Lessons learned from cancer vaccine trials and target antigen choice

Butterfield, Lisa H.

doi:10.1007/s00262-016-1801-1

Cited by 25 publications

(19 citation statements)

References 44 publications

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“…Thus, all these previous experiences with DC trials (and its failures) has led to the proposal that in order to realize the potential of DCs, it is important that multicenter phase II/III trials should be performed after standardizing the production of DC vaccines between centers [68]. The ability of DC vaccination to induce diverse neo-antigen specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition has also been implicated as one of the mechanism responsible for better tumor control [69], and needs to be considered for future immunomonitoring with the DC vaccine trials to establish its advantage over other immunotherapy regimens [70]. In addition, it has been suggested that strategy to incorporate DC-targeting via nanoparticles and combinatorial targeting of multiple human DC subsets may further improve the efficacy of DC vaccination [71].…”

Section: Discussionmentioning

confidence: 99%

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

et al. 2017

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BackgroundDendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).MethodsWe generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.ResultsTwelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.ConclusionVaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.Trial registration NCT01410968; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0459-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

et al. 2017

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“…Most antigens identified earlier as cancer-specific have been derived from self proteins. Investigated in hundreds of therapeutic clinical trials, these have been mostly clinically disappointing, partially due to central tolerance mechanisms and the elimination of high-avidity T-cells recognizing such normal proteins ( 3 – 6 ). In recent years, the remarkable clinical efficacy of the immune checkpoint blocking therapies has again motivated researchers to discover the immunogenic T-cell epitopes that mediate disease control or long-term cure ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

et al. 2017

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The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Human leukocyte antigen (HLA)-binding peptides derived from processing and presentation of mutated proteins are one of the leading targets for T-cell recognition of cancer cells. Currently, most studies attempt to identify neoantigens based on predicted affinity to HLA molecules, but the performance of such prediction algorithms is rather poor for rare HLA class I alleles and for HLA class II. Direct identification of neoantigens by mass spectrometry (MS) is becoming feasible; however, it is not yet applicable to most patients and lacks sensitivity. In an attempt to capitalize on existing immunopeptidomics data and extract information that could complement HLA-binding prediction, we first compiled a large HLA class I and class II immunopeptidomics database across dozens of cell types and HLA allotypes and detected hotspots that are subsequences of proteins frequently presented. About 3% of the peptidome was detected in both class I and class II. Based on the gene ontology of their source proteins and the peptide’s length, we propose that their processing may partake by the cellular class II presentation machinery. Our database captures the global nature of the in vivo peptidome averaged over many HLA alleles, and therefore, reflects the propensity of peptides to be presented on HLA complexes, which is complementary to the existing neoantigen prediction features such as binding affinity and stability or RNA abundance. We further introduce two immunopeptidomics MS-based features to guide prioritization of neoantigens: the number of peptides matching a protein in our database and the overlap of the predicted wild-type peptide with other peptides in our database. We show as a proof of concept that our immunopeptidomics MS-based features improved neoantigen prioritization by up to 50%. Overall, our work shows that, in addition to providing huge training data to improve the HLA binding prediction, immunopeptidomics also captures other aspects of the natural in vivo presentation that significantly improve prediction of clinically relevant neoantigens.

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“…These include antigens such as Her2/Neu [70], mesothelin [71], lineage and tissue restricted differentiation antigens such as melanoma differentiation antigens (Tyrosinase Related Protein-2 and Melan-A (MART-1)) and Oncofetal antigens (Carcinoembryonic antigen) [72]. …”

Section: Figmentioning

confidence: 99%

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines

Saxena

Bhardwaj

2017

Current Opinion in Immunology

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Development of therapeutic cancer vaccines has been hindered by the many pro-tumorigenic mechanisms at play in cancer patients that serve to suppress both antigen presenting cells and T cells. In face of these obstacles, cancer vaccines are most likely to promote anti-tumorigenic immune responses only when formulated with strong adjuvants, and in combination with new immune interventions designed to reverse immune suppression and exhaustion of T cells in the tumor microenvironment. Dendritic cells (DCs) are often termed “nature’s adjuvant” due to their exceptional capacity for initiating both innate and adaptive immune responses. Hence, the past decade has witnessed a flurry of activity in testing DC based immunotherapies for cancer intervention. In this review we will discuss advances in conventional adjuvants and provide insight into new adjuvants as they pertain to DC cancer therapy.

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Lessons learned from cancer vaccine trials and target antigen choice

Cited by 25 publications

References 44 publications

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines

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