Phase i immunotherapy trial with two chimeric HER-2 B-Cell peptide vaccines emulsified in montanide ISA 720VG and Nor-MDP adjuvant in patients with advanced solid tumors

Tanios Bekaii-Saab, Robert Wesolowski, Daniel Ahn, Christina Wu, Amir Mortazavi, Maryam Lustberg, Bhuvaneswari Ramaswamy, Jeffrey Fowler, Lai Wei, Jay Overholser, Pravin T.P. Kaumaya

Research output: Contribution to journalArticle

Abstract

Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/ biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumabbinding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyldipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Original languageEnglish (US)
Pages (from-to)3495-3507
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2019

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Subunit Vaccines
Immunotherapy
B-Lymphocytes
Vaccines
Neoplasms
B-Lymphocyte Epitopes
Vaccination
T-Lymphocyte Epitopes
Oils
Therapeutics
Monoclonal Antibodies
Safety
Drug Therapy
Peptides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase i immunotherapy trial with two chimeric HER-2 B-Cell peptide vaccines emulsified in montanide ISA 720VG and Nor-MDP adjuvant in patients with advanced solid tumors. / Bekaii-Saab, Tanios; Wesolowski, Robert; Ahn, Daniel; Wu, Christina; Mortazavi, Amir; Lustberg, Maryam; Ramaswamy, Bhuvaneswari; Fowler, Jeffrey; Wei, Lai; Overholser, Jay; Kaumaya, Pravin T.P.

In: Clinical Cancer Research, Vol. 25, No. 12, 15.06.2019, p. 3495-3507.

Research output: Contribution to journalArticle

Bekaii-Saab, Tanios ; Wesolowski, Robert ; Ahn, Daniel ; Wu, Christina ; Mortazavi, Amir ; Lustberg, Maryam ; Ramaswamy, Bhuvaneswari ; Fowler, Jeffrey ; Wei, Lai ; Overholser, Jay ; Kaumaya, Pravin T.P. / Phase i immunotherapy trial with two chimeric HER-2 B-Cell peptide vaccines emulsified in montanide ISA 720VG and Nor-MDP adjuvant in patients with advanced solid tumors. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 12. pp. 3495-3507.
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T1 - Phase i immunotherapy trial with two chimeric HER-2 B-Cell peptide vaccines emulsified in montanide ISA 720VG and Nor-MDP adjuvant in patients with advanced solid tumors

AU - Bekaii-Saab, Tanios

AU - Wesolowski, Robert

AU - Ahn, Daniel

AU - Wu, Christina

AU - Mortazavi, Amir

AU - Lustberg, Maryam

AU - Ramaswamy, Bhuvaneswari

AU - Fowler, Jeffrey

AU - Wei, Lai

AU - Overholser, Jay

AU - Kaumaya, Pravin T.P.

PY - 2019/6/15

Y1 - 2019/6/15

N2 - Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/ biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumabbinding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyldipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

AB - Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/ biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumabbinding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyldipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

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