Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39’: An analysis of safety and immune response

Vreeland, Timothy J.; Litton, Jennifer K.; Qiao, Na; Philips, Anne V.; Alatrash, Gheath; Hale, Diane F.; Jackson, Doreen O.; Peace, Kaitlin M.; Greene, Julia M.; Berry, John; Clifton, Guy T.; Peoples, George E.; Mittendorf, Elizabeth A.

doi:10.1016/j.clim.2018.03.010

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…Furthermore, OC patients with high FRα expression have reduced relapse-free survival (RFS) and overall survival (OS) rates relative to patients with low FRα expression 8 . Numerous other studies have validated FRα as a target antigen for diverse approaches to OC immunotherapy, including tumor vaccines, antibody treatment, and CAR-T cells [9][10][11][12][13][14][15][16][17][18][19] . We tested OC (and breast cancer) patients for spontaneous immune responses to putative HLA class II-binding epitopes and identified five FRαderived epitopes to which patients (but not healthy volunteers) exhibit an immune response 20 .…”

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confidence: 99%

Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients

et al. 2020

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In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.

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confidence: 99%

Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients

et al. 2020

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“…The benefit of boosting in this trial must be interpreted with caution as only patients who remained disease‐free 12 months after enrollment received boosters, creating some inherent bias in the comparison to the control group. We have, however, shown the efficacy of boosting in previous trials, and will continue to incorporate booster inoculations into future studies . With respect to boosting with full strength or attenuated peptides, the current study serves to show the safety of this approach, but additional trials with higher power are needed to elucidate any differences.…”

Section: Discussionmentioning

confidence: 94%

“…In contrast with this finding, however, there are concerns that repeated stimulation by a single immunogenic TAA may lead to increased tolerance and decreased immunologic memory over time . For this reason, we have developed an attenuated version of the E39 vaccine, E39′ (EIWTFSTKV, also known as J65), which has been shown in preclinical testing to induce effective FBP‐specific cytotoxicity and has shown efficacy when combined with E39 in an early clinical trial . Given concerns about repeated stimulation with the same peptide, and the promising preclinical work with E39′, we randomized patients in this trial to boosting with either E39 or E39′ to examine the long‐term immunologic effects…”

Section: Introductionmentioning

confidence: 99%

“…12 For this reason, we have developed an attenuated version of the E39 vaccine, E39′ (EIWTFSTKV, also known as J65), which has been shown in preclinical testing to induce effective FBP-specific cytotoxicity and has shown efficacy when combined with E39 in an early clinical trial. 13 Given concerns about repeated stimulation with the same peptide, and the promising preclinical work with E39′, we randomized patients in this trial to boosting with either E39 or E39′ to examine the long-term immunologic effects. 14 We have completed a prospective phase I/IIa trial of E39 + granulocyte macrophage-colony stimulating factor (GM-CSF) to prevent recurrence in endometrial and ovarian cancer patients at high risk for recurrence after being rendered disease-free by standard of care therapy.…”

Section: Introductionmentioning

confidence: 99%

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Final analysis of a phase I/IIa trial of the folate‐binding protein‐derived E39 peptide vaccine to prevent recurrence in ovarian and endometrial cancer patients

et al. 2019

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Background E39, an HLA‐A2‐restricted, immunogenic peptide derived from the folate‐binding protein (FBP), is overexpressed in multiple malignancies. We conducted a phase I/IIa trial of the E39 + GM‐CSF vaccine with booster inoculations of either E39 or E39′ (an attenuated version of E39) to prevent recurrences in disease‐free endometrial and ovarian cancer patients(pts). Here, we present the final 24‐month landmark analysis. Patients and methods HLA‐A2 + patients receiving E39 + GM‐CSF were included in the vaccine group (VG), and HLA‐A2‐ pts (or HLA‐A2 + patients refusing vaccine) were followed as the control group (CG). VG group received 6 monthly inoculations as the primary vaccine series (PVS) and were randomized to receive either E39 or E39′ booster inoculations. Demographic, safety, immunologic, and disease‐free survival (DFS) data were collected and evaluated. Results Fifty‐one patients were enrolled; 29 in the VG and 22 in the CG. Fourteen patients received <1000 μg and 15 received 1000 μg of E39. There were no clinicopathologic differences between VG and CG or between dose groups. E39 was well tolerated. At the 24 months landmark, DFS was 55.5% (VG) vs 40.0% (CG), P = 0.339. Patients receiving 1000 μg and boosted patients also showed improved DFS ( P < 0.03). DFS was improved in the 1000 μg group after treatment of primary disease (90.0% vs CG:42.9%, P = 0.007), but not in recurrent patients. In low‐FBP expressing patients, DFS was 100.0% (1000 μg), 50.0% (<1000 μg), and 25.0% (CG), P = 0.029. Conclusions This phase I/IIa trial reveals that E39 + GM‐CSF is safe and may be effective in preventing recurrence in high‐risk ovarian and endometrial cancer when optimally dosed (1000 μg) to FBP low patients being treated for primary disease.

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“…They also synthesized peptide 1412 (QPEQQETKKEEQ) and this peptide showed outstanding binding activity to most of the applied MHCs ( Mahdavi and Moreau, 2016 ). Peptide E39 (EIWTHSYKV) ( Vreeland et al, 2018 ) was combined with peptide E39’ (EIWTFSTKV), an attenuated version of E39. Immune analyses suggested that the optimal cytotoxic T lymphocyte population was induced by administering with E39 and E39’ in t urn.…”

Section: Peptide-based Cancer Vaccinesmentioning

confidence: 99%

Recent advances in peptide-based therapeutic strategies for breast cancer treatment

Duns

Dessie

et al. 2023

Front. Pharmacol.

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Breast cancer is the leading cause of cancer-related fatalities in female worldwide. Effective therapies with low side effects for breast cancer treatment and prevention are, accordingly, urgently required. Targeting anticancer materials, breast cancer vaccines and anticancer drugs have been studied for many years to decrease side effects, prevent breast cancer and suppress tumors, respectively. There are abundant evidences to demonstrate that peptide-based therapeutic strategies, coupling of good safety and adaptive functionalities are promising for breast cancer therapy. In recent years, peptide-based vectors have been paid attention in targeting breast cancer due to their specific binding to corresponding receptors overexpressed in cell. To overcome the low internalization, cell penetrating peptides (CPPs) could be selected to increase the penetration due to the electrostatic and hydrophobic interactions between CPPs and cell membranes. Peptide-based vaccines are at the forefront of medical development and presently, 13 types of main peptide vaccines for breast cancer are being studied on phase III, phase II, phase I/II and phase I clinical trials. In addition, peptide-based vaccines including delivery vectors and adjuvants have been implemented. Many peptides have recently been used in clinical treatments for breast cancer. These peptides show different anticancer mechanisms and some novel peptides could reverse the resistance of breast cancer to susceptibility. In this review, we will focus on current studies of peptide-based targeting vectors, CPPs, peptide-based vaccines and anticancer peptides for breast cancer therapy and prevention.

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Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39’: An analysis of safety and immune response

Abstract: NCT02019524.

Cited by 9 publications

References 23 publications

Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients

Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients

Final analysis of a phase I/IIa trial of the folate‐binding protein‐derived E39 peptide vaccine to prevent recurrence in ovarian and endometrial cancer patients

Recent advances in peptide-based therapeutic strategies for breast cancer treatment

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