scholarly journals Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer

2018 ◽  
Vol 97 (6) ◽  
pp. 627-634 ◽  
Author(s):  
Y.S. Tan ◽  
K. Sansanaphongpricha ◽  
M.E.P. Prince ◽  
D. Sun ◽  
G.T. Wolf ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck ◽  
Cancer Vaccines ◽  
Immune Escape ◽  
Cell Repertoire ◽  
Antigen Uptake ◽  
Immune Priming ◽  
Extensive Collection ◽  
Checkpoint Receptors ◽  
Antigen Presenting

The recent Food and Drug Administration’s approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8+ T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.

scholarly journals Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 696 ◽  
Author(s):  
Bianca Simon ◽  
Dennis C. Harrer ◽  
Beatrice Schuler-Thurner ◽  
Gerold Schuler ◽  
Ugur Uslu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Dna And Rna ◽  
Antigen Loss ◽  
Antigen Presenting

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

scholarly journals New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 55 ◽  
Author(s):  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Cell Mediated Immunity ◽  
Anti Cancer ◽  
Antigen Presenting ◽  
Molecular Patterns

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

scholarly journals In vitro correlate for a clonal deletion mechanism of immune response gene-controlled nonresponsiveness.

1983 ◽  
Vol 157 (3) ◽  
pp. 998-1005 ◽  
Author(s):  
N Ishii ◽  
Z A Nagy ◽  
J Klein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Response Gene ◽  
Mouse Strains ◽  
Single Chain ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Class Ii Mhc ◽  
Antigen Presenting

We used T cell-antigen-presenting cell (APC) combinations from two pairs of recombinant mouse strains, B10.A(4R)-B10.A(2R) and B10.S(7R)-B10.S(9R) (abbreviated 4R, 2R, 7R, 9R, respectively), which differ from each other only in the nonexpression vs. expression of cell-surface E molecules, to study the mechanism of the Ir gene-controlled (E-restricted) response to the terpolymer poly(glu51lys34tyr15) (GLT). No response to GLT occurred when the APC were from E-nonexpressor strains 4R and 7R. When APC from E-expressor strains were used and alloreactivity against the incompatible E molecules was removed by BUdR + light treatment, 7R T cells responded to GLT presented by 9R APC, but 4R T cells failed to respond to GLT presented by 2R APC. However, 4R T cells mounted a proliferative response to GLT presented by fully allogeneic 5R or 9R APC. The latter response was completely abolished by the depletion of cells alloreactive against 2R and 5R or 2R and 9R. Since removal of alloreactivity against 5R plus 9R did not affect the response of 4R T cells to GLT presented by either 5R or 9R cells, we conclude that the 4R T cells generated in response to GLT cross-react with the additional incompatibility presented by 2R cells, that is, the Ek beta chain. In contrast, 7R T cells recognizing GLT presented by 9R APC do not cross-react with Ek beta. These results demonstrate that "blind spots" in the T cell repertoire produced by depletion of cells alloreactive against a single chain of a class II MHC molecule can render a strain nonresponsive to a synthetic polypeptide antigen, and that this nonresponsiveness corresponds to that attributed to the MHC-linked Ir genes.

scholarly journals Tumor Antigen-Dependent and Tumor Antigen-Independent Activation of Antitumor Activity in T Cells by a Bispecific Antibody-Modified Tumor Vaccine

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Philippe Fournier ◽  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cancer Patients ◽  
Tumor Antigen ◽  
Immune Escape ◽  
Tumor Vaccine ◽  
Cell Repertoire ◽  
Tumor Immune Escape

New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV—which is obtained by isolation, shortin vitroculture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV)—with bispecific antibodies (bsAbs) binding to this vaccine and introducing anti-CD3 (signal 1) and anti-CD28 (signal 2) antibody activities. This vaccine called ATV-NDV/bsAb showed the unique ability to reactivate a preexisting potentially anergized antitumor memory T cell repertoire. But it also activated naive T cells to have antitumor propertiesin vitroandin vivo. This innovative concept of direct activation of cancer patients' T cells via cognate and noncognate interactions provides potential for inducing strong antitumor activities aiming at overriding T cell anergy and tumor immune escape mechanisms.

scholarly journals Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

2020 ◽  
Author(s):  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Lucia Montorsi ◽  
Amelia Acha-Sagredo ◽  
Lorena Benedetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Critical Threshold ◽  
Mutational Burden ◽  
Antigen Presenting

To dissect the determinants of the heterogeneous response of colorectal cancer (CRC) to immune checkpoint blockade, we profile tumour and immune infiltrates of 721 cancer regions from 29 patients treated with Pembrolizumab or Nivolumab. Combining multi-regional whole exome, RNA and T-cell receptor sequencing we show that anti-PD1 agents are most effective in CRCs with high mutational burden and low activation of the WNT pathway. However, above a critical threshold defining the hypermutated phenotype, response is no longer associated with mutational burden but rather with high clonality of immunogenic mutations, expanded T cells and active immune escape mechanisms. Using high-dimensional imaging mass cytometry and multiplexed immunofluorescence, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 infiltrates interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting their expansion in intra-tumour niches.

scholarly journals Pathogenic CD4+ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes

2013 ◽  
Vol 210 (11) ◽  
pp. 2403-2414 ◽  
Author(s):  
James F. Mohan ◽  
Boris Calderon ◽  
Mark S. Anderson ◽  
Emil R. Unanue
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Diabetic Mouse ◽  
Cell Repertoire ◽  
Highly Pathogenic ◽  
Nonobese Diabetic ◽  
Predominant Component ◽  
Antigen Presenting

In the nonobese diabetic mouse, a predominant component of the autoreactive CD4+ T cell repertoire is directed against the B:9-23 segment of the insulin B chain. Previous studies established that the majority of insulin-reactive T cells specifically recognize a weak peptide-MHC binding register within the B:9-23 segment, that to the 12–20 register. These T cells are uniquely stimulated when the B:9-23 peptide, but not the insulin protein, is offered to antigen presenting cells (APCs). Here, we report on a T cell receptor (TCR) transgenic mouse (8F10) that offers important new insights into the biology of these unconventional T cells. Many of the 8F10 CD4+ T cells escaped negative selection and were highly pathogenic. The T cells were directly recruited into islets of Langerhans, where they established contact with resident intra-islet APCs. Immunogenic insulin had to be presented in order for the T cells to localize and cause disease. These T cells bypassed an initial priming stage in the pancreatic lymph node thought to precede islet T cell entry. 8F10 T cells induced the production of antiinsulin antibodies and islets contained immunoglobulin (IgG) deposited on β cells and along the vessel walls.

Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3171-3176 ◽  
Author(s):  
Susanne Auffermann-Gretzinger ◽  
Emmet B. Keeffe ◽  
Shoshana Levy
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dendritic Cell Maturation ◽  
Tumor Formation ◽  
Hcv Infection ◽  
Surface Markers ◽  
Antigen Uptake ◽  
Healthy Donors ◽  
Antigen Presenting

Abstract Dendritic cells (DCs) are important for the initiation of immune responses to foreign antigens. Their antigen uptake and presentation capacities enable them to prime and activate T cells. Immature DCs capture antigens; however, they must be activated to mature before serving as efficient antigen-presenting cells. The antigen-presenting capacity of DCs can be diminished during viral infection and as a consequence of tumor formation. Chronic infection with hepatitis C virus (HCV) has been shown to affect the allostimulatory function of DCs. In this study, it is demonstrated that monocyte-derived DCs from patients with chronic HCV infection do not respond to maturation stimuli. Instead, they maintain their immature phenotype, reflected by the pattern of cell surface markers and by their continued capacity to uptake antigen. Moreover, their allostimulatory abilities are impaired compared with those of mature DCs derived from healthy donors. To investigate a possible correlation between viral clearance and this DC maturation defect, patients with resolved HCV infection after a course of antiviral therapy were studied. Results demonstrate that DCs from patients who cleared HCV behaved like DCs from healthy donors: in response to maturation stimuli, they decrease antigen uptake, up-regulate expression of appropriate surface markers, and are potent stimulators of allogeneic T cells.

Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14637-e14637 ◽  
Author(s):  
Derek J. Jonker ◽  
Sebastien J. Hotte ◽  
Albiruni Ryan Abdul Razak ◽  
Daniel John Renouf ◽  
Brian Lichty ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Killer Cell ◽  
Solid Tumours ◽  
Fixed Dose ◽  
Activation Markers ◽  
Immune Priming ◽  
Cell Immunity ◽  
Suppressive Cytokine ◽  
Antigen Presenting

e14637 Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.

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