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Vaccine Apr 2024Malaria caused byPlasmodium vivaxis a pressing public health problem in tropical and subtropical areas.However, little progress has been made toward developing a P....
Malaria caused byPlasmodium vivaxis a pressing public health problem in tropical and subtropical areas.However, little progress has been made toward developing a P. vivaxvaccine, with only three candidates being tested in clinical studies. We previously reported that one chimeric recombinant protein (PvCSP-All epitopes) containing the conserved C-terminus of the P. vivax Circumsporozoite Protein (PvCSP), the three variant repeat domains, and aToll-like receptor-3 agonist,Poly(I:C), as an adjuvant (polyinosinic-polycytidylic acid, a dsRNA analog mimicking viral RNA), elicits strong antibody-mediated immune responses in mice to each of the three allelic forms of PvCSP. In the present study, a pre-clinical safety evaluation was performed to identify potential local and systemic toxic effects of the PvCSP-All epitopes combined with the Poly-ICLC (Poly I:C plus poly-L-lysine, Hiltonol®) or Poly-ICLC when subcutaneously injected into C57BL/6 mice and New Zealand White Rabbits followed by a 21-day recovery period. Overall, all observations were considered non-adverse and were consistent with the expected inflammatory response and immune stimulation following vaccine administration. High levels of vaccine-induced specific antibodies were detected both in mice and rabbits. Furthermore, mice that received the vaccine formulation were protected after the challenge with Plasmodium berghei sporozoites expressing CSP repeats from P. vivax sporozoites (Pb/Pv-VK210). In conclusion, in these non-clinical models, repeated dose administrations of the PvCSP-All epitopes vaccine adjuvanted with a Poly-ICLC were immunogenic, safe, and well tolerated.
Topics: Mice; Animals; Rabbits; Malaria, Vivax; Poly I-C; Polylysine; Plasmodium vivax; Protozoan Proteins; Malaria Vaccines; Mice, Inbred C57BL; Adjuvants, Immunologic; Recombinant Proteins; Epitopes; Antibodies, Protozoan; Carboxymethylcellulose Sodium
PubMed: 38448321
DOI: 10.1016/j.vaccine.2024.02.070 -
Cancer Immunology, Immunotherapy : CII Aug 2020This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding...
A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial.
BACKGROUND
This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers.
METHODS
HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients' cohort; in total, 11 patients were enrolled for the recommended dose.
RESULTS
Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival.
CONCLUSIONS
This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.
Topics: Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Carboxymethylcellulose Sodium; Cohort Studies; Female; Follow-Up Studies; Gastrointestinal Neoplasms; Glypicans; HLA-A Antigens; HLA-G Antigens; HSP70 Heat-Shock Proteins; Humans; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Peptide Fragments; Poly I-C; Polylysine; Prognosis; Survival Rate
PubMed: 32219501
DOI: 10.1007/s00262-020-02518-7 -
Cancers Oct 2022Personalized neoantigen vaccines are a highly specific cancer treatment designed to induce a robust cytotoxic T-cell attack against a patient's cancer antigens. In this... (Review)
Review
Personalized neoantigen vaccines are a highly specific cancer treatment designed to induce a robust cytotoxic T-cell attack against a patient's cancer antigens. In this study, we searched ClinicalTrials.gov for neoantigen vaccine clinical trials and systematically analyzed them, a total of 147 trials. Peptide vaccines are the largest neoantigen vaccine type, comprising up to 41% of the clinical trials. However, mRNA vaccines are a growing neoantigen vaccine group, especially in the most recent clinical trials. The most common cancer types in the clinical trials are glioma, lung cancer, and malignant melanoma, being seen in more than half of the clinical trials. Small-cell lung cancer and non-small-cell lung cancer are the largest individual cancer types. According to the results from the clinical trials, neoantigen vaccines work best when combined with other cancer treatments, and popular combination treatments include immune checkpoint inhibitors, chemotherapy, and radiation therapy. Additionally, half of the clinical trials combined neoantigen vaccines with an adjuvant to boost the immune effects, with poly-ICLC being the most recurrent adjuvant choice. This study clarifies the rapid clinical trial development of personalized neoantigen vaccines as an emerging class of cancer treatment with increasingly diversified opportunities in classes, indications, and combinatorial treatments.
PubMed: 36291947
DOI: 10.3390/cancers14205163 -
NPJ Vaccines May 2023Immunization with the Amastigote Surface Protein-2 (ASP-2) and Trans-sialidase (TS) antigens either in the form of recombinant protein, encoded in plasmids or human...
Immunization with the Amastigote Surface Protein-2 (ASP-2) and Trans-sialidase (TS) antigens either in the form of recombinant protein, encoded in plasmids or human adenovirus 5 (hAd5) confers robust protection against various lineages of Trypanosoma cruzi. Herein we generated a chimeric protein containing the most immunogenic regions for T and B cells from TS and ASP-2 (TRASP) and evaluated its immunogenicity in comparison with our standard protocol of heterologous prime-boost using plasmids and hAd5. Mice immunized with TRASP protein associated to Poly-ICLC (Hiltonol) were highly resistant to challenge with T. cruzi, showing a large decrease in tissue parasitism, parasitemia and no lethality. This protection lasted for at least 3 months after the last boost of immunization, being equivalent to the protection induced by DNA/hAd5 protocol. TRASP induced high levels of T. cruzi-specific antibodies and IFNγ-producing T cells and protection was primarily mediated by CD8 T cells and IFN-γ. We also evaluated the toxicity, immunogenicity, and efficacy of TRASP and DNA/hAd5 formulations in dogs. Mild collateral effects were detected at the site of vaccine inoculation. While the chimeric protein associated with Poly-ICLC induced high levels of antibodies and CD4 T cell responses, the DNA/hAd5 induced no antibodies, but a strong CD8 T cell response. Immunization with either vaccine protected dogs against challenge with T. cruzi. Despite the similar efficacy, we conclude that moving ahead with TRASP together with Hiltonol is advantageous over the DNA/hAd5 vaccine due to pre-existing immunity to the adenovirus vector, as well as the cost-benefit for development and large-scale production.
PubMed: 37258518
DOI: 10.1038/s41541-023-00676-0 -
Journal of Pediatric Hematology/oncology Aug 2014Brain tumors are the most common solid tumor diagnosed in childhood that account for significant morbidity and mortality. New therapies are urgently needed; hence, we...
Brain tumors are the most common solid tumor diagnosed in childhood that account for significant morbidity and mortality. New therapies are urgently needed; hence, we conducted the first ever prospective open-label phase II trials of the biological response modifier, poly-ICLC, in children with brain tumors. Poly-ICLC is a synthetic double-stranded RNA that has direct antiviral, antineoplastic, and immune adjuvant effects. A total of 47 children representing a variety of brain tumor histopathologic subtypes were treated with poly-ICLC. On the basis of the results of the initial phase II trial, an expanded prospective phase II trial in low-grade glioma (LGG) has been initiated. MRI was used to acquire volume-based measures of tumor response. No dose-limiting toxicities have been observed. In the initial study 3 of 12 subjects with progressive high-grade gliomas (HGGs) responded, and 2 of 4 children with progressive LGG experienced stable disease for 18 to 24 months. In the follow-up LGG phase II study, 2 of 5 LGG patients were stable over 18 months, with 1 stable for 6 months. Overall 5 of 10 LGG patients have responded. On the basis of low toxicity and the promising LGG response, poly-ICLC may be effective for childhood LGG, and the results justify biomarker studies for personalization of poly-ICLC as a single agent or adjuvant.
Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboxymethylcellulose Sodium; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Glioma; Humans; Infant; Magnetic Resonance Angiography; Male; Neoplasm Grading; Poly I-C; Polylysine; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 24309609
DOI: 10.1097/MPH.0000000000000047 -
Neuro-oncology Jul 2019Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we...
BACKGROUND
Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients.
METHODS
Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses.
RESULTS
The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
CONCLUSION
We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.
TRIAL REGISTRATION
Clinicaltrials.gov NCT01920191.
Topics: Adult; Aged; Astrocytoma; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Chemoradiotherapy; Combined Modality Therapy; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Middle Aged; Peptides; Poly I-C; Polylysine; Prognosis; Survival Rate; Vaccines, Subunit; Young Adult
PubMed: 30753611
DOI: 10.1093/neuonc/noz040 -
Clinical Cancer Research : An Official... Oct 2018Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and...
Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells. In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood. Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (
poly-ICLC treatment, including upregulation of genes associated with chemokine activity, T-cell activation, and antigen presentation. Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). . Topics: Aged; Biopsy; Carboxymethylcellulose Sodium; Drug Administration Schedule; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Immunologic Factors; Immunomodulation; Injections, Intralesional; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Pilot Projects; Poly I-C; Polylysine; Prognosis; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 29950349
DOI: 10.1158/1078-0432.CCR-17-1866 -
Frontiers in Immunology 2019Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if... (Randomized Controlled Trial)
Randomized Controlled Trial
Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants ( = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4 T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4 T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV subjects indicating promise as an adjuvant for HIV therapeutic vaccines. www.ClinicalTrials.gov, identifier: NCT02071095.
Topics: Adult; CD4-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Double-Blind Method; Female; HIV; HIV Infections; Humans; Immunity, Innate; Male; Middle Aged; Poly I-C; Polylysine; Toll-Like Receptor 3
PubMed: 31024557
DOI: 10.3389/fimmu.2019.00725 -
Research Square Sep 2023Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been...
UNLABELLED
Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01204684.
PubMed: 37790490
DOI: 10.21203/rs.3.rs-3287211/v1 -
Cancer Immunology, Immunotherapy : CII Feb 2017The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory... (Review)
Review
The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system's way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.
Topics: Animals; Cancer Vaccines; Disease Models, Animal; Humans; Melanoma, Experimental; Vaccines, Subunit; Virus Diseases
PubMed: 27052572
DOI: 10.1007/s00262-016-1834-5