Novel technologies and emerging biomarkers for personalized cancer immunotherapy

Yuan, Jianda; Hegde, Priti S.; Clynes, Raphael; Foukas, Periklis; Harari, Alexandre; Kleen, Thomas O.; Kvistborg, Pia; Maccalli, Cristina; Maecker, Holden T.; Page, David B.; Robins, Harlan; Song, Wenru; Stack, Edward C.; Wang, Ena; Whiteside, Theresa L.; Zhao, Yingdong; Zwierzina, Heinz; Butterfield, Lisa H.; Fox, Bernard A.

doi:10.1186/s40425-016-0107-3

Cited by 186 publications

(168 citation statements)

References 253 publications

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“…Given their involvement in virtually any immune process, PBMC isolation is a key step in many immunological experiments. Once isolated, PBMCs can be used for a wide range of downstream applications such as studying autoimmune diseases [1][2][3], cancer research [4][5][6][7][8][9][10], developing new vaccines [11][12][13] and immunotherapies [6][7][8][9][10], drug discovery and testing [14][15][16] etc.…”

Section: Introductionmentioning

confidence: 99%

Optimization of a Density Gradient Centrifugation Protocol for Isolation of Peripheral Blood Mononuclear Cells

Șerban

Bărcuțean

Manu

et al. 2018

Acta Medica Marisiensis

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Objective: Peripheral blood mononuclear cells (PBMC) are extremely important in the body's immune response. Their isolation represents a major step in many immunological experiments. In this two phase study, we aimed to establish an optimum protocol for PBMC isolation by density-gradient centrifugation. Methods: During Phase-1, we compared two commercially available PBMC isolation protocols, Stemcell Technologies (ST) and Miltenyi Biotec (MB), in terms of PBMC recovery and purity. Twelve blood samples were assigned to each protocol. Each sample was divided in three subsamples of 1ml, 2ml and 3ml in order to assess the influence of blood sample volume on isolation performance. During Phase-2, a hybrid protocol was similarly tested, processing six blood samples. Additionally, we performed a flow cytometric analysis using an Annexin-V/Propidium-Iodide viability staining protocol. Results: Phase-1 results showed that, for all subsample volumes, ST had superior PBMC recovery (mean values: 56%, 80% and 87%, respectively) compared to MB (mean values: 39%, 54% and 43%, respectively). However, platelet removal was significantly higher for MB (mean value of 96.8%) than for ST (mean value of 75.2%). Regarding granulocyte/erythrocyte contamination, both protocols performed similarly, yielding high purity PBMC (mean values: 97.3% for ST and 95.8% for MB). During Phase-2, our hybrid protocol yielded comparable results to MB, with an average viability of 89.4% for lymphocytes and 16.9% for monocytes. Conclusions: ST yields higher cell recovery rates and MB excels at platelet removal, while the hybrid protocol is highly similar to MB. Both cell recovery and viability increase with blood sample volume.

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Section: Introductionmentioning

confidence: 99%

Optimization of a Density Gradient Centrifugation Protocol for Isolation of Peripheral Blood Mononuclear Cells

Șerban

Bărcuțean

Manu

et al. 2018

Acta Medica Marisiensis

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“…It is crucial to find better ways to monitor the magnitude, and ideally the broadness, of therapy-generated T cell immune responses. 20 Here we show that an allogeneic, tumor-derived autophagosome preparation derived from a mixed histology adenocarcinoma/squamous cancer cell line, can be used as a monitoring tool to detect vaccine-induced CD8 + T cell responses in PBMC from patients with prostate cancer. This approach provides an alternative to MHC-multimer or peptide-based approaches to capture the breadth of the anti-cancer immune response, especially for those cases where screening of autologous tumors for over-expressed proteins or neo-epitopes is impossible or impractical due to absence or limited availability of material.…”

Section: Discussionmentioning

confidence: 86%

“…In 2017, the generally applied immune monitoring strategies focus on identifying responses against selected well-known antigens, the specific antigen(s) used as a vaccine or, when tumor sequence data is available, evaluate for response to possible neo-epitopes. 20 These approaches will miss immune responses against other over-expressed targets, whether or not they are mutated, will generally miss epitope spreading, and might underestimate the magnitude of the induced anti-cancer immune response.…”

Section: Introductionmentioning

confidence: 99%

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

Ven

Hilton

Hu³

et al. 2018

OncoImmunology

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The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy. Here we tested whether a tumor-derived antigen source called DRibbles®, which contain a pool of defective ribosomal products (DRiPs), long-lived and short-lived proteins (SLiPs) and danger-associated molecular patterns (DAMPs), can be used to identify tumor-associated antigen (TAA)-specific responses in patients before or after immunotherapy treatment. Protein content, gene expression and non-synonymous – single nucleotide variants (ns-SNVs) present in UbiLT3 DRibbles were compared with prostate adenocarcinomas and the prostate GVAX vaccine cell lines (PC3/LNCaP). UbiLT3 DRibbles were found to share proteins, as well as match tumor sequences for ns-SNVs with prostate adenocarcinomas and with the cell lines PC3 and LNCaP. UbiLT3 DRibbles were used to monitor anti-tumor responses in patients vaccinated with allogeneic prostate GVAX. UbiLT3-DRibble-reactive CD8+ T-cell responses were detected in post-vaccine PBMC of 6/12 patients (range 0.85–22% of CD8+ cells) after 1 week in vitro stimulation (p = 0.007 vs. pre-vaccine). In conclusion, a cancer-derived autophagosome-enriched preparation, packaging over 100 proteins over-expressed in prostate cancer into microvesicles containing DAMPs, could be used to identify CD8+ T cells in peripheral blood from patients after prostate GVAX vaccination and may represent a general method to monitor anti-cancer T cell responses following immunotherapy.

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“…In order to provide stronger evidence that the tumor mutanome can be used as a potential biomarker of clinical benefit in cancer immunotherapies, either alone or in combination with immune landscape signatures, analyses of larger cohorts of patients are required. In these studies, whole-genome or whole-exome sequencing data would be combined with a detailed evaluation of the immune infiltrates, either by using RNA sequencing and gene expression techniques or multiplexed IHC/IF approaches (Figure 2), in order to not only interrogate the spatial distribution of adaptive and innate immunity cell subsets but importantly, to ascribe functional characteristics, as well (40).…”

Section: The Prognostic and Predictive Value Of The Mutational Load Imentioning

confidence: 99%

Neoantigen-based cancer immunotherapy

Bobisse¹,

Foukas²,

Coukos³

et al. 2016

Ann. Transl. Med.

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Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression.Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as "non-self" or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the "mutanome") and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4 + and CD8 + neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome.Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited 'gold mine' for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy.

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Novel technologies and emerging biomarkers for personalized cancer immunotherapy

Cited by 186 publications

References 253 publications

Optimization of a Density Gradient Centrifugation Protocol for Isolation of Peripheral Blood Mononuclear Cells

Optimization of a Density Gradient Centrifugation Protocol for Isolation of Peripheral Blood Mononuclear Cells

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

Neoantigen-based cancer immunotherapy

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