scholarly journals MUC1-Specific Cytotoxic T Lymphocytes in Cancer Therapy: Induction and Challenge

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
David Roulois ◽  
Marc Grégoire ◽  
Jean-François Fonteneau
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Vaccine ◽  
Therapeutic Vaccines ◽  
T Cell Vaccine ◽  
Clinical Responses

MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed,in vitroandin vivoexperiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.

scholarly journals Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide.

1990 ◽  
Vol 171 (5) ◽  
pp. 1815-1820 ◽  
Author(s):  
P Aichele ◽  
H Hengartner ◽  
R M Zinkernagel ◽  
M Schulz
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Lymphocytic Choriomeningitis ◽  
Effector T Cells ◽  
T Cell Response ◽  
Class I ◽  
Cytotoxic T Cell ◽  
Effector T Cell

Induction in vivo of antiviral cytotoxic T cell response was achieved in a MHC class I-dependent fashion by immunizing mice three times with a free unmodified 15-mer peptide derived from the nucleoprotein of lymphocytic choriomeningitis virus in IFA. The effector T cells are CD8+, restricted to the class I Ld allele of the analyzed mouse strain, and are specific both at the level of secondary restimulation in vitro and at the effector T cell level. These results suggest that cocktails of viral peptides may be used as antiviral T cell vaccines.

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

scholarly journals Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches.

1987 ◽  
Vol 165 (3) ◽  
pp. 830-847 ◽  
Author(s):  
S D London ◽  
D H Rubin ◽  
J J Cebra
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Peyer's Patches ◽  
Cytotoxic T Cell ◽  
Peyer’S Patches ◽  
Memory Cells ◽  
Mucosal Tissues

In this report we have shown that reovirus 1/L is an effective mucosal immunogen capable of generating a cytotoxic T cell (CTL) and associated helper T cell response to the nominal antigens associated with reovirus 1/L. The effectors that mediate reovirus-specific cytotoxicity are Thy-1+, Lyt-2+, and major histocompatibility complex (MHC)-restricted in their recognition of reovirus antigens, and can therefore be classified as CTLs. Frequency analysis of precursor CTLs occurring in Peyer's patches (PP) and peripheral lymph nodes (PLN) 6 d and 6 mo after intraduodenal stimulation have demonstrated that a persistent gradient of precursors is established, with higher frequencies present in PP. The generation of a CTL response in PP may be important in preferentially repopulating mucosal tissues with effector CTLs that could result in the local containment of infections in the gut. We also found that reovirus 1/L generates a virus-specific B cell response that is dominated by IgA memory cells after intraduodenal immunization. We hypothesize that the efficacy of reovirus 1/L at stimulating T and B cells in the gut mucosa is related to its ability to selectively enter PP via microfold (M) cells after enteric application. In this study we have also demonstrated that PP cells, upon in vitro culture and unrelated to prior reovirus priming, can generate natural killer-like (NK) cytotoxic activity. This may be an in vitro correlate of the in vivo generation of effectors that may populate mucosal tissues (i.e., the intestinal epithelium) with NK-like effector cells.

scholarly journals Effective Suppression of HIV-1 Replication by Cytotoxic T Lymphocytes Specific for Pol Epitopes in Conserved Mosaic Vaccine Immunogens

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Chengcheng Zou ◽  
Hayato Murakoshi ◽  
Nozomi Kuse ◽  
Tomohiro Akahoshi ◽  
Takayuki Chikata ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Lymphocytes ◽  
Cell Vaccine ◽  
Specific Ctls ◽  
T Cell Vaccine ◽  
Hiv 1 ◽  
Strong Ability

ABSTRACTCytotoxic T lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize circulating HIV-1 could be key for both HIV-1 cure and prophylaxis. We recently designed conserved mosaic T-cell vaccine immunogens (tHIVconsvX) composed of 6 Gag and Pol regions. Since the tHIVconsvX vaccine targets conserved regions common to most global HIV-1 variants and employs a bivalent mosaic design, it is expected that it could be universal if the vaccine works. Although we recently demonstrated that CTLs specific for 5 Gag epitopes in the vaccine immunogens had strong ability to suppress HIV-1 replicationin vitroandin vivo, it remains unknown whether the Pol region-specific CTLs are equally efficient. In this study, we investigated CTLs specific for Pol epitopes in the immunogens in treatment-naive Japanese patients infected with HIV-1 clade B. Overall, we mapped 20 reported and 5 novel Pol conserved epitopes in tHIVconsvX. Responses to 6 Pol epitopes were significantly associated with good clinical outcome, suggesting that CTLs specific for these 6 Pol epitopes had a strong ability to suppress HIV-1 replication in HIV-1-infected individuals.In vitroT-cell analyses further confirmed that the Pol-specific CTLs could effectively suppress HIV-1 replication. The present study thus demonstrated that the Pol regions of the vaccine contained protective epitopes. T-cell responses to the previous 5 Gag and present 6 Pol protective epitopes together also showed a strong correlation with better clinical outcome. These findings support the testing of the conserved mosaic vaccine in HIV-1 cure and prevention in humans.IMPORTANCEIt is likely necessary for an effective AIDS vaccine to elicit CD8+T cells with the ability to recognize circulating HIV-1 and suppress its replication. We recently developed novel bivalent mosaic T-cell vaccine immunogens composed of conserved regions of the Gag and Pol proteins matched to at least 80% globally circulating HIV-1 isolates. Nevertheless, it remains to be proven if vaccination with these immunogens can elicit T cells with the ability to suppress HIV-1 replication. It is well known that Gag-specific T cells can suppress HIV-1 replication more effectively than T cells specific for epitopes in other proteins. We recently identified 5 protective Gag epitopes in the vaccine immunogens. In this study, we identified T cells specific for 6 Pol epitopes present in the immunogens with strong abilities to suppress HIV-1in vivoandin vitro. This study further encourages clinical testing of the conserved mosaic T-cell vaccine in HIV-1 prevention and cure.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

2012 ◽  
Vol 6 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Jessica M. S. Jutzy ◽  
Salma Khan ◽  
Malyn May Asuncion-Valenzuela ◽  
Terry-Ann M. Milford ◽  
Kimberly J. Payne ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cell Function ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Function

scholarly journals Influenza virus hemagglutinin-specific cytotoxic T cell response induced by polypeptide produced in Escherichia coli.

1985 ◽  
Vol 162 (2) ◽  
pp. 663-674 ◽  
Author(s):  
A Yamada ◽  
M R Ziese ◽  
J F Young ◽  
Y K Yamada ◽  
F A Ennis
Keyword(s):  
Influenza Virus ◽  
Recombinant Dna ◽  
Cytotoxic T Lymphocyte ◽  
Nonstructural Protein ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Protein Immunization ◽  
Recombinant Dna Techniques

We have tested the abilities of various polypeptides of A/PR/8/34 (H1N1) virus, constructed by recombinant DNA techniques, to induce influenza virus-specific secondary cytotoxic T lymphocyte (CTL) responses. A hybrid protein (c13 protein), consisting of the first 81 amino acids of viral nonstructural protein (NS1) and the HA2 subunit of viral hemagglutinin (HA), induced H-2-restricted, influenza virus subtype-specific secondary CTL in vitro, although other peptides did not. Using a recombinant virus, the viral determinant responsible for recognition was mapped to the HA2 portion of c13 protein. Immunization of mice with c13 protein induced the generation of memory CTL in vivo. The CTL precursor frequencies of A/PR/8/34 virus- and c13 protein-immune mice were estimated as one in 8,047 and 50,312, respectively. These results indicate that c13 protein primed recipient mice, even though the level of precursor frequency was below that observed in virus-immune mice.

scholarly journals Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Manoj Patidar ◽  
Naveen Yadav ◽  
Sarat K. Dalai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Therapeutic Potential ◽  
Chimeric Protein ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

scholarly journals Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002503
Author(s):  
Miok Kim ◽  
Yong Ki Min ◽  
Jinho Jang ◽  
Hyejin Park ◽  
Semin Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
In Vivo Models ◽  
Single Cell Rna Sequencing ◽  
Tcr Diversity ◽  
Cancer Immunotherapies

BackgroundAlthough cancer immunotherapy is one of the most effective advanced-stage cancer therapies, no clinically approved cancer immunotherapies currently exist for colorectal cancer (CRC). Recently, programmed cell death protein 1 (PD-1) blockade has exhibited clinical benefits according to ongoing clinical trials. However, ongoing clinical trials for cancer immunotherapies are focused on PD-1 signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. In this study, we focused on revealing the distinct response mechanism for the potent CD73 ectoenzyme selective inhibitor AB680 as a promising drug candidate that functions by blocking tumorigenic ATP/adenosine signaling in comparison to current therapeutics that block PD-1 to assess the value of this drug as a novel immunotherapy for CRC.MethodsTo understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings.ResultsWe initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay.ConclusionsThe intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.

scholarly journals PD-L1hi plasmablasts limit the T cell response during the acute phase of parasite infections

2020 ◽  
Author(s):  
Melisa Gorosito Serrán ◽  
Facundo Fiocca Vernengo ◽  
Laura Almada ◽  
Cristian G Beccaria ◽  
Pablo F Canete ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Chronic Phase ◽  
Surface Expression ◽  
T Cell Response

ABSTRACTDuring infections with protozoan parasites or virus, T cell immunosuppression is generated simultaneously with a high B cell activation. Here, we show that in T. cruzi infection, all plasmablasts detected had higher surface expression of PD-L1, than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in an antigen-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection express PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. PD-L1hi plasmablasts suppressed T cell response, via PD-L1, in vitro and in vivo. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, which precede the germinal center (CG) response, are a suppressive population in infections that may influence T cell response.Brief summaryPathogens develop different strategies to settle in the host. We identified a plasmablats population induced by pathogens in acute infections which suppress T cell response.

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