Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Wiedermann, Ursula; Garner-Spitzer, Erika; Chao, Yee; Maglakelidze, Marina; Bulat, Iurie; Dechaphunkul, Arunee; Arpornwirat, Wichit; Charoentum, Chaiyut; Yen, Chia‐Jui; Yau, Thomas Cheung; Tanasanvimon, Suebpong; Maneechavakajorn, Jedzada; Sookprasert, Aumkhae; Bai, Li‐Yuan; Chou, Wen‐Chi; Ungtrakul, Teerapat; Drinić, Mirjana; Tobias, Joshua; Zielinski, Christoph; Chong, Leslie; Ede, Nicholas J.; Marino, Mark T.; Good, Anthony J.

doi:10.1158/1078-0432.ccr-20-3742

Cited by 28 publications

(51 citation statements)

References 45 publications

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“…The antitumor effect by mimotope JT-mPD1 was shown to be associated with a significant reduction of proliferation and increased apoptotic rates in the tumors in the employed Her-2/neu-expressing syngeneic tumor mouse model. Further, the antitumor effect of our Her-2/neu vaccine (HerVaxx) 62 , 63 was shown to be potentiated when combined with JT-mPD1. 39 Our ongoing investigations have further indicated that active immunization has not led to increased inflammatory responses.…”

Section: Pd-1/pd-l1 Inhibitors Under Developmentmentioning

confidence: 88%

“…We have recently shown, for the first time, the concept of vaccination with mimotopes (B-cell epitope) of anti-PD-1 mAbs. 39 Active immunization with a mimotope, as monotherapy or as a combination therapy together with our anti-Her-2/neu vaccine (HerVaxx), 62 , 63 was shown to induce a strong antitumor effect 39 in vivo , similar to the corresponding mAb ( Table 1 ). Along these lines, a peptide (PD-1-Vaxx) residing at the position 92-101 of hPD-1 was identified and shown to have a strong antitumor effect in vivo ( Table 1 ).…”

Section: Current Ongoing Clinical Trialsmentioning

confidence: 95%

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Emerging targets for anticancer vaccination: PD-1

et al. 2021

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Among the mechanisms by which tumor cells escape the immune surveillance, one is the interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1). Inhibition of the PD-1/ PD-L1 pathway with monoclonal antibodies as immune checkpoint inhibitors targeting PD-1 or its ligand, PD-L1, represents a milestone in cancer therapy. The application of these antibodies, however, suffers from drawbacks including failure to show a response or benefit in a majority of patients following monotherapy or combination therapy, their frequent administration, and cost intensiveness. Small peptides capable of interfering with PD-1/PD-L1 interaction represent interesting alternatives to antibody-based immune checkpoint inhibitors. Moreover, peptides representing PD-1 or PD-L1 sequences can be used in active immunization approaches to induce antibodies that enhance antitumor immunity by effectively preventing PD-1-mediated inhibition in the host. Importantly, such peptides can readily be combined with peptides derived from cancer antigens to effectively induce an antitumor immune response. In this review, we have summarized the recent developments in the use of small molecules and peptides either to directly block PD-1/PD-L1 interaction, or in vaccination approaches to induce antibody responses stimulating anticancer immunity by blocking PD-1-mediated T-cell inhibition.

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Section: Pd-1/pd-l1 Inhibitors Under Developmentmentioning

confidence: 88%

Section: Current Ongoing Clinical Trialsmentioning

confidence: 95%

Emerging targets for anticancer vaccination: PD-1

et al. 2021

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“…(B) A diagram depicting the development of the two generations of our Her-2/neu vaccine with the different examined formulations, and their evaluation in preclinical and clinical studies. 68 , 70 , 72 , 73 , 76 , 77 The extracellular domain (ECD) of Her-2/neu was initially subjected to computer-aided algorithms and resulted in the identification of one B-cell peptide (P4) on the ECD-III and two additional B-cell peptides (P6 and P7) on the ECD-IV. These single peptides were the basis for the different indicated formulations of our Her-2/neu vaccine’s first generation, leading to the vaccine HER-Vaxx.…”

Section: Anti-her-2/neu Vaccines Under Developmentmentioning

confidence: 99%

“… 76 Applying the mouse model, we have also shown that the combination of HER-Vaxx with immune checkpoint (PD-1) blockade enhanced the vaccine’s anti-tumor effect. 76 As described below, HER-Vaxx has been evaluated in phase Ib 77 and phase II trials 78 involving patients with Her-2/neu-overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.…”

Section: Anti-her-2/neu Vaccines Under Developmentmentioning

confidence: 99%

Vaccination against Her-2/neu, with focus on peptide-based vaccines

et al. 2022

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Immunotherapy has been a milestone in combatting cancer, by complementing or even replacing classic treatments like surgery, chemotherapy, radiation, and anti-hormonal therapy. In 15%-30% of breast cancers, overexpression of the human epidermal growth factor receptor 2 (Her-2/neu) is associated with more aggressive tumor development.Passive immunization/immunotherapy with the recombinantly produced Her-2/neu-targeting monoclonal antibodies (mAbs) pertuzumab and trastuzumab has been shown to effectively treat breast cancer and lead to a significantly better prognosis. However, allergic and hypersensitivity reactions, cardiotoxicity, development of resistance, lack of immunological memory which results in continuous application over a long period, and cost-intensiveness are among the drawbacks associated with this treatment. Furthermore, intrinsic or acquired resistance is associated with the application of therapeutic mAbs, leading to the disease recurrence. Conversely, these drawbacks could be potentially overcome by vaccination, i.e. an active immunization/immunotherapy approach by activating the patient's own immune system to target cancer, along with inducing immunological memory. This review aims to summarize the main approaches investigated and undertaken for the production of Her-2/neu vaccine candidates, with the main focus on peptide-based vaccines and their evaluation in clinical settings.

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“…Hence, accurate assessment of the ACL in patients with AGC may have important reference signi cance for clinical diagnosis, treatment and prognosis of patients with solid tumors. Now, chemotherapy, immunotherapy and immune response of vaccine have been studied in AGC patients (AGCs) [15][16][17]. Nevertheless, the ACL in AGCs in the clinical prognosis evaluation research are unknown [18].…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Significance of The Absolute Counts of Peripheral Blood Lymphocyte Subsets In Patients With Advanced Gastric Cancer

Zhang

Xia

Liu

et al. 2021

Preprint

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Background: At present, the percentages of lymphocyte subsets (PL) which mainly include CD3+, CD3+CD4+, CD3+CD8+, B and NK cells are widely focused in tumor clinic, but the absolute counts of lymphocyte subsets (ACL) are seldom concerned yet. The clinical significance and value of ACL are not clear. It is still unclear whether the immune status of advanced gastric cancer (AGC) patients, especially the PL and ACL of peripheral blood, are closely related to the disease progression and prognosis.Methods: The research was a retrospective cohort study, which including 291 patients with untreated AGC and 63 normal controls (NCs). The PL and ACL of peripheral blood were detected by flow cytometry based single-platform method. The end points were progression free survival (PFS) and overall survival (OS).Results: Compared to NCs, the percentages of CD3+, CD3+CD4+ and NK cells were no significantly different, but that of CD3+CD8+ and B cells were decrease in all AGC patients (AGCs) obviously (p = 0.022; p = 0.004, respectively). The AC of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells were significantly lower than those in the NCs (p﹤0.001). The percentages of CD3+CD8+ and B cells in AGCs with stage Ⅲ were lower than those in NCs (p = 0.032; p =0.036, respectively). But, the AC of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells in AGCs with stage Ⅲ were all significantly decrease than that of NCs (p < 0.001). Compared with normal controls, only the percentage of B cells in AGCs with stage IV was lower (p = 0.005), while the ACL in AGCs with stage IV were all significantly lower (p﹤0.001). There was no significant difference in the percentage between stage Ⅳ and Ⅲ, but the ACL in AGCs with stage Ⅳ were significantly lower than those in stage Ⅲ (p ≤ 0.001). The results showed that the ACL in AGCs were significantly impaired and were closely related to the progression of the disease. The Binary logistic regression and Kaplan-Meier showed that patients with high ACL had longer PFS and OS than those with low ACL (p < 0.0001, respectively). Multivariate analysis showed that when the number of CD3+CD4+ cells were more than 405 cells/μL, the PFS and OS of AGCs were significantly prolonged (HR 0.192, 95% CI [0.092 to 0.398], p﹤0.001; HR 0.196, 95% CI [0.093 to 0.411], p﹤0.001, respectively), and the sensitivity and specificity were the most obvious.Conclusion: The ACL in AGCs were significantly impaired, and were closely related to PFS and OS. Thereinto, the AC of CD3+CD4+ cells was the most sensitive and specific parameter for the prognosis of AGCs and have more important clinical value.Chinese Clinic Trial Registry number: ChiCTR-IOR-17014139; Registry date: 2017/12/25.

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Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001

Abstract: Clinical and immunologic responses to a B-cell epitope vaccine in HER2/neuoverexpressing advanced gastric cancer patients -results from Phase 1b trial IMU.ACS.

Cited by 28 publications

References 45 publications

Emerging targets for anticancer vaccination: PD-1

Emerging targets for anticancer vaccination: PD-1

Vaccination against Her-2/neu, with focus on peptide-based vaccines

The Prognostic Significance of The Absolute Counts of Peripheral Blood Lymphocyte Subsets In Patients With Advanced Gastric Cancer

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