scholarly journals Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy

Cell Reports ◽  
2021 ◽  
Vol 37 (6) ◽  
pp. 109992
Author(s):  
Pavan Bachireddy ◽  
Elham Azizi ◽  
Cassandra Burdziak ◽  
Vinhkhang N. Nguyen ◽  
Christina S. Ennis ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Therapy ◽  
Adoptive Cellular Therapy

scholarly journals Augmented expansion of Treg cells from healthy and autoimmune subjects via adult progenitor cell co-culture

2020 ◽  
Author(s):  
JL Reading ◽  
VD Roobrouck ◽  
CM Hull ◽  
PD Becker ◽  
J Beyens ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Regulatory T Cell ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Fold Increase ◽  
Adoptive Cellular Therapy ◽  
T Cell Therapy

AbstractRecent clinical experience has demonstrated that adoptive regulatory T cell therapy is a safe and feasible strategy to suppress immunopathology via induction of host tolerance to allo- and autoantigens. However, clinical trials continue to be compromised due to an inability to manufacture a sufficient Treg cell dose. Multipotent adult progenitor cells (MAPCⓇ) promote regulatory T cell differentiation in vitro, suggesting they may be repurposed to enhance ex vivo expansion of Tregs for adoptive cellular therapy. Here, we use a GMP compatible Treg expansion platform to demonstrate that MAPC cell-co-cultured Tregs (MulTreg) exhibit a log-fold increase in yield across two independent cohorts, reducing time to target dose by an average of 30%. Enhanced expansion is linked with a distinct Treg cell-intrinsic transcriptional program, characterized by diminished levels of core exhaustion (BATF, ID2, PRDM1, LAYN, DUSP1), and quiescence (TOB1, TSC22D3) related genes, coupled to elevated expression of cell-cycle and proliferation loci (MKI67, CDK1, AURKA, AURKB). In addition, MulTreg display a unique gut homing (CCR7lo β7hi) phenotype and importantly, are more readily expanded from patients with autoimmune disease compared to matched Treg lines, suggesting clinical utility in gut and/or Th1-driven pathology associated with autoimmunity or transplantation. Relative to expanded Tregs, MulTreg retain equivalent and robust purity, FoxP3 TSDR demethylation, nominal effector cytokine production and potent suppression of Th1-driven antigen specific and polyclonal responses in vitro and xeno graft vs host disease (xGvHD) in vivo. These data support the use of MAPC cell co-culture in adoptive Treg therapy platforms as a means to rescue expansion failure and reduce the time required to manufacture a stable, potently suppressive product.

scholarly journals Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000247
Author(s):  
Brett A Schroeder ◽  
Ralph Graeme Black ◽  
Sydney Spadinger ◽  
Shihong Zhang ◽  
Karan Kohli ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Low Dose ◽  
Cellular Therapy ◽  
Tumor Regression ◽  
High Dose ◽  
Adoptive Cellular Therapy ◽  
Link Type ◽  
T Cell Infiltration ◽  
Ifn Γ

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

scholarly journals Adoptive cellular therapy enhances the helper T cell response and reduces the number of regulatory T cells

2011 ◽  
Vol 2 (4) ◽  
pp. 737-743 ◽  
Author(s):  
TAKESHI ISHIKAWA ◽  
SATOSHI KOKURA ◽  
NAOYUKI SAKAMOTO ◽  
TSUGUHIRO MATSUMOTO ◽  
JUN FUNAKI ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Response ◽  
Cellular Therapy ◽  
T Cell Response ◽  
Helper T Cell ◽  
Adoptive Cellular Therapy

scholarly journals PDCT-11. QUANTITATIVE TRACKING OF T-CELL CLONES AFTER ADOPTIVE CELLULAR THERAPY TARGETING RECURRENT MEDULLOBLASTOMA USING MASSIVELY PARALLEL RNA SEQUENCING TECHNOLOGY

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi148-vi148
Author(s):  
Oleg Yegorov ◽  
Anjelika Dechkovskaia ◽  
Marcia Hodik ◽  
Jianping Huang ◽  
Elias Sayour ◽  
...  
Keyword(s):  
T Cell ◽  
Rna Sequencing ◽  
Cellular Therapy ◽  
Massively Parallel ◽  
Sequencing Technology ◽  
Adoptive Cellular Therapy ◽  
T Cell Clones ◽  
Cell Clones

scholarly journals Chimeric antigen receptor T cell therapy comes to clinical practice

2019 ◽  
Vol 27 (S2) ◽  
Author(s):  
D. Wall ◽  
J. Krueger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Cellular Therapy ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptor ◽  
Adoptive Cellular Therapy ◽  
T Cell Therapy ◽  
Non Hodgkin Lymphoma ◽  
Car T

Adoptive cellular therapy with chimeric antigen receptor T cells (car-ts) has recently received approval from Health Canada and the U.S. Food and Drug Administration after remarkable and durable remissions were seen in children with recurrent or refractory leukemia and adults with non-Hodgkin lymphoma—responses that were so impressive that a shift in the paradigm of care has now occurred for children with acute lymphoblastic leukemia.    The concept behind car-t immunotherapy is that modification of a patient’s own T cells to facilitate their localization to the cancer cell, with subsequent activation of the T cell effector mechanism and proliferation, will result in targeted killing of cancer cells. The car-ts are a novel drug in that the starting material for the manufacture of the car-t product comes from the patient, whose viable T cells are then genetically modified. Thus, collaboration is needed between the pharmaceutical companies, which must meet good manufacturing standards for each patient’s unique product, and the treating sites. For regulators and health authorities, this new class of drugs requires new paradigms for assessment and approval. Treatments with car-ts require that institutions address unique logistics requirements and management of novel toxicities.    The Hospital for Sick Children has had early experience with both the licensing of clinical trials and the introduction of the first commercial product. Here, we provide an overview of basic concepts and treatment, with caveats drawn from what we have learned thus far in bringing this new therapy to the clinical front line.

scholarly journals PDCT-12. TRACKING T-CELL IMMUNE RECONSTITUTION AFTER ADOPTIVE CELLULAR THERAPY TARGETING RECURRENT MEDULLOBLASTOMA AND PNETS USING DEEP T-CELL RECEPTOR (TCR) REPERTOIRE SEQUENCING

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi186-vi186
Author(s):  
Oleg Yegorov ◽  
Yanina Yegorova ◽  
Anjelika Dechkovskaia ◽  
Jianping Huang ◽  
Sridharan Gururangan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Immune Reconstitution ◽  
Cellular Therapy ◽  
Cell Receptor ◽  
Adoptive Cellular Therapy ◽  
Tcr Repertoire ◽  
Repertoire Sequencing

scholarly journals Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy

2020 ◽  
Author(s):  
Pavan Bachireddy ◽  
Elham Azizi ◽  
Cassandra Burdziak ◽  
Vinhkhang N Nguyen ◽  
Christina Ennis ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Therapy ◽  
Deep Understanding ◽  
Cell Receptor ◽  
Chromatin Accessibility ◽  
Donor Lymphocyte Infusion ◽  
Learning Tools ◽  
Adoptive Cellular Therapy ◽  
Cell Dynamics ◽  
Pre Treatment

Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of ‘terminal’ (TEX) and ‘precursor’ (TPEX) exhausted subsets, respectively, defined DLI response. A contrasting, heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, TPEX cells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Our unbiased dissection of the TME using a Bayesian method, Symphony, defined the T cell circuitry underlying effective human anti-leukemic immune responses that may be broadly relevant to other exhaustion antagonists across cancers. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of therapeutic scenarios beyond oncology.

In Vitro Expansion of CMV-Specific T Cells from CMV Seronegative Donors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3927-3927
Author(s):  
Stephanie Verfuerth ◽  
Arnold R. Pizzey ◽  
Shoon-Ling C. Chow ◽  
Noha Chowdhry ◽  
Stephen Mackinnon
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cellular Therapy ◽  
T Cell Proliferation ◽  
Adoptive Cellular Therapy ◽  
Size Classes ◽  
Pulsed Dc ◽  
Ifn Γ

Abstract CMV infection is still a negative prognostic factor in hematopoietic stem cell transplantation, largely due to adverse effects of antiviral chemotherapy. Advances have been made in the development of adoptive cellular therapy for CMV with cell products derived from CMV seropositive donors. However no such cell products from CMV negative donors are currently available, although CMV negative recipients of CMV positive grafts bear the greatest risk of CMV induced morbidity and mortality. Mature DC are capable of inducing in vivo primary T cell responses. We used an in vitro culture system employing MoDC generated with GM-CSF and IL-4, pulsed with CMV lysate and matured with CD40L to induce primary immune responses to CMV. CMV-specific T cell proliferation measured by 3H-Thymidine uptake could be induced in some 6 to 9-day cultures, however, the success rate was very low, and T cells could usually not be kept alive after becoming activated. The addition of IL-15 to cultures after 7 days resulted in some improvement, although some non-CMV specific T cell proliferation in response to control lysate or in the absence of antigen also occurred in some cultures. IL-12 added to cultures from day 0 resulted in a short-term increase in T cell proliferation that was followed by increased cell death and was also not entirely CMV-specific. The real benefit of IL-15, alone or in combination with IL-12, was seen in 2-week cultures: In 6/7 cultures from different CMV seronegative donors counts of viable T cells (by trypan blue exclusion) increased up to 10-fold. Two cultures that were additionally set up with control lysate-pulsed DC to detect proliferation in response to non-CMV components of the antigen, confirmed CMV-specificity. CMV-specificity was also shown by T cell receptor (TCR) complement determining region (CDR) 3 spectratyping. TCR-BV(variable region β)-size class expression patterns across 23 BV families were very similar in pre-culture unstimulated T cells and in T cells stimulated with control lysate-pulsed DC for 2 weeks, showing the typical near-normal distribution of PCR product amongst the different size classes indicative of un-stimulated T cells. T cells co-cultured with CMV lysate-pulsed DC for 2 weeks produced very skewed spectratypes, indicative of oligoclonal T cell expansion in response to the antigen. The effect of IL-15 on T cell spectratypes from CMV antigen-driven cultures was tested using cells from another donor. With or without IL-15, post-culture spectratypes showed oligoclonal T cell expansions in the same BV families and size classes. However, despite their similar shapes, spectratypes from IL-5 containing cultures were skewed to a greater extent, possibly indicating a greater effect of IL-15 on already activated T cells. No CD8+ T cells specific for single immunodominant epitopes could be detected by staining with up to 5 different HLA-CMVpeptide-tetramers in culture output from 4/4 donors. In 1 of 2 cultures analyzed by cytokine secretion assay, a significant sub-population of T cells (1%), in CD4 positive and negative fractions, secreted IFN-γ in response to re-stimulation with CMV antigen. No IFN-γ secreting CMV-specific pre-cursor T cells were detected in fresh PBMC, as expected. Whilst further work is required to make generation of CMV specific T cells from CMV seronegative donors more reproducible and to ensure antigen-specificity, these preliminary data are encouraging for the future generation of CMV-specific T cells from CMV seronegative donors for adoptive cellular therapy.

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