Use of tumor cell lysate to develop peptide vaccine targeting cancer-testis antigens.
Ontology highlight
ABSTRACT:
SUBMITTER: Malhotra J
PROVIDER: S-EPMC8674589 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Monoclonal antibodies have been successfully utilized as cancer-targeting therapeutics and diagnostics, but the efficacies of these treatments are limited in part by the size of the molecules and non-specific uptake by the reticuloendothelial system. Peptides are much smaller molecules that can specifically target cancer cells and as such may alleviate complications with antibody therapy. Although many endogenous and exogenous peptides have been developed into clinical therapeutics, only a subset of these consists of cancer-targeting peptides. Combinatorial biological libraries such as bacteriophage-displayed peptide libraries are a resource of potential ligands for various cancer-related molecular targets. Target-binding peptides can be affinity selected from complex mixtures of billions of displayed peptides on phage and further enriched through the biopanning process. Various cancer-specific ligands have been isolated by in vitro, in vivo, and ex vivo screening methods. As several peptides derived from phage-displayed peptide library screenings have been developed into therapeutics in current clinical trials, which validates peptide-targeting potential, the use of phage display to identify cancer-targeting therapeutics should be further exploited.
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Project description:The prognosis of patients with advanced pancreatic cancer is extremely poor and there are only a few standard treatments. Here, we report the results of a Phase I clinical trial to investigate the safety, immunostimulatory effects, and antineoplastic activity of a multi-target vaccine composed of four distinct peptides derived from cancer-testis (CT) antigens and vascular endothelial growth factor receptors (VEGFRs). Nine patients with unresectable, advanced pancreatic cancer who were refractory to standard chemotherapy were enrolled. Each patient was vaccinated with HLA-A*2402-restricted peptides derived from the CT antigens kinesin family member 20A (KIF20A) and cell division cycle-associated 1 (CDCA1) as well as from VEGFR1 and VEGFR2 subcutaneously once a week, and disease progression was evaluated up to 6 mo later. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v. 3.0. Immunological responses were monitored by ELISPOT assays and flow cytometry based on peptide-specific dextramers. The clinical outcomes that were measured were tumor response, progression-free survival (PFS) and overall survival (OS). In general, the multi-peptide vaccine was well-tolerated, and no grade 3 or 4 adverse events were observed upon vaccination. Peptide-specific T-cell responses were detected in all 9 patients, and clinical benefits were observed in four of them. Median PFS and OS were 90 and 207 d, respectively. The elicitation of multiple and robust peptide-specific T-cell responses as well as the status of host lymphocytes may be useful prognostic factors among patients with advanced pancreatic cancer treated with peptide-based anticancer vaccines.
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Project description:BackgroundNowadays, researchers are leveraging the mRNA-based vaccine technology used to develop personalized immunotherapy for cancer. However, its application against glioma is still in its infancy. In this study, the applicable candidates were excavated for mRNA vaccine treatment in the perspective of immune regulation, and suitable glioma recipients with corresponding immune subtypes were further investigated.MethodsThe RNA-seq data and clinical information of 702 and 325 patients were recruited from TCGA and CGGA, separately. The genetic alteration profile was visualized and compared by cBioPortal. Then, we explored prognostic outcomes and immune correlations of the selected antigens to validate their clinical relevance. The prognostic index was measured via GEPIA2, and infiltration of antigen-presenting cells (APCs) was calculated and visualized by TIMER. Based on immune-related gene expression, immune subtypes of glioma were identified using consensus clustering analysis. Moreover, the immune landscape was visualized by graph learning-based dimensionality reduction analysis.ResultsFour glioma antigens, namely ANXA5, FKBP10, MSN, and PYGL, associated with superior prognoses and infiltration of APCs were selected. Three immune subtypes IS1-IS3 were identified, which fundamentally differed in molecular, cellular, and clinical signatures. Patients in subtypes IS2 and IS3 carried immunologically cold phenotypes, whereas those in IS1 carried immunologically hot phenotype. Particularly, patients in subtypes IS3 and IS2 demonstrated better outcomes than that in IS1. Expression profiles of immune checkpoints and immunogenic cell death (ICD) modulators showed a difference among IS1-IS3 tumors. Ultimately, the immune landscape of glioma elucidated considerable heterogeneity not only between individual patients but also within the same immune subtype.ConclusionsANXA5, FKBP10, MSN, and PYGL are identified as potential antigens for anti-glioma mRNA vaccine production, specifically for patients in immune subtypes 2 and 3. In summary, this study may shed new light on the promising approaches of immunotherapy, such as devising mRNA vaccination tailored to applicable glioma recipients.
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Project description:Synovial sarcoma (SS) is a rare cancer that disproportionately affects children and young adults. Cancer testis antigens (CTAs) are proteins that are expressed early in embryonic development, but generally not expressed in normal tissue. They are aberrantly expressed in many different cancer types and are an attractive therapeutic target for immunotherapies. CTAs are expressed at high levels in SS. This high level of CTA expression makes SS an ideal cancer for treatment strategies aimed at harnessing the immune system to recognize aberrant CTA expression and fight against the cancer. Pivotal clinical trials are now underway, with the potential to dramatically alter the landscape of SS management and treatment from current standards of care. In this review, we describe the rationale for targeting CTAs in SS with a focus on NY-ESO-1 and MAGE-A4, the current state of vaccine and T-cell receptor-based therapies, and consider emerging opportunities for future development.
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Project description:Oncolytic viruses represent a promising therapeutic modality, but they have yet to live up to their therapeutic potential. Safety and efficacy concerns impel us to identify least toxic oncolytic agents that would generate durable and multifaceted anti-tumor immune responses to disrupt the tumors. Here we describe a rational engineered oncolytic herpes virus (OVH) that is a selective killer for targeting tumors, has strong safety records, induces complete regression of tumors in multiple tumor models, and elicits potent antitumor immunity. By far, the potential of OVs in promoting the tumor antigen-specific humoral immune responses remains obscure. In this study, we found that effective treatment by OVH induced immunogenic cell death, which facilitates to elicit humoral immune responses. Depletion experiments revealed that B cells were required for maximal antitumor efficacy of oncolytic immunotherapy. Both serum transfer and antibody treatment experiments revealed that endogenous oncolysis-induced antigen-targeting therapeutic antibodies can lead to systemic tumor regression. Our data demonstrate that tumor-targeting immune modulatory properties confer oncolytic OVH virotherapy as potent immunotherapeutic cancer vaccines that can generate specific and efficacious antitumor humoral responses by eliciting endogenous tumor antigen-targeting therapeutic antibodies in situ, resulting in an efficacious and tumor-specific therapeutic effect.
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Project description:Introduction: Triple-negative breast cancer (TNBC) is an important subtype of breast cancer, which occurs in the absence of estrogen, progesterone and HER-2 receptors. According to the recent studies, TNBC may be a cancer testis antigen (CTA)-positive tumor, indicating that the CTA-based cancer vaccine can be a treatment option for the patients bearing such tumors. Of these antigens (Ags), the MAGE-A family and NY-ESO-1 as the most immunogenic CTAs are the potentially relevant targets for the development of an immunotherapeutic way of the breast cancer treatment. Methods: In the present study, immunoinformatics approach was used to design a multi-epitope peptide vaccine to combat the TNBC. The vaccine peptide was constructed by the fusion of three crucial components, including the CD8+ cytotoxic T lymphocytes (CTLs) epitopes, helper epitopes and adjuvant. The epitopes were predicted from the MAGE-A and NY-ESO-1 Ags. In addition, the granulocyte-macrophage-colony-stimulating factor (GM-CSF) was used as an adjuvant to promote the CD4+ T cells towards the T-helper for more strong induction of CTL responses. The components were conjugated by proper linkers. Results: The vaccine peptide was examined for different physiochemical characteristics to confirm the safety and immunogenic behavior. Furthermore, the 3D-structure of the vaccine peptide was predicted based on the homology modeling approach using the MODELLER v9.17 program. The vaccine structure was also subjected to the molecular dynamics simulation study for structure refinement. The results verified the immunogenicity and safety profile of the constructed vaccine as well as its capability for stimulating both the cellular and humoral immune responses. Conclusion: Based on our in-silico analyses, the proposed vaccine may be considered for the immunotherapy of TNBC.
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Project description:While the expression of genes that are normally involved in spermatogenesis is frequently detected in tumors, the extent to which these gene products are required for neoplastic behaviors is unclear. To begin to address their functional relevance to tumorigenesis, we identified a cohort of proteins which display synthetic lethality with paclitaxel in non-small-cell lung cancer and whose expression is biased toward testes and tumors. Remarkably, these testis proteins, FMR1NB, NXF2, MAGEA5, FSIP1, and STARD6, are required for accurate chromosome segregation in tumor cells. Their individual depletion enhances the generation of multipolar spindles, increases mitotic transit time, and induces micronucleation in response to an otherwise innocuous dose of paclitaxel. The underlying basis for abnormal mitosis is an alteration in microtubule function, as their depletion increases microtubule cytaster formation and disrupts microtubule stability. Given these observations, we hypothesize that reactivated testis proteins may represent unique tumor cell vulnerabilities which, if targeted, could enhance responsiveness to antimitotic therapy. Indeed, we demonstrate that combining paclitaxel with a small-molecule inhibitor of the gametogenic and tumor cell mitotic protein TACC3 leads to enhanced centrosomal abnormalities, activation of death programs, and loss of anchorage-independent growth.
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Project description:Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a surrogate pan-immunogen that mimics both. This CMP, referred to as P10s, is the N-terminal half of a peptide vaccine named P10s-PADRE, the C-terminal half of which (PADRE) is a Pan-T-cell epitope. A Phase I dose-escalation trial of P10s-PADRE plus adjuvant MONTANIDE™ ISA 51 VG was conducted in subjects with metastatic breast cancer to test 300 and 500 ?g/injection in two cohorts of 3 subjects each. Doses of the P10s-PADRE vaccine were administered to research participants subcutaneously on weeks 1, 2, 3, 7 and 19. Antibody responses to P10s, GD2, and LeY were measured by ELISA. The P10s-PADRE vaccine induced antibodies specifically reactive with P10s, LeY and GD2 in all 6 subjects. Serum antibodies displayed Caspase-3-dependent apoptotic functionality against LeY or GD2 expressing breast cancer cell lines. Immunization with the P10s-PADRE vaccine was well-tolerated and induced functional antibodies, and the data suggest potential clinical benefit.
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Project description:INTRODUCTION:Peptide vaccines offer anti-tumor efficacy with very low toxicity. However, repeat stimulation with an immunogenic peptide leads to activation induced cell death (AICD), decreasing efficacy. We engineered variants of an immunogenic peptide (E39) and tested their ability to induce a robust, sustainable immune response. METHODS:Multiple variants of E39 were created by exchanging 1 or 2 amino acids. We tested the PBMC proliferation, cytokine production and cytolytic activity induced by each variant peptide. RESULTS:Repeated stimulation with E39 likely led to in vitro AICD, while stimulation with E39' led to T-cell proliferation with less evidence of AICD, modest cytokine production and high CTL activity. CONCLUSIONS:E39' appears to be the optimal variant of E39 for inducing effective long-term immunity.
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