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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3426-3433 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7842 Results of the First Phase I Clinical Trial of the Novel Ii-Key Hybrid Preventive HER-2/neu Peptide (AE37) Vaccine
From the Department of Medicine, Division of Hematology and Medical Oncology, Naval Medical Center San Diego, San Diego, CA; Department of Surgery, General Surgery Service, Brooke Army Medical Center, Fort Sam Houston; The University of Texas, M.D. Anderson Cancer Center, Houston, TX; Department of Medicine, Hematology and Medical Oncology Service, Walter Reed Army Medical Center, Washington, DC; Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD; Joyce Murtha Breast Care Center, Windber Medical Center, Windber, PA; and Antigen Express, Worchester, MA Corresponding author: COL George E. Peoples, MD, FACS, Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX, 78234; e-mail: george.peoples{at}amedd.army.mil
Purpose HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4+ T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four–amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients. Patients and Methods The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 µg, 500 µg, 1,000 µg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 µg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [3H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790). Results All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 µg; GM-CSF, 250 µg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36. Conclusion The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu–specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.
Breast cancer is the most common cancer in women. Treatment is multimodal, including surgery, chemotherapy, radiation, and immunotherapy, as indicated.1,2 Despite this intensive therapy, many women with high-risk features, such as overexpression of HER-2/neu protein, will develop recurrent disease.3 HER-2/neu is a member of the epidermal growth factor receptor family, normally expressed during fetal development and overexpressed in 30% of breast cancer.4 This protein is also a source of immunogenic peptides.5,6 Immunogenic peptides of HER-2/neu stimulate cytotoxic T lymphocytes (CTLs) to recognize and kill HER-2/neu–expressing cancer cells in vitro.5,6 Some of the peptides (E75 and GP2) are being used as clinical vaccines in patients with HER-2/neu–positive breast cancer.7,8 Thus far, they have been shown to be safe and effective in stimulating antigen-specific immunity; more importantly, we have shown that the immunity conferred by E75 seems to have clinical benefit in decreasing breast cancer recurrence.9 Unfortunately, vaccine-induced immunity is not sustained without booster vaccinations.9,10 CD4+ T-helper peptides may be required to increase efficiency of induction and establishment of long-term immunity.11,12 CD4+ T-helper peptides for HER-2/neu have been described; the first was G89 (HER-2/neu: 777-789) by Tuttle et al.13 A similar peptide (HER-2/neu:776-790) was used in combination with two other peptides by Disis et al,14 producing encouraging immunologic responses. A novel method to increase antigen-specific stimulation of T-helper cells has been the use of the invariant protein (Ii-Key). Specifically, the addition of a four–amino-acid sequence (LRMK) added to T-helper peptides facilitates direct antigenic epitope charging of major histocompatibility complex (MHC) class II molecules at the cell surface.15,16 This enhanced epitope charging and concomitant increase in antigen presentation can increase potency 250 times or more compared with the unmodified class II epitope in vitro.17,18 Animal models have shown Ii-Key hybrid methodology to be highly efficient using melanoma peptides, but no human data exist to date applying this hybrid peptide.19 AE37 is the Ii-Key hybrid of HER-2/neu peptide 776 to 790 (AE36). We have performed a phase Ib trial of AE37 peptide vaccine in HER-2/neu–positive breast cancer patients to document safety and measure immunologic responses to escalating vaccine doses. The results of the first human trial of the Ii-Key hybrid technology are reported here.
Patient Characteristics and Clinical Protocol The trial was institutional review board approved and conducted at Walter Reed Army Medical Center (Washington, DC) under investigational new drug application #12,229. All patients had histologically confirmed, node-negative breast cancer and completed standard course of surgery, chemotherapy, and radiation (as required) before enrollment. Patients receiving hormonal therapy continued their regimens. After proper counseling/consent, breast cancer patients were enrolled and HLA typed (DNA genomic typing). Before vaccination, patients were skin tested with a panel of recall antigens (Mantoux test). Patients were considered immunocompetent if they reacted (> 5 mm) to two or more antigens.
Vaccine
Vaccination Series The study was performed as a dose escalation trial to define vaccine and GM-CSF optimal dosing. Each dosing group consisted of three patients. The first three dose groups (patients A1-A9) received escalating amounts of AE37 peptide and fixed initial GM-CSF dose (Table 1). GM-CSF dose was chosen on the basis of our previous E75 trials. GM-CSF was reduced 50% in subsequent inoculations for local reactions of 100 mm or more or grade 2 systemic toxicities. The cutoff of 100 mm was determined from previous experience; at 100 mm and greater, the sites become confluent and local toxicity increases, and our goal is to minimize toxicity and prevent skin disruptions. All patients received six monthly inoculations. Because each patient in the 500:250:6 group (patients A4-A6) required multiple GM-CSF reductions, the 1,000:0:6 group (patients A7-A9) was inoculated without GM-CSF. One patient in this group (1,000:0:6) failed to respond with a local reaction during inoculations 1 to 3, so on the fourth inoculation, GM-CSF was reinstated to produce a local reaction. The two subsequent dose groups (patients A10-A15) received a fixed dose of AE37 (500 µg) with varying GM-CSF (Table 1).
Toxicity
Control Peptides and Proteins
Peripheral-Blood Mononuclear Cell Isolation and Cultures
Proliferation Assay
Delayed-Type Hypersensitivity
Statistical Analysis
Patients We enrolled and vaccinated 15 disease-free, node-negative breast cancer patients all expressing varying levels of HER-2/neu (ranging from IHC 1+ to 3+). No patient withdrew from this study. Patient demographics, prognostic factors, and treatment profiles are presented in Table 2.
Vaccine and Vaccination Series Table 1 provides the dose escalation strategy utilized, and Figure 1 illustrates the robust local reactions to the hybrid vaccine. GM-CSF dose reductions (or peptide if no GM-CSF), as dictated by local or systemic reactions, are depicted. Dose groups are designated as peptide(µg):GM-CSF(µg):number of inoculations. The first group (100:250:6) required no dose reductions. However, all three patients in the second group (500:250:6) required GM-CSF dose reduction by the third vaccination. Given the significant local reactions, the third group (1,000:0:6) was initiated without GM-CSF; two of three patients in this group required reduction of peptide from 1,000 µg. Another patient in this group did not show a strong local response, and GM-CSF was added back to the patients' vaccine schedule on the fourth inoculation in an escalating fashion. For the latter dose groups, a fixed amount of peptide (500 µg) was administered with varying GM-CSF doses. Dose reductions occurred in all patients in the 500:125:6 dose group, but later in the vaccination series compared with the 500:250:6 group. No reductions occurred in the patients in the 500:30:6 dose group.
Combined Dosing Group Results There were no grade 3 to 5 toxicities among the 15 patients receiving a total of 90 doses of AE37 ± GM-CSF. Among all patients, maximum local toxicities were grade 1 (40%) or grade 2 (60%). Maximum systemic toxicity was mild; grade 0 (13%), grade 1 (73%), and grade 2 (13%). Grade 1 toxicities included fatigue, nausea, myalgias, rhinitis, diarrhea, headache, and cough. Grade 2 toxicities included joint pain and stiffness. Local reaction measurement of 100 mm or greater in duration or systemic grade 2 toxicity caused 47% of patients to undergo dose reductions. Taken as a whole, the vaccine is safe with minimal local and systemic toxicity, as depicted in Figure 2A.
The AE37 peptide vaccine was capable of eliciting an immune response both in vitro and in vivo. To assess in vitro immune response, we analyzed peptide-induced proliferation of T lymphocytes by [3H]thymidine incorporation. The average proliferative response to AE36 and AE37 increased significantly pre- to postvaccine (1 month postcompletion), and prevaccine to long term (6 months postcompletion; Fig 2B). The vaccine's in vivo effectiveness was demonstrated by significantly increased DTH comparing pre- with postvaccination (1 month postcompletion) reactions (Fig 2C). Overall, all doses of AE37 were highly immunogenic.
Toxicity per Dosing Group
Immunologic Response per Dosing Group Proliferation assays. Mean proliferative responses to AE37 by dose group increased significantly pre- to postvaccine in all dose groups (Fig 4A). There was a significant increase in proliferation response at long-term follow-up compared with prevaccine in all of the 500-µg peptide dosing groups. The patients also responded to AE36, the wild-type peptide (Fig 4B). The 500:125:6 dosing group demonstrated the most consistent proliferative responses to both AE37 and AE36 in both short- and long-term postvaccine time points. Immunologic responses were decreased in the 500:30:6 dose group.
DTH. All of the dosing groups had statistically significant increases in their pre- to postvaccine DTH responses, and reaction measurements were enhanced as peptide dose increased (Fig 4C). There was negligible decrease in DTH reactions noted with GM-CSF reduction from 250 to 125 µg, but significant DTH decrease with GM-CSF of 30 µg.
In our phase I clinical trial, we have shown the AE37 peptide vaccine to be both safe and effective in raising HER-2/neu–specific immunity both in vitro and in vivo as long as the vaccine is dosed correctly. In preclinical models, the Ii-Key hybrid peptide AE37 is more immunogenic than its wild-type counterpart23 and is more sensitive in detecting pre-existing HER-2/neu immunity.18,24 In our trial, dose reductions were required to the point of eliminating adjuvant GM-CSF altogether, demonstrating potency of the hybrid peptide vaccine. The goal of our phase I testing was to determine safety and optimal biologic dose (OBD) with an emphasis on the community; that is, striking a balance between stimulating as strong an immune response as possible without the need for dose reductions so the vaccine can be administered safely and effectively to a large population. The OBD of the novel AE37 hybrid vaccine seems to be 500 µg of peptide with GM-CSF more than 30 µg and less than 125 µg. The OBD was established in two parts: the peptide dose and adjuvant dose. The optimal AE37 peptide dose (500 µg) is based on the fact that two of three patients receiving 1,000 µg of peptide required reduction in peptide to less than 250 µg by the end of their vaccine series, as well as the fact that all patients receiving 500 µg AE37 showed significant immune responses that were sustained long term (Fig 4). We propose a GM-CSF dose of 62.5 µg because 250 and 125 µg of immunoadjuvant were equivalent immunologically, but had significant local and systemic reactions requiring dose reductions, whereas 30 µg was well tolerated but had decreased immunologic response. GM-CSF has been used in our laboratory as an immunoadjuvant on the basis of previous data from animal and human trials in breast25 and melanoma.26 A randomized clinical trial in melanoma revealed that GM-CSF and Q2-21 were superior to incomplete Freund's adjuvant.26 Even at low doses (< 80 µg), immune response was induced with increasing vaccine doses.26,27 The 62.5-µg GM-CSF dose is consistent with these findings. We are proceeding with this dose in our phase II trial further investigating the AE37 hybrid vaccine. As stated, our goals are to provide a safe vaccine at a consistent dose that stimulates a reproducible immune response in the general public. Peptide vaccine trials have been ongoing for many years and have focused predominately on stimulating CTLs, which can directly kill tumor cells but lack long-lasting immunity. This AE37 peptide vaccine focuses on stimulating CD4+ T-helper cells with two goals: immunologic memory and persistent stimulation of CTLs.28 This concept is being studied by others, including Disis et al,29 who are performing ongoing breast cancer clinical trials with class II peptide vaccines. In melanoma there are other class II peptide vaccines in clinical trials, but this is the first clinical trial using the Ii-Key modification.30-33 The hybrid AE37 vaccine has been designed to overcome some of the problems with peptide vaccines. By taking advantage of the Ii-Key protein interaction with class II MHC molecules, AE37 is able to directly charge MHC class II molecules with the antigenic epitope of HER-2/neu, bypassing the normal antigen processing pathway. The antigen can then be presented to the immune system, stimulating a specific CD4-positive T lymphocyte response. When compared with an unmodified epitope, these Ii-Key/antigenic epitope hybrids can display 250 times the potency or greater in vitro.17,18 Because of the increased potency of these hybrids in stimulating immune responses, it has been suggested that less efficiency in the interaction between epitope and MHC class II molecule can be tolerated, such that these hybrids may be active in individuals having HLA alleles with which the wild-type epitope interacts only weakly. In our hands, the hybrid vaccine AE37 is sufficiently potent, that at times peptide did not require the use of immunoadjuvant GM-CSF. Historically, peptides alone are minimally immunogenic and require coadministration with immunologic adjuvants to induce detectable T-cell responses.34,35 Local and systemic reactions in the second dose group (500:250:6) necessitated dose reductions in all three patients, so the third dose group (1,000:0:6) was initiated without GM-CSF. As noted earlier, two of three patients in this group developed robust local reactions without GM-CSF and required reductions in peptide dose. Additionally, three patients in other dose groups required reductions of GM-CSF to the point of receiving peptide-only vaccinations. Further evidence of vaccine potency is seen in DTH reactions; the DTH reaction for AE37 is double the size of optimally dosed E75-peptide vaccine patients.9 To our knowledge, this is the first peptide vaccine tested in humans not requiring an immunoadjuvant. Stimulating CD4+ T-helper cells is thought to be the key to long-term immunity, but there have been concerns implicating a subset of these cells with tissue destruction, tumorigenesis, and autoimmune diseases.11 The cells associated with these pathologies are classified as CD4+CD25+FoxP3-positive T-regulatory cells (Tregs).36,37 Because of these theoretical concerns, and because Tregs are elevated in breast cancer patients,38 we have measured Tregs in our AE37 trial. Although there was no change in the total CD4+ population (prevaccination, 52.4%; postvaccination, 51.0%; P = .5), Tregs as measured by FoxP3 (1+) in nine patients statistically decreased (prevaccination, 2.1%; postvaccination, 1.0%; P = .0008). Further analysis on all 15 AE37 trial patients is currently underway (manuscript in preparation).39,40 At present, it is unclear whether the decrease in Tregs is a result of the peptide vaccine or immunoadjuvant; this is being addressed in our phase II trial with a control arm, consisting of GM-CSF alone. One limitation of peptide vaccines has been the preferential binding of peptides to certain MHC class I and II molecules. E75 (HER-2/neu:369-377) binds to HLA-A2–positive/A3–positive patients, and Tuttle13,41,42 has suggested that G89 peptide is preferentially recognized by HLA-DR4–positive patients; however, Salazar et al43 have presented findings that the parent epitope in AE37, HER-2/neu:776-790 (which contains G89) interacts with a variety of MHC class II alleles. Whether the Ii-Key moiety in AE37 confers additional MHC class II promiscuity to the HE2/neu epitope it contains is unclear. Variability was seen within dose groups suggesting binding preferences. Additional studies are being performed to determine optimal HLA-DR types for this specific vaccine. There are numerous potential and theoretical advantages of HER-2/neu–directed vaccination therapies compared with other directed therapies like trastuzumab. These advantages include ease of administration, decreased systemic toxicity, broad applicability to all levels of HER-2/neu expression (1+ to 3+), and, most importantly, stimulation of broad immunologic response to include memory response with continued benefit after therapy is completed. In conclusion, the hybrid AE37 vaccine seems safe and elicits a HER-2/neu–specific immune response, even without use of an adjuvant. A multicenter phase II trial of the AE37 vaccine is presently underway to further assess these intriguing findings. Eventually, our goal is to develop a combination multiepitope vaccine to stimulate antigen-specific CTL responses both directly and indirectly.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Eric von Hofe, Antigen Express Inc (C) Consultant or Advisory Role: None Stock Ownership: Eric von Hofe, Antigen Express Inc Honoraria: None Research Funding: George E. Peoples, Antigen Express Inc Expert Testimony: None Other Remuneration: None
Conception and design: George E. Peoples Financial support: Eric von Hofe Provision of study materials or patients: George E. Peoples Collection and assembly of data: Jarrod P. Holmes, Matthew T. Hueman, Asna Amin, Sathibalan Ponniah, George E. Peoples Data analysis and interpretation: Jarrod P. Holmes, Linda C. Benavides, Jeremy D. Gates, Mark G. Carmichael, Matthew T. Hueman, Elizabeth A. Mittendorf, James L. Murray, Dianna Craig, Sathibalan Ponniah, George E. Peoples Manuscript writing: Jarrod P. Holmes, Linda C. Benavides, Jeremy D. Gates, Mark G. Carmichael, Sathibalan Ponniah, George E. Peoples Final approval of manuscript: George E. Peoples
Supported by the United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences; the Department of Clinical Investigation, Walter Reed Army Medical Center; and Antigen Express Inc. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. National Cancer Institute SEER Surveillance Epidemiology and End Results Cancer Statistics Review, 1975-2003: Summary Figures and Tables. 2006. http://seer.cancer.gov/csr/1975_2003/ 2. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxol or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-820, 2006 3. Pritchard KI, Shepherd LE, O'Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103-2111, 2006 4. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 5. Fisk B, Blevins TL, Wharton JT, et al: Identification of immunodominant peptide of the HER2/neu proto-oncogene recognized by ovarian tumor-specific CTL lines. J Exp Med 181:2109-2117, 1995 6. Peoples GE, Goedegburre PS, Smith R, et al: Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci U S A 92:432-436, 1995 7. Peoples GE, Gurney JM, Hueman MT, et al: Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high risk breast cancer patients. J Clin Oncol 23:7536-7545, 2005 8. Mittendorf E, Storrer C, Foley R: Evaluation of the HER2/neu-derived peptide GP2 for use in peptide-based breast cancer vaccine trial. Cancer 106:2309-2317, 2006[Medline] 9. Peoples GE, Holmes JP, Hueman MT, et al: Combined clinical trial results of a HER2/neu (E75) vaccine for prevention of recurrence in high-risk breast cancer patients: United States Military Cancer Institute Clinical Trials Group Study I-01 & I-02. Clin Cancer Res 14:797-803, 2008 10. Knutson KL, Schiffman K, Cheever MA, et al: Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369-377, results in short-lived peptide-specific immunity. Clin Cancer Res 8:1014-1018, 2002 11. Knutson KL, Disis ML: Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. 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Wong R, Lau R, Change J, et al: Immune responses to a class II helper peptide epitope in patients with stage III/IV resected melanoma. Clin Cancer Res 10:5004-5013, 2004 31. Phan GQ, Touloukian CE, Yang JC, et al: Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens. J Immunother 26:349-356, 2003[CrossRef][Medline] 32. Kobayashi H, Lu J, Celis E: Identification of helper T-cell epitopes that encompass or lie proximal to cytotoxic T-cell epitopes in the gp100 melanoma tumor antigen. Cancer Res 61:7577-7584, 2001 33. Kallinteris NL, Lu X, Wu S, et al: Ii-Key/MHC class II epitope hybrid peptide vaccines for HIV. Vaccine 21:4128-4132, 2003[CrossRef][Medline] 34. Jäeger E, Bernhard H, Romero P, et al: Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: Implications for tumor vaccines with melanoma-associated antigens. 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Hueman MT, Stojadinovic A, Storrer CE, et al: Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. Br Cancer Res Treat 98:17-29, 2006[CrossRef][Medline] 40. Hueman MT, Holmes JP, Storrer CE, et al: Immune monitoring of CD4+CD25+FoxP3+ regulatory T cells in a novel HLA Class-II HER2/neu peptide vaccine clinical trial in breast cancer patients. Ann Surg Oncol S14:91, 2007 (suppl; abstr) 41. Parker KC, Bednarek MA, Coligan JE: Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side chains. J Immunol 152:163-175, 1994[Abstract] 42. Patil R, Holmes JP, Amin A, et al: Clinical and immunologic responses of HLA-A3+ breast cancer patients vaccinated with the HER2/neu-derived peptide vaccine, E75, in a phase I clinical trial. Br Cancer Res Treat 106:S123-S124, 2007 (suppl) 43. Salazar LG, Fikes J, Southwood S, et al: Immunization of cancer patients with HER-2/neu-derived peptides demonstrating high-affinity binding to multiple class II alleles. Clin Cancer Res 9:5559-5565, 2003 Submitted December 15, 2007; accepted March 25, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test as appropriate. P values for comparing pre- and postvaccine proliferative assays and DTH were calculated using the t test, paired or unpaired, as appropriate. 
100 mm in duration necessitated 50% dose reduction in GM-CSF (dashed lines). GM-CSF and local reaction dosing groups: (A) 100:250:6, (B) 500:250:6, (C) 1,000:0:6, (E) 500:125:6, and (F) 500:30:6. (D) Peptide and local reaction dosing group 1,000:0:6. The 1,000-µg peptide dose group did not receive GM-CSF initially. (C) One patient required addition of GM-CSF due to low reactivity, but (D) two patients required peptide dose reductions due to robust reactions.
-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151-1164, 1995
