Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination

Aarntzen, Erik H.J.G.; Vries, I. Jolanda M. de; Lesterhuis, W. Joost; Schuurhuis, Danita H.; Jacobs, Joannes F M; Bol, Kalijn F.; Schreibelt, Gerty; Mus, Roel; Wilt, Johannes H. W. de; Haanen, John B.A.G.; Schadendorf, Dirk; Croockewit, Alexandra J.; Blokx, Willeke A.M.; Rossum, Michelle M. van; Kwok, William W.; Adema, Gosse J.; Punt, Cornelis J.A.; Figdor, Carl G.

doi:10.1158/0008-5472.can-12-1127

Cited by 131 publications

(93 citation statements)

References 51 publications

(48 reference statements)

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“…There is compelling evidence suggesting that effective anticancer responses depend on Th activity, [16][17][18][33][34][35][36] but adoptive therapy with Th cells is a largely unexplored strategy. We hypothesize that the employment of millions of activated hTERT-specific Th cells may transform the inflammatory milieu and overcome established tumor tolerance.…”

Section: Discussionmentioning

confidence: 99%

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

et al. 2016

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We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4 C Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted Tcell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNg, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4C and CD8 C T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.

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Section: Discussionmentioning

confidence: 99%

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

et al. 2016

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“…Several methods of loading of DC with relevant tumor epitopes have been examined (Box 2). At present, the optimal method for antigen loading remains unknown but would ideally induce both CD4 þ and CD8 þ T-cell responses, as this is of crucial importance for the induction of a strong and sustained antitumor T-cell response (26,27). Besides the induction of an immune response against an antigen loaded on the DC vaccine, antigen spreading, i.e., the induction of immune responses against antigens that were not in the vaccine, may occur, indicating that a secondary round of T-cell priming has occurred with antigens taken directly from tumor cells (28,29).…”

Section: Tumor Antigens and Loading Of Dcsmentioning

confidence: 99%

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

Bol

Schreibelt

Gerritsen

et al. 2016

Clinical Cancer Research

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Dendritic cell (DC) vaccination in cancer patients aims to induce or augment an effective antitumor immune response against tumor antigens and was first explored in a clinical trial in the 1990s. More than two decades later, numerous clinical trials have been performed or are ongoing with a wide variety of DC subsets, culture protocols, and treatment regimens. The safety of DC vaccination and its ability to induce antitumor responses have clearly been established; however, although scattered patients with long-term benefit were reported, DC vaccines have not yet fulfilled their promise, perhaps mainly due to the lack of large-scale well-conducted phase II/III trials. To allow meaningful multicenter phase III trials, the production of DC vaccines should be standardized between centers which is now becoming feasible. To improve the efficacy of DC-based immunotherapy, it could be combined with other treatments.

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“…Efficient and long-lasting TAA-specific immunity requires both CD8 C CTL and CD4 C T lymphocytes during priming and effector phases of TAA-specific immune responses. 20,21 However, not only exogeneous, but also endogeneous peptides can be loaded onto HLA class II molecules; 22 this process is mediated by an Ii-independent, but proteasome-and peptide transporter-dependent presentation pathway. 23 …”

Section: Organization Of the Hla Class II Antigen-processing Machinerymentioning

confidence: 99%

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

2017

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The human leukocyte antigen (HLA) class II antigen-processing machinery (APM) presents to cognate CD4 C T-cells antigenic peptides mainly generated from exogeneous proteins in the endocytic compartment. These CD4 C T cells exert helper function, but may also act as effector cells, thereby recognizing HLA class II antigen-expressing tumor cells. Thus, HLA class II antigen expression by tumor cells influences the tumor antigen (TA)-specific immune responses and, depending on the cancer type, the clinical course of the disease. Many types of human cancers express HLA class II antigens, although with marked differences in their frequency. Some types of cancer lack HLA class II antigen expression, which could be due to structural defects or deregulation affecting different components of the complex HLA class II APM and/or from lack of cytokine(s) in the tumor microenvironment. In this review, we have summarized the information about HLA class II antigen distribution in normal tissues, the structural organization of the HLA class II APM, their expression and regulation in malignant cells, the defects, which have been identified in malignant cells, and their functional and clinical relevance.

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Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination

Abstract: To evaluate the relevance of directing antigen-specific CD4

Cited by 131 publications

References 51 publications

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

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