Abstract:Vaccine therapies for treatment andprevention of cancer have seen modest degrees of efficacy with wide variationrelated to the tumor type, vaccine type, adjuvants and clinical setting fortheir study. Over the course of the last two decades, various peptide vaccinesfor breast cancer have been studied. The current leading peptide vaccine forhuman application is a HER2-based vaccine known as Nelipepimut-S, which hasdemonstrated immune activity and promising clinical activity in some settings.This review covers the development of this newer peptide vaccine for both HER2amplified and non-amplified breast cancer.

Keywords:vaccine, breast cancer, HER2, peptide,human

INTRODUCTION

The human epidermal growth factor receptor 2 (HER2) proteinhas been one of the most extensively studied and targeted markers in oncologyin the last 30 years. The identification of the HER2 receptor and thedevelopment of antibodies to target it such as trastuzumab, pertuzumab andothers, are among the most successful advances in the treatment of breastcancer in the past 50 years. The research community learned that HER2signalling through its membrane-bound tyrosine kinase domain results indownstream activation of a cascade of events leading to angiogenesis, cellularinvasiveness, proliferation and survival proficiency. It is well known thatabout 20 percent of breast cancers will have marked overexpression of the HER2receptor and will benefit from HER2 targeting agents. It is generally acceptedthat most of the other 80% of breast cancers will express HER2, but at lowerlevels. There remains debate about the potential role of the HER2 protein andHER2 targeting in lower expressing breast cancers. Nevertheless, as a targetfor either passive or active immunotherapy, HER2 has been immunogenic due toantigens such as HER2369-377(also known as the E75 peptide)that are easily recognized by T cells and dendritic cells.

The currently available agents approved for HER2-overexpressing breast cancer include: trastuzumab, ado-trastuzumab, pertuzumab, lapatinib, neratinib, most recently trastuzumab deruxtecan, and five trastuzumab biosimilars (as of 1/2020). Additionally, the novel HER2 targeted monoclonal antibody, margetuximab, and a small molecule inhibitor, tucatinib, are currently being reviewed by the US FDA for possible approvals. While some of those drugs have been tested in HER2-low settings and non-breast settings, none have been approved to date for an indication outside of HER2-high or HER2 over-expressed cancer. Likewise, vaccine strategies have tested peptides, whole cell vaccines, dendritic cell vaccines, DNA vaccines and multipeptide vaccine in both HER2-high and HER2-low settings. The present review will examine the activity, development, efficacy and safety of the E75 peptide (also known as Nelipepimut-S when combined with GMCSF) as a peptide vaccine for breast cancer. Nelipepimut-S is currently in Phase III clinical development (NCT01479244) and has strong evidence of immunologic activity, though there is mixed evidence to date of clinical activity against early stage HER2-overexpressed breast cancer and there is little clinical activity reported against advanced metastatic disease. There is emerging data on Nelipepimut-S for HER2-low and triple negative breast cancer that will be reviewed.1

METHODS: LITERATURE SEARCH, INCLUSION AND EXCLUSION CRITERIA

We performed a systematic search of peer-reviewed literaturedatabases from 11/1/2019 to 12/9/2019. This review was limited to manuscripts,abstracts and chapters available in the English language and catalogued inPubmed, Web of Science, Scopus and proceedings of national meetings including:ASCO, SITC, SABCS, ESMO (American Society of Clinical Oncology, Society forImmunoTherapy of Cancer, San Antonio Breast Cancer Symposium, and EuropeanSociety of Medical Oncology). We searched for keywords including: HER2peptide E75 peptide, Nelipepimut-S, Neu-vax, breast cancer. Weexcluded trials examining cancers other than breast cancer and other related peptidesoutside the studied amino acid sequence from HER2369-377.Multipeptide vaccine studies were included for completeness.

BACKGROUND OF NELIPEPIMUT-S

The aim of a cancer vaccine is to stimulate a cancerpatients immune system to recognize tumor associated antigens via activeimmunotherapy. Successful active immunotherapy results in T cell recognitionand killing of cells expressing the antigen of interest. Ideally, successful Tcell mediated tumor killing should lead to epitope spreading to increase therepertoire of T cells for cytolysis, and lead to long term T cell memory.Several peptide vaccines have been investigated for these purposes, and apeptide sequence that is successful to date is the E75 HER2 peptide vaccine,otherwise known as Nelipepimut-S.2This vaccine has severalpublished clinical and preclinical reports and has been studied in aregistrational phase III study.3Nelipepimut-S, or the E75vaccine, is a 9 amino acid sequence from the extracellular domain of the HER2receptor (residues 369377 of HER2neu: KIFGSLAFL4). This 9 aminoacid sequence has long been known to be the immunologically dominant epitope ofthe protein and is presented both by HLA-A2 and HLA-A3 (HLA restricted).2,5,6Thesetwo alleles represent a majority of patients with breast cancer. HER2 is ofcourse a self-antigen, but overexpression is largely limited to breast cancers(and occasionally lung, gastric and colon cancers). Surprisingly, there doesnot appear to be negative thymic selection of HER2369-377specificT cells as shown by several groups.710Thus the E75 antigenfrom HER2 is a reasonable target for a variety of immunotherapies.

During in vitro preclinical development, the E75 peptide wasrecognized by CD8+ T lymphocytes. Subsequently, it was demonstrated thatE75-stimulated cytotoxic T lymphocytes were capable of lysis of HER2-expressingcancer cell lines.4,10,11The specificity of pulsed T cells forHER2 expressing cells was replicated in mouse models of cancer.8,12Additionally,it was found by multiple groups that lymphocytes in circulation occasionallyharbor pre-existing responses against the E75, 9 amino acid sequence HER2neu369-377usedin the subsequent development of Nelipepimut-S.6,11-13Likewise,dendritic cells from normal donor blood sources have been shown to be able topresent the E75 peptide and to generate E75-specific T cells.14

CLINICALS TRIALS WITH THE E75 PEPTIDE

The earliest Phase I pilot study of the E75 peptide inhumans also incorporated a MUC1 peptide (M1.2) in an autologous dendritic cellvaccine in breast and ovarian cancer.14Among 10 patients, CD8responses to E75 and M1.2 were observed (via intracellular interferon assay andchromium release assays) in 5 patients. The authors also reported evidence ofepitope spreading in two patients after repeat vaccination.

A study by Zaks and Rosenberg (Table 1) examined theactivity of the single E75 peptide formulated with incomplete Freunds adjuvantin various solid tumors, including breast cancer. CD8 responses were againobserved in human leukocyte antigen (HLA) -A2 and HLA-A3 patients, but anergyrather than memory was the long term outcome,15possibly due tooverstimulation related to incomplete Freunds adjuvant.

Subsequently, the E75 peptide was combined with GM-CSF toattempt to overcome the anergy suspected to be due to the incomplete Freundsadjuvant in the prior study. When combined with GM-CSF, the vaccine is termedNelipepimut-S (also previously called Neu-vax). Two phase I studies of 6 and 14patients respectively with advanced disease were completed using Nelipepimut-Sby intradermal injection, and safety was observed for up to 1000 micrograms(mcg) of Nelipepimut-S along with 250mcg of GM-CSF. Immune response wasobserved by means of ELIspot and delayed type hypersensitivity analysis.16,17Patientsreceived monthly vaccinations for up to 10 months and no dose limiting toxicitywas observed.

Given the challenge of developing an immunotherapy inheavily pre-treated metastatic patients, the Nelipepimut-S was subsequentlytested in early stage, surgically resected breast cancer patients. Testing inearly stage disease was expected to be safe given the excellent safety profileobserved in the metastatic setting. Thus, a paired set of trials (NCT00841399,NCT00584789) were performed for stage II or stage III, HER2-expressing breastcancer as defined as any immunohistochemical (IHC) staining from 1+ to 3+. Thesister clinical trials (phase II) were performed in the United States and havesince been published.7,18,19In the studies, all patients wereclinically disease-free and were permitted to use concomitant endocrinetherapies as well as prior Trastuzumab therapy. The dose and schedule wereoptimized in these early adjuvant trials. Ultimately, 195 patients wereenrolled and followed for 60 months.18,19There were 100patients vaccinated and 95 control patients. In the primary analysis, with amedian 20 months follow-up after vaccination, the recurrence rates were 5.6% vs14.2% in vaccinated vs unvaccinated participants (p=0.04).20Thusthe studies met their primary endpoint. However, for secondary analysis it wasfound that the short-term recurrence difference observed at 20 months did notpersist at any of the later analyses. For example, there was no difference inrecurrence at the 26month analysis (p=0.15) nor at 60 months (p=0.08). Therewas no difference in overall survival (OS) with p value=0.1. The authorssuggested that waning immunity due to lack of boosting contributed to the lackof long term benefit of the vaccine strategy.20Interestingly,there was a higher rate of visceral metastases in the vaccine-treated patientswhen they recurred. The toxicities of this vaccine strategy included flu-likesymptoms, fatigue, and bone pain. Less than 2% of patients experienced any highgrade toxicity (highest grade=3). The study concluded that an optimal dosewould be 1000mcg and that a potential phase III trial should be performed.

In the sister Phase II trials, boosting was explored and asuggestion of benefit was observed with boosting once every 6 months.Exploratory analysis also showed that the low-grade breast cancers seemed toderive greater benefit from Nelipepimut-S vaccination than higher grade breastcancers. In a late followup report, there was only one recurrence observed inthe 21 participants with optimal dosing of booster vaccines.18

Following completion of the phase II studies, a phase IIIstudy of Nelipepimut-S as a single agent, was designed and given the acronym,PRESENT. The PRESENT study (NCT01479244) fully accrued across 197 researchsites by Galena Biopharma Inc. PRESENT was a registrational study of 758patients with early stage, node positive breast cancer with low to intermediateHER2 expression with a primary endpoint of 3 year disease free survival (DFS).Patients received either Nelipepimut-S with GM-CSF or GM-CSF alone over thecourse of six intradermal injections followed by boosting every 6 months for 3years.3The interim analysis was published in 2019 anddemonstrated no overall difference in disease free survival (DFS) between armsat 16 months follow-up. There was a numerically higher number ofimaging-detected recurrences in the Nelipepimut-S vaccinated patients (54.1%)compared to placebo (29.2%).3The phase III PRESENT study wasdiscontinued due to futility in 2016, based on that interim analysis and thedata monitoring committee recommendation. No new safety signals were reported,and no cardiac signals were seen. The protocol design required empiriccross-sectional body imaging yearly in all patients. This imaging requirementwas a deviation from the existing standard of care (which would be for no crosssectional imaging unless symptoms arise). The required cross sectional imagingmay have impacted on the early termination of the study. The control arm had arecurrence rate comparable to rates seen in contemporary trials in early stagepatients. There is some speculation about whether pseudoprogression findingsmight have been observed in the radiographic recurrences, but biopsyconfirmation was not undertaken, so no conclusion can be drawn. Given anegative phase III result in PRESENT, there is unclear future for thedevelopment of Nelipepimut-S in the node positive, HER2-low, adjuvant breastcancer population.

COMBINATION CLINICAL TRIALS WITH NELIPEPIMUT-S

Given the challenge and phase III disappointment ofdeveloping Nelipepimut-S as a stand-alone therapy, it is now also beingexamined in combinatorial studies. Preclinical data had suggested thattrastuzumab could increase cross presentation of the E75 epitope and moreefficient expansion of specific CD8+T cells. The first phaseIIb combination trial of E75 and trastuzumab (NCT01570036) enrolled 275patients with HER2 low (IHC 1+ or 2+) breast cancer in the United States andcombined Nelipepimut-S with trastuzumab.1The patients receivedeither Nelipepimut-S with trastuzumab or trastuzumab/GM-CSF. The study designwas based on the observation, during the early phase Nelipepimut-S studies,that 12 patients were concurrently exposed to trastuzumab as a standard of careand none of those 12 patients experienced recurrent breast cancer.21Inthis newer phase IIb combinatorial study of Nelipepimut-S with trastuzumab,overall, there was no statistically significant difference in DFS (p=0.18),although there was a benefit seen in the subgroup of patients deemed to betriple negative. In this subset of 97 patients, the DFS for Nelipepimut-S plustrastuzumab was 92.6% compared with 71.9% for the trastuzumab/GM-CSF group (HR=0.26, p=0.01).1This encouraging subset finding has reportedlyled to the design of an upcoming clinical trial in the triple-negative earlystage setting.

NELIPEPIMUT-S WITH TRASTUZUMAB IN HER2 IHC3+ BREAST CANCER

In a recently completed randomized phase II trial (NCT02297698), 100 patients with traditionally-defined HER2 overexpression (IHC 3+) and otherwise high risk, non-metastatic breast cancer were enrolled to 1 to 1 randomized study of trastuzumab Nelipepimut-S and followed for DFS. This study completed accrual in 2017, and interim results demonstrated that Nelipepimut-S was well tolerated, and no significant difference in side effect profile nor cardiac ejection fraction was observed between the two arms of the study.22Clinical results have not been released to date.

TRIAL OF NELIPEPIMUT-S IN DCIS OF THE BREAST

A phase II study (NCT02636582) termed the VADIS study isassessing Nelipepimut-S against GM-CSF for ductal carcinoma in situ (DCIS) inthe neo-adjuvant window of opportunity design.23The premisefor this is supported by work published by Lowenfeld et al.24Inthis ongoing VADIS study, Nelipepimut-S or GM-CSF is given as two injectionsprior to definitive breast surgery. The primary endpoint is circulating immuneresponse at 6 months after vaccination. Secondary endpoints are toxicity andsafety. The study completed accrual in July 2019, and findings are stillpending.

OTHER E75 STUDIES IN BREAST CANCER

The potential promise of Nelipepimut-S vaccines, butnegative results in the large phase III trial, raise questions of whetheralternate vaccine formulations may induce stronger and more effective immuneresponses. A recently published study created and tested a liposomalformulation of the vaccine by attaching the E75 peptide to the surface ofdistearoyl phosphocholine and distearoyl phophoglycerol of nano-liposomes forvaccination.25ELISpot analysis and flow cytometry demonstratedsignificantly enhanced antitumor responses as well as tumor inhibition andprolonged survival time in the mouse TUBO model, which is a cell line thatoverexpresses the rHER/neu protein. Thus, this approach offers promise fortranslation to human clinical trials. There is also an ongoing autologous dendriticcell vaccine of the E75 peptide in combination with vinorelbine and trastuzumabin human cancer patients at the University of North Carolina (NCT00266110).26Finally,a series of four clinical trials performed at the University of Virginiaincorporated the E75 peptide into multipeptide vaccines for breast and ovariancancer, and using either polyICLC or incomplete Freunds adjuvant, rather thanGM-CSF (NCT00892567, NCT00304096, NCT01532960, NCT00091273). Immune responseswere detected, but clinical activity was not observed.27,28

DISCUSSION

The Nelipepimut-S vaccine alone demonstrates immune activityin patients expressing HLA-A2 or HLA-A3. As detailed above, the use of theNelipepimut-S vaccine in adjuvant breast cancer settings has not led toclinically meaningful improvements in overall survival or disease free survivalin a large randomized trial to date. Nevertheless, there are hints that thisparticular vaccine may hold potential clinical value in selected settings. Forexample, a meta-analysis of the 5 human clinical trials that involvedrandomization was performed in an effort to combine data from the smallertrials. In a published meta-analysis, the delayed hypersensitivity (DTH)responses and DFS combined data across trials suggested significant benefits tovaccination over control (p<0.05 and p=0.001 respectively). The combineddata for OS and recurrence were suggested to also have relevance (p=0.863 andp=0.388).29The conclusions of the meta-analysis do notablydiffer from some of the individual trials and obviously the patient populationshad major differences, thus rendering the impact of a meta-analysis unclear.Despite the criticisms of aggregation of data in the meta-analysis, it doessuggest that in appropriate settings that the Nelipepimut-S may have clinicalbenefits for some patients without untoward toxicity. Raw data from the large750 patient randomized phase III PRESENT trial, which was stopped for futility,was not available for analysis in that meta-analysis.

Thus, vaccine researchers in breast cancer are leftwondering which direction to focus limited resources on. Clearly there isimmunogenicity when vaccinating with the E75 peptide, and it tends todemonstrate synergy with passive antibody-based immunotherapy (ie, trastuzumabcombinations). It is also intriguing that the triple negative early stagebreast cancer population may have the greatest relative benefit afterNelipepimut-S vaccination. To date, there has been little traction indeveloping combinatorial strategies with checkpoint inhibitors or with myeloidsuppressing immunotherapy strategies. With checkpoint inhibitors approved inthe metastatic triple negative setting and expected in the triple negativeadjuvant setting, it is unclear what role peptide vaccination strategies may beable to play in the future triple negative treatment landscape.

Some remaining concerns for the E75 HER2 peptide developmentinclude the criticism that the peptide is HLA restricted and thus not availableuniversally to all patients. Also there is an unresolved question about how toaddress waning immunity and the need for long-term boosting strategies. Finally,the question about how best to select patients, especially in light of majorimmune system modulation that occurs during and immediately following adjuvantchemotherapy. It remains unknown whether the rebounding immune system in the 6months following cytotoxic chemotherapy presents a stimulatory or suppressiveenvironment for peptide vaccine generally and specifically for thisNelipepimut-S vaccine. Likewise, since HER2 targeting antibodies also impact onthe immune recognition of antigens from HER2, it is further unclear whetherearly adjuvant vaccination at the time of adjuvant HER2 antibodies or followingthe course of HER2 maintenance antibodies will be optimal.

CONCLUSION

Nelipepimut-S demonstrated immune activity against HER2positive breast cancer and suggestion of activity against triple negativebreast cancer. Its development in the adjuvant HER2 low to intermediatepopulation might be unlikely to continue based on the negative phase IIIPRESENT trial. Nevertheless, several important studies are yet to be performedfor the Nelipepimut-S and related E75 vaccines, such as combinatorial studies,novel adjuvant studies, boosting strategies, and biomarker driven studies.Recently there is rising interest in vaccine therapy for breast cancer, so thisor related vaccine strategies are likely to continue to be explored. Optimalpatient selection and monitoring may aid in future development of this cancertherapy.

Acknowledgments

Drs. Dillon, Brenin and Slingluff are supported by NCIsupport grant: 2P30CA044579-26 for the University of Virginia Cancer Center.

Disclosure

Drs. Dillon and Slingluff have published studies on peptidesreferenced in this manuscript. The University of Virginia was a subsite for aclinical trial referenced in this manuscript. Dr Dillon participated in aclinical trial for Galena Pharmaceuticals. Dr. Slingluff is an inventor onlicensed patents held by the University of Virginia Licensing and Venturesgroup for peptides used in melanoma vaccines. Dr Slingluff reports grants,non-financial support from Celldex for providing antibodies for clinical trialsand for preclinical studies. He also reports grants and/or non-financialsupport from Merck, Immatics, Polynoma, and GlaxoSmithKline; non-financialsupport from Theraclion, outside the submitted work. Dr Slingluff also in theprocess of joining the scientific advisory board with CureVac. In addition, DrSlingluff has patents on peptides used in cancer vaccines with royalties paid,a pending patent on biomarkers, a patent for a surgical device issued. Theauthors report no other conflicts of interest in this work.

Patrick M. Dillon,1Christiana M. Brenin,1Craig L. Slingluff Jr2

1University of Virginia, Division of Hematology/Oncology, Charlottesville, VA 22908, USA;2University of Virginia, Department of Surgery, Charlottesville, VA 22908, USA

Correspondence: Patrick M DillonDivision of Hematology/Oncology, University of Virginia, Box 800716, Charlottesville, VA 22908, USATel +1-434-982-1495Fax +1-434-244-7534Email Pmd5b@hscmail.mcc.virginia.edu

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Source: Breast Cancer: Targets and Therapy.Originally published April 3, 2020.

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