathibalan 2 designed for the prevention of clinical recurrences in high risk, disease-free breast Ponniah , Elizabeth Mittendorf3 & George E cancer patients. Although cancer vaccines such as NeuVax represent promising Peoples*,1 approaches to cancer immunotherapy, much remains to be elucidated regarding their 13AN!NTONIO-ILITARY-EDICAL#ENTER mechanisms of action: particularly given that multiple cancer vaccine trials have failed $EPARTMENTOF'ENERAL3URGERY &ORT to demonstrate a correlation between immunologic data and clinical outcome. Here, 3AM(OUSTON 48 53! we briefly discuss our clinical trial experience with NeuVax focusing on immunologic #ANCER6ACCINE$EVELOPMENT response data and its implication on how the immune system may be affected by this ,ABORATORY 5NIFORMED3ERVICES 5NIVERSITYOFTHE(EALTH3CIENCES peptide vaccine. Most importantly, we demonstrate the potential capability of certain "ETHESDA -$ 53! immunologic assays to predict clinical benefit in our trials. 35NIVERSITYOF4EXAS-$!NDERSON #ANCER#ENTER (OUSTON 48 53! Keywords:BREASTCANCERs%s(%2PEPTIDEVACCINEsIMMUNOTHERAPYsNELIPEPIMUT 3 !UTHORFORCORRESPONDENCE 4EL &AX Background breast cancer patients decreasing recurrence GEORGEPEOPLES HOTMAILCOM The HER2/neu proto-oncogene, a member rates by approximately 50% [6–8]. of the EGF receptor family, is expressed in Recent data show that patients with a a variety of malignancies including breast HER2-overexpressing tumor treated with cancer. Historically, HER2 overexpression trastuzumab have a much better prognosis (immunohistochemistry [IHC] 3+ and/or than HER2 low-to-intermediate (IHC 1–2+) FISH >2.2]) has been associated with a poor patients not treated with trastuzumab [9]. How- prognosis. Given that the overexpression of ever, trastuzumab is limited in that it has only HER2 is associated with more aggressive been shown to be efficacious in the 20–30% subtypes of breast cancer and other adeno- of patients with tumors of the highest level of + carcinomas, HER2 is an attractive immuno- HER2 expression (IHC 3 ) [10] . HER2 low- logic target for both cell-mediated immunity, to-intermediate patients represent over 50% of including cytotoxic T cells, and antibody- breast cancer patients [10,11]. Thus, there exists mediated immunotherapy approaches [1,2]. a need to develop other adjuvant approaches Currently, in addition to traditional thera- to treat this HER2 low-to- intermediate- pies of surgery, chemotherapy, radiation and expressing population while avoiding the tox- endocrine therapy, a small percentage of icities associated with trastuzumab and other breast cancer patients benefit from trastu- HER2-targeted therapies. zumab and other HER2-targeted therapies An ideal immunologic therapy would including pertuzumab [3,4] and trastuzumab induce immunologic memory, making clinical emtasine [5]. Trastuzumab, a mono clonal response long-acting and sustainable. Trastu- antibody targeting the highest level of zumab and other monoclonal antibodies are HER2-overexpressing tumor cells, provides limited by passive mechanism of actions such as a proven disease-free survival (DFS) benefit ADCC. Without full activation of the immune to high-risk node- negative and node-positive system, there is little to no immunologic part of 10.2217/IMT.14.22 Immunotherapy (2014) 6(5), 519–531 ISSN 1750-743X 519 Drug Evaluation Schneble, Berry, Trappey et al. memory. Cancer vaccines are a form of active immu- Laboratory & clinical studies notherapy where the body’s own immune system is uti- Nelipepimut-S has been studied in multiple labora- lized to target and kill tumor cells. The appeal of this tory and clinical studies [13,14,20–27]. The ability for active immunotherapeutic strategy includes the ability nelipepimut -S to stimulate CTL to lyse HER2- expressing to generate a sustained T-cell response and immunologic targets in the preclinical setting was established in both memory with minimal toxicity. More specifically, vac- ex vivo/in vitro studies of ovarian and breast tumor cells cines target tumor-associated antigens (TAAs) that are lines [13,27] and animal models (Table 1) [28,29]. Pharmoki- recognized by human cytotoxic T lymphocytes (CTLs), netic studies within animal models were not performed which are critical for the removal of tumor cells in vivo. given the small peptide dose used and rapid peptide HER2, the most studied TAA in breast cancer, has been clearance. As such, typical pharmokinetic parameters shown to elicit a specific immune response. Identification (e.g., absorption, plasma protein binding, distribution, of HLA-A2 as a restriction element in HER2-expressing metabolism and excretion) were not established. cancers [12] led to the discovery of CTL-eliciting epi- In addition to administering nelipepimut-S with GM- topes, nelipepimut-S and GP2 [13,14]. Nelipepimut-S, a CSF, other vaccine formulations utilizing the peptide have nine-amino-acid peptide derived from the extracellular included: loading the peptide onto autologous dendritic HER2 protein (KIFGSLAFL, HER2 p369-377) [13], is cells [20,24], inclusion into longer peptides to elicit both + the most studied HER2-derived peptide to date [15] . CTL and CD4 helper T-cell response [21,22], and use of a single peptide with different immuno adjuvants [23,25,26]. Introduction to NeuVax™ (Galena, OR, USA) All Phase I clinical trials utilizing GM-CSF as an immu- NeuVax™ (Galena, OR, USA), a vaccine comprised of noadjuvant revealed nelipepimut-S-specific CTL expan- nelipiminut-S and the hematopoietic growth factor, gran- sion [23,25,31]. However, despite the effective stimulation ulocyte–macrophage colony-stimulating factor (GM- of a nelipepimut-S-specific T-cell response, little was CSF), holds promise as an effective adjuvant therapy known from the initial trials regarding antitumor activ- for women with low-to-intermediate HER2 expression. ity secondary to the fact that these trials enrolled patients GM-CSF is known to induce proliferation, maturation with advanced disease (Table 2) [23,25,26]. and migration of dendritic cells [16,17], and it is intended Our group has extensively studied the nelipepimut-S to enhance nelipepimut-S-specific immunity through peptide as a vaccine but with a shift of focus from the augmentation of antigen presentation to CTLs [1,16,17]. treatment of late-stage disease to the prevention of disease Nelipepimut-S binds HLA-A2 and HLA-A3 [18,19] mol- recurrence in high-risk patients after standard-of-care ecules (expressed in ∼60–75% of the general population) therapy. In our Phase I/II clinical trials, we enrolled both on antigen presenting cells that then stimulate CTLs to node-positive and high-risk node-negative breast cancer recognize and lyse HER2-expressing tumor cells. patients who have been rendered clinically free of disease Table 1. Selected preclinical studies of the ability for nelipepimut-S to stimulate cytotoxic T lymphocytes to lyse HER2-expressing targets. Study (year) Study design Immunologic response/study conclusion Ref. Fisk et al. (1995) Fresh cell lines from ovarian s First described nelipepimut-S (KIFGSLAFL, HER2/neu, p369-377) [13] cancer pts s Identified common immunogenic epitopes of HER2 that were recognized by isolated CD3+CD4+CD8+ ovarian-specific CTL lines s Nelipepimut-S epitope from tumor-associated lymphocytes from HLA-A2+ tumor-associated lymphocytes dominantly recognized by all CTL lines tested Lustgarten et al. In vitro/in vivo animal model s Nelipepimut-S capable of stimulating potent CTL response that lysed [28] (1997) tumor cells in vivo s Nelipepimut-S dose-dependent HER2 tumor-killing effect by nelipepimut-S-specific CTL in this mouse model Disis et al. (1998) In vitro/in vivo animal model; s No dose-limiting toxicity on necropsy [29] nelipeminut-S-containing s No evidence of autoimmunity HER2-derived peptides plus s Significant T-cell response detected GM-CSF or IFA Anderson et al. Ten healthy human donors s Nelipepimut-S-specific cytolytic activity in healthy donors when [30] (2000) presented on autologous DCs elicited in 50% of healthy donors #4,#YTOTOXIC4LYMPHOCYTE$#$ENDRITICCELL'- #3&'RANULOCYTEnMACROPHAGECOLONY STIMULATINGFACTOR)&!)NCOMPLETE&REUNDSADJUVANTPTS0ATIENTS 520 Immunotherapy (2014) 6(5) future science group HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence Drug Evaluation Table 2. Selected clinical studies examining the ability of nelipepimut-S to stimulate cytotoxic T lymphocytes. Study (year), phase, Patient sample Clinical response Toxicity/immunogenic response Ref. design size Zaks and Rosenberg Four pts Not disclosed s Peptide-specific CTLs detected in post- but not pre- [26] (1998), nelipepimut-S (breast, ovarian immunization blood plus IFA and colorectal s CTLs failed to react with HER2+ tumor cells cancer) Disis et al. (1999) and 64 pts (breast, Not disclosed s 92% of patients develop T-cell immunity to HER2 peptide [21,22]
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