Novel strategy for manufacturing autologous dendritic cell / allogeneic tumor lysate vaccines for glioblastoma

curncman
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Novel strategy for manufacturing autologous dendritic cell / allogeneic tumor lysate vaccines for glioblastoma

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Novel strategy for manufacturing autologous dendritic cell / allogeneic tumor lysate vaccines for glioblastoma'

https://academic.oup.com/noa/advance-ar ... 05/5897132

Abstract
Background
Glioblastoma, the most common primary malignant brain tumor, is nearly universally fatal by five years. Dendritic cell vaccines are promising but often limited clinically by antigen choice, dendritic cell potency, and/or manufacturing yield. We optimized vaccine manufacture, generating potent mature autologous dendritic cells pulsed with allogeneic glioblastoma lysates.

Methods
Platelet lysate-based supplement was used establishing human glioblastoma cell lines. Phenotype and genotype were assessed. An improved culture technique to generate mature dendritic cells from glioblastoma patients’ monocytes was developed. The ability of T cells stimulated with autologous dendritic cells pulsed with allogeneic glioblastoma cell lysate to kill HLA-A2-matched glioblastoma cells was assessed.

Results
Glioblastoma cell lines established with platelet-lysate supplement grew faster and expressed more stem-like markers than lines grown in neural stem cell media or in the presence of serum. They expressed a variety of glioma-associated antigens and had genomic abnormalities characteristic of glioblastoma stable up to 15 doublings. Unlike standard culture techniques, our optimized technique produced high levels of mature dendritic cells from glioblastoma patients’ monocytes. Autologous T cells stimulated with mature dendritic cells pulsed with allogeneic glioblastoma cell line lysate briskly killed HLA-A2-matched glioblastoma cells.

Conclusions
Our glioblastoma culture method provides a renewable source for a broad spectrum glioblastoma neoantigens while our dendritic cell culture technique results in more mature dendritic cells in glioblastoma patients than standard techniques. This broadly applicable strategy could be easily integrated into patient care.
curncman
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Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute mye

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Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit

https://www.biorxiv.org/content/10.1101 ... 499v1.full
curncman
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Tolerance-inducing medicines in autoimmunity: rheumatology and beyond

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Tolerance-inducing medicines in autoimmunity: rheumatology and beyond

https://www.sciencedirect.com/science/a ... 1320301004

Summary
Autoimmunity is currently managed with generalised immunosuppression, which is associated with serious side-effects such as infection and cancer. An ideal treatment strategy would be to induce immune tolerance—ie, to reprogramme the immune system to stop recognising the host itself as a threat. Drug-free remission should follow such an intervention, representing a change in the approach to the treatment of autoimmune disease. Tolerance induction is achievable in animal models of autoimmunity but translation to the clinic has been slow. Nonetheless, progress has been made—eg, restoration of therapeutic responsiveness and drug-free remission have been achieved with stem cell transplantation in refractory autoimmunity, and significant delays in onset of type 1 diabetes in individuals at high risk have been achieved following a brief treatment with anti-CD3 monoclonal antibody. In the future, antigen-specific interventions should provide highly targeted, personalised approaches, avoiding generalised immunosuppression entirely. Such trials have already started, using both direct autoantigenic peptide administration, cellular therapies, and other modalities. In this Series paper, we discuss the history of immune tolerance induction with a focus on rheumatological disease while also highlighting essential data from other specialties. We propose key unanswered questions, which will be covered in other papers in this Series.
curncman
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Innate Myeloid Cells Remember and Reject Allogeneic Nonself in Transplantation

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Innate Myeloid Cells Remember and Reject Allogeneic Nonself in Transplantation

https://onlinelibrary.wiley.com/doi/ful ... /ajt.16238

Summary and Analysis
Dai, H, Lan, P, Zhao, D, et al. PIRs mediate innate myeloid cell memory to nonself MHC molecules. Science. 2020; 368: 1122– 1127.

Memory is a cardinal feature of the immune system and is traditionally ascribed to cells in the adaptive arm (i.e., T and B cells). Recent studies suggest that innate natural killer (NK) cells, macrophages and innate lymphoid cells (ILCs) can also acquire features of “memory” and become capable of mounting a “secondary” response against invading pathogens. In most cases, however, those enhanced secondary responses are not necessarily antigen specific but rather represent a state of epigenetic and metabolic reprogramming of such innate cells acquired in the primary responses.

A recent paper in Science by Dai et al. demonstrated in a mouse model that innate monocytes and macrophages can develop into memory cells that exhibit exquisite donor antigen specificity; they require donor alloantigen presensitization for their induction and are involved in the rejection of kidney and heart allografts. Importantly, the authors identify paired Ig‐like receptor‐A (PIR‐A) as MHC class I–binding receptors that mediate donor‐specific myeloid cell memory.

The studies are extensive but can be broken down into three parts for the purpose of this discussion: (a) induction of memory myeloid cells (monocytes and macrophages) that are donor antigen specific, (b) identification of PIR‐A as donor MHC class I–specific receptors that mediate myeloid cell memory, and (c) the role of PIR‐A in triggering the rejection of kidney and heart allografts in mice. The basic approach that generates the memory monocytes and macrophages involves presensitization of the Rag−/−Il2rg−/− mice (H‐2b), which are deficient in T, B, and NK cells, as well as ILCs, with allogenic BALB/c cells (H‐2d). Challenge of these presensitized mice showed that monocytes and macrophages only respond to the donor antigens to which they are sensitized, but not the third‐party antigens. In this secondary response, monocytes recognize donor BALB/c antigens and transform into dendritic cells to prime for rejection, whereas macrophages specifically recognize and kill donor cells. None of those activities occurred in the absence of donor antigen presensitization, nor did they occur after sensitization with syngeneic C57BL/6 cells. This state of donor antigen specificity and memory is also observed when the Rag−/−Il2rg−/− mice were presensitized with C3H (H‐2k) or NOD (H‐2g7) cells. Importantly, this type of specific memory can be passively transferred by monocytes and macrophages from the presensitized Rag−/−Il2rg−/− hosts to naïve ones, thus demonstrating the role of monocytes and macrophages in mediating donor‐specific myeloid cell memory. Further studies using the MHC congenic mice, MHC class I–deficient mice, and the MHC class I–binding tetramers led to the subsequent revelation of donor‐specific MHC class I molecules in the induction of myeloid cell memory.

The identification of PIR‐A as receptors for donor MHC class I molecules mediating the memory monocytes and macrophages, which involved the use of multiple approaches and cutting‐edge technologies, is significant. PIR is the ortholog of human leukocyte Ig‐like receptor (LILR), and consists of PIR‐A and PIR‐B. PIR‐A is highly polymorphic, consists of at least six isoforms and transmits activating signals, while PIR‐B is nonpolymorphic and triggers inhibitory signals. The authors showed in scRNA‐seq and Pira reporter systems that PIR‐A3 is the predominant isoform that engages donor class I molecules; they further showed that treatment of the presensitized Rag−/−Il2rg−/− hosts with PIR‐A3/Fc, a fusion protein that blocks donor class I molecules, inhibited donor‐specific myeloid cell memory. Finally, in models of kidney and heart transplants, genetic deletion of Pira or treatment with the PIR‐A3/Fc inhibited chronic rejection and markedly prolonged graft survival, suggesting that this pathway is involved in rejection and can be therapeutically targeted to promote graft survival.

Clearly, the finding that innate myeloid cells can acquire donor‐specific memory is exciting, and the involvement of these cells in chronic allograft rejection is significant. However, the studies by Dai et al. are exclusively in mice, and further inquiries into human myeloid cells, investigating whether they also acquire features similar to those of their mouse counterparts in transplant settings, will be paramount in moving the field forward.

Xian C. Li, MD, PhD is professor and director at the Immunobiology and Transplant Science Center and Department of Surgery at Houston Methodist Hospital in Texas.
curncman
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Tolerance-inducing medicines in autoimmunity: rheumatology and beyond

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Tolerance-inducing medicines in autoimmunity: rheumatology and beyond

https://www.thelancet.com/journals/lanr ... 4/fulltext

Summary
Autoimmunity is currently managed with generalised immunosuppression, which is associated with serious side-effects such as infection and cancer. An ideal treatment strategy would be to induce immune tolerance—ie, to reprogramme the immune system to stop recognising the host itself as a threat. Drug-free remission should follow such an intervention, representing a change in the approach to the treatment of autoimmune disease. Tolerance induction is achievable in animal models of autoimmunity but translation to the clinic has been slow. Nonetheless, progress has been made—eg, restoration of therapeutic responsiveness and drug-free remission have been achieved with stem cell transplantation in refractory autoimmunity, and significant delays in onset of type 1 diabetes in individuals at high risk have been achieved following a brief treatment with anti-CD3 monoclonal antibody. In the future, antigen-specific interventions should provide highly targeted, personalised approaches, avoiding generalised immunosuppression entirely. Such trials have already started, using both direct autoantigenic peptide administration, cellular therapies, and other modalities. In this Series paper, we discuss the history of immune tolerance induction with a focus on rheumatological disease while also highlighting essential data from other specialties. We propose key unanswered questions, which will be covered in other papers in this Series.
curncman
Posts: 1126
Joined: Fri Jun 26, 2020 8:27 am

Allogeneic Bone Marrow Transplantation | Dr. Sarita Jaiswal

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Allogeneic Bone Marrow Transplantation | Dr. Sarita Jaiswal

curncman
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What is an Allogeneic Stem Cell Transplant?

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curncman
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Lecture 6: "Target cells and the innate response"

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Lecture 6: "Target cells and the innate response"

curncman
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Immunotherapy for T-cell malignancies

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Immunotherapy for T-cell malignancies

curncman
Posts: 1126
Joined: Fri Jun 26, 2020 8:27 am

Robert Rich: Dendritic

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Robert Rich: Dendritic

From the album Neurogenesis
Soundscape Productions SP038
Released December 2020
© 2020 by Robert Rich

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