scholarly journals Ex Vivo Generation of Human Anti–Pre-B Leukemia-Specific Autologous Cytolytic T Cells

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 549-561 ◽  
Author(s):  
Angelo A. Cardoso ◽  
Mark J. Seamon ◽  
Hernani M. Afonso ◽  
Paolo Ghia ◽  
Vassiliki A. Boussiotis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Antigen Presenting Cells ◽  
Cell Leukemia ◽  
B Cell Leukemia ◽  
Antigen Presenting

Abstract In contrast to other neoplasms, antigen-specific autologous cytolytic T cells have not been detected in patients with human pre-B–cell leukemias. The absence of efficient B7 family (B7-1/CD80; B7-2/CD86) -mediated costimulation has been shown to be a major defect in tumor cells' capacity to function as antigen-presenting cells. We show here the generation of autologous anti–pre-B–cell leukemia-specific cytolytic T-cell lines from the marrows of 10 of 15 patients with pre-B–cell malignancies. T-cell costimulation via CD28 is an absolute requirement for the generation of these autologous cytolytic T cells (CTL). Although costimulation could be delivered by either bystander B7 transfectants or professional antigen-presenting cells (indirect costimulation), optimal priming and CTL expansion required that the costimulatory signal was expressed by the tumor cell (direct costimulation). These anti–pre-B–cell leukemia-specific CTL lysed both unstimulated and CD40-stimulated tumor cells from each patient studied but did not lyse either K562 or CD40-stimulated allogeneic B cells. Cytolysis was mediated by the induction of tumor cell apoptosis by CD8+ T cells via the perforin-granzyme pathway. Although we were able to generate anti–leukemia-specific CTL from the bone marrow, we were unable to generate such CTL from the peripheral blood of these patients. These studies show that antigen-specific CTL can be generated from the bone marrow of patients with pre-B–cell leukemias and these findings should facilitate the design of adoptive T-cell–mediated immunotherapy trials for the treatment of patients with B-cell precursor malignancies.

scholarly journals Ex Vivo Generation of Human Anti–Pre-B Leukemia-Specific Autologous Cytolytic T Cells

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 549-561 ◽  
Author(s):  
Angelo A. Cardoso ◽  
Mark J. Seamon ◽  
Hernani M. Afonso ◽  
Paolo Ghia ◽  
Vassiliki A. Boussiotis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Antigen Presenting Cells ◽  
Cell Leukemia ◽  
B Cell Leukemia ◽  
Antigen Presenting

In contrast to other neoplasms, antigen-specific autologous cytolytic T cells have not been detected in patients with human pre-B–cell leukemias. The absence of efficient B7 family (B7-1/CD80; B7-2/CD86) -mediated costimulation has been shown to be a major defect in tumor cells' capacity to function as antigen-presenting cells. We show here the generation of autologous anti–pre-B–cell leukemia-specific cytolytic T-cell lines from the marrows of 10 of 15 patients with pre-B–cell malignancies. T-cell costimulation via CD28 is an absolute requirement for the generation of these autologous cytolytic T cells (CTL). Although costimulation could be delivered by either bystander B7 transfectants or professional antigen-presenting cells (indirect costimulation), optimal priming and CTL expansion required that the costimulatory signal was expressed by the tumor cell (direct costimulation). These anti–pre-B–cell leukemia-specific CTL lysed both unstimulated and CD40-stimulated tumor cells from each patient studied but did not lyse either K562 or CD40-stimulated allogeneic B cells. Cytolysis was mediated by the induction of tumor cell apoptosis by CD8+ T cells via the perforin-granzyme pathway. Although we were able to generate anti–leukemia-specific CTL from the bone marrow, we were unable to generate such CTL from the peripheral blood of these patients. These studies show that antigen-specific CTL can be generated from the bone marrow of patients with pre-B–cell leukemias and these findings should facilitate the design of adoptive T-cell–mediated immunotherapy trials for the treatment of patients with B-cell precursor malignancies.

Cross-presentation of tumor antigens by bone marrow–derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1070-1077 ◽  
Author(s):  
Eduardo M. Sotomayor ◽  
Ivan Borrello ◽  
Frédérique-Marie Rattis ◽  
Alex G. Cuenca ◽  
Jacob Abrams ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Tumor Antigen ◽  
Antigen Presenting Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Antigen Presenting

Tumor antigen-specific T-cell tolerance may limit the efficacy of therapeutic cancer vaccines. Direct presentation of antigens by tumor cells incapable of providing adequate costimulation to tumor-specific T cells has been suggested as the basis for this unresponsiveness. Using parent-into-F1 bone marrow (BM) chimeras, this study unambiguously demonstrates that the induction of this tolerant state requires T-cell recognition of tumor antigen presented by BM-derived antigen-presenting cells (APCs), not tumor cells themselves. In the absence of host APC presentation, tumor-specific T cells remained functional, even in the setting of antigen expressed by B-cell lymphomas residing in secondary lymphoid tissues. The intrinsic APC capacity of tumor cells has therefore little influence over T-cell priming versus tolerance, a decision that is regulated at the level of host APCs.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

scholarly journals Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 41-48 ◽  
Author(s):  
AA Cardoso ◽  
JL Schultze ◽  
VA Boussiotis ◽  
GJ Freeman ◽  
MJ Seamon ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Human Tumor ◽  
Clinically Significant ◽  
Antigen Presenting

Abstract Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

Cyclophosphamide Plus Allogeneic CD4+ T Cell Infusion Induces Anti-Lymphoma Immunity Despite Lack of Graft-Versus-Host Disease (GVHD) or Sustained Engraftment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3063-3063
Author(s):  
Sanju Jalla ◽  
Jie Wang ◽  
Leo Luznik ◽  
Ephraim J. Fuchs
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Leukemia ◽  
B Cell Leukemia ◽  
T Cell Help

Abstract Recent evidence suggests that tumor-bearing animals contain CD8+ T cells that can respond productively to a tumor vaccine, but that these T cells do not respond because of insufficient help from tumor-specific CD4+ T cells, which have either been inactivated or turned into anti-tumor suppressor T cells. We therefore devised a strategy to augment anti-tumor immunity by administering cyclophosphamide (Cy), to eliminate suppressor CD4+ T cells, followed by combining autologous tumor cell vaccination and infusion of partially MHC-mismatched, or haploidentical, CD4+ T cells as a source of T cell help for endogenous CD8+ T cells. Interestingly, the combination of Cy followed by haploidentical T cell infusion, with or without vaccine, induced potent systemic anti-tumor immunity resulting in cure of 40-50% of BALB/c mice harboring the A20 B cell leukemia/lymphoma. Depletion of CD8+ T cells from the infusate abrogated GVHD but did not compromise anti-tumor immunity. Allogeneic donor spleen cells that contained CD8+ T cells engrafted durably and caused lethal GVHD. In contrast, the combination of Cy plus CD8+ T cell-depleted spleen cell infusion induced only transient engraftment, peaking on day 7 and declining to undetectable levels by day 14. In the absence of Cy conditioning, allogeneic donor spleen cell infusions did not induce detectable chimerism beyond day 3. In summary, Cy plus allogeneic CD4+ T cell infusion induces potent anti-tumor immunity in a mouse model of B cell leukemia/lymphoma. Potential mechanisms of the therapeutic effect include direct tumor cytotoxicity by CD4+ T cells or allogeneic CD4+ T cell help for endogenous, tumor-specific CD8+ T cells.

scholarly journals Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 41-48 ◽  
Author(s):  
AA Cardoso ◽  
JL Schultze ◽  
VA Boussiotis ◽  
GJ Freeman ◽  
MJ Seamon ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Human Tumor ◽  
Clinically Significant ◽  
Antigen Presenting

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.

scholarly journals CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3475-3484 ◽  
Author(s):  
Josef Kurtz ◽  
Forum Raval ◽  
Casey Vallot ◽  
Jayden Der ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Tolerance ◽  
Antigen Presenting ◽  
Marrow Cells

Abstract Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell–intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell–intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86+ non–T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells.

scholarly journals Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts

2021 ◽  
Vol 9 (6) ◽  
pp. e001514
Author(s):  
Concetta Quintarelli ◽  
Marika Guercio ◽  
Simona Manni ◽  
Iolanda Boffa ◽  
Matilde Sinibaldi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Leukemia Cells ◽  
Cell Leukemia ◽  
Car T Cell ◽  
Car T ◽  
B Cell Leukemia

Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells.BackgroundMethodsWe evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing.ResultsThe presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells.ConclusionsTaken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.

scholarly journals Efficient T cell–B cell collaboration guides autoantibody epitope bias and onset of celiac disease

2019 ◽  
Vol 116 (30) ◽  
pp. 15134-15139 ◽  
Author(s):  
Rasmus Iversen ◽  
Bishnudeo Roy ◽  
Jorunn Stamnaes ◽  
Lene S. Høydahl ◽  
Kathrin Hnida ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Disease Onset ◽  
Antigen Presenting Cells ◽  
Autoantibody Production ◽  
Antigen Presenting

B cells play important roles in autoimmune diseases through autoantibody production, cytokine secretion, or antigen presentation to T cells. In most cases, the contribution of B cells as antigen-presenting cells is not well understood. We have studied the autoantibody response against the enzyme transglutaminase 2 (TG2) in celiac disease patients by generating recombinant antibodies from single gut plasma cells reactive with discrete antigen domains and by undertaking proteomic analysis of anti-TG2 serum antibodies. The majority of the cells recognized epitopes in the N-terminal domain of TG2. Antibodies recognizing C-terminal epitopes interfered with TG2 cross-linking activity, and B cells specific for C-terminal epitopes were inefficient at taking up TG2-gluten complexes for presentation to gluten-specific T cells. The bias toward N-terminal epitopes hence reflects efficient T-B collaboration. Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells. The link between B cell epitopes, antigen presentation, and disease onset provides insight into the pathogenic mechanisms of a T cell-mediated autoimmune condition.

Sign in / Sign up

Export Citation Format

Share Document