Haptoglobin Proved a Prognostic Biomarker in Peripheral Blood of Patients with Personalized Peptide Vaccinations for Advanced Castration-Resistant Prostate Cancer

Pang, Xiaoliang; Tashiro, Kosuke; Eguchi, Rieko; Komatsu, Nobukazu; Sasada, Tetsuro; Itoh, Kyogo; Kuhara, Satoru

doi:10.1271/bbb.120893

Cited by 10 publications

(7 citation statements)

References 26 publications

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“…The present study showed that both CTL and IgG responses, favorable markers for a cancer vaccine as reported previously, were more frequently increased after the vaccination of patients in the 20‐mg cohort as compared with the other two groups. In contrast, soluble inflammatory factors, including C‐reactive protein and haptoglobin, which are unfavorable markers for cancer vaccines as previously reported, were somewhat increased after the vaccination of patients in the 10‐mg group. These results suggest that a dose of 20 mg of KRM‐10 should be recommended for any future phase II study for not only its observed safety but also because of the demonstration of having the most potent activity that augments the immune response, with minimal effects on soluble inflammatory factors among the three different doses tested.…”

Section: Discussionsupporting

confidence: 64%

“…It has been well documented that efficiently primed CTL induced by cancer vaccines often lose their responsiveness to tumor cells, primarily due to immunosuppression by Tregs and myeloid‐derived suppressor cell (MDSC), and also by T cell inhibition mediated by checkpoint molecules, such as CTL‐associated protein 4 (CTLA‐4) and programmed cell death 1 (PD‐1) . Acute‐phase inflammatory factors, including C‐reactive protein, haptoglobin, serum amyloid A and IL‐6, are well known soluble mediators for Treg‐induced and MDSC‐induced suppression against vaccine‐induced immune activation . Precise mechanisms involved in the phenomenon of lower and higher peptide doses (10 and 30 mg of peptides), but not the modest dose (20 mg of peptides), inducing lower levels of CTL and IgG responses are presently unknown.…”

Section: Discussionmentioning

confidence: 99%

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Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients

et al. 2016

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A phase I study of a new cancer vaccine (KRM‐10), consisting of a mixture of 10 different short peptides, was conducted for patients with advanced gastrointestinal cancers. Primary or secondary endpoints included the dose‐limiting toxicity (DLT), or safety and immune responses, respectively. Peptide‐specific cytotoxic T lymphocytes (CTL) and immunoglobulin G (IgG), together with soluble inflammatory factors, were measured before and after vaccination. Twenty‐one patients were vaccinated with KRM‐10 at dose levels of 10 (n = 6), 20 (n = 8) or 30 mg (n = 7) of peptides every week for 6 weeks. No DLT were observed in the dose range evaluated. Common treatment‐related adverse events were a grade 1 injection site reaction in 15 patients, and fever in three patients (grade 1 in two patients and grade 2 in one patient). CTL activity to at least one peptide at the time of the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively. IgG levels, at the third and sixth vaccination, were also increased in 1 and 1 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 1 and 3 of 6 (30 mg) patients, respectively. The KRM‐10 vaccine consisting of 20 mg of peptides was determined as the optimal dose for a coming phase II trial because of its safety, and also for demonstrating the most potent activity for augmenting the immune response of the three doses tested. This trial was registered at the UMIN Clinical Trials Registry as UMIN000008820.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients

et al. 2016

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“…HP mRNA expression of PBMC before vaccination was significantly lower in CRPC patients with good vaccine response than those with poor response. This gene was identified in our previous study and quantitatively validated in the small number of patients [10,11]. In humans, the HP locus is polymorphic, with two codominant alleles referred to as HP1 and HP2 that yield three distinct phenotypes (HP1-1, HP2-1, and HP2-2).…”

Section: Introductionmentioning

confidence: 86%

Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients

Araki

Pang

Komatsu

et al. 2015

Cancer Immunol Immunother

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Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in castration-resistant prostate cancer (CRPC) patients before administration of PPV. Cox regression analysis revealed that mRNA expression of myeloperoxidase, haptoglobin, and neutrophil elastase was significantly associated with overall survival (OS) among vaccinated CRPC patients (adjusted P < 0.01). By promoter sequence analysis of these three genes, we found that rs5472 of haptoglobin (HP), an acute-phase plasma glycoprotein, was strongly correlated to OS of vaccinated CRPC patients (P = 0.0047, hazard ratio 0.47; 95 % confidence interval 0.28-0.80). Furthermore, both HP mRNA expression in PBMCs and protein level in plasma of CRPC patients before administration of PPV exhibited rs5472 dependence (P < 0.001 for mRNA expression and P < 0.05 for protein level). Our findings suggest that rs5472 may play an important role in the immune response to PPV via regulation of HP. Thus, we concluded that rs5472 is a potential prognostic biomarker for PPV.

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“…Possible biomarkers with predictive roles have also been investigated. Haptoglobin levels were directly related to OS, whereas IL-6 levels were inversely associated with OS [76,78,79]. Moreover, in a post-hoc analysis of the phase III trial, a very low (<26%) or very high (>64%) proportion of lymphocytes at baseline determined an OS benefit [74].…”

Section: Other Taas and Personalized Peptide Vaccination (Ppv)mentioning

confidence: 98%

Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

et al. 2021

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Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

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Haptoglobin Proved a Prognostic Biomarker in Peripheral Blood of Patients with Personalized Peptide Vaccinations for Advanced Castration-Resistant Prostate Cancer

Cited by 10 publications

References 26 publications

Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients

Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients

Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients

Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

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