CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia

Zebley, Caitlin C.; Brown, Charmaine; Tian, Mi; Fan, Yiping; Alli, Shanta; Boi, Shannon K.; Galletti, G; Lugli, Enrico; Langfitt, Deanna; Métais, Jean‐Yves; Lockey, Timothy; Meagher, Michael M.; Triplett, Brandon M.; Talleur, Aimee C; Gottschalk, Stephen; Youngblood, Ben

doi:10.1016/j.celrep.2021.110079

Cited by 62 publications

(45 citation statements)

References 55 publications

(72 reference statements)

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“…Additionally, a subset of patients (n=6) received repeat CD19-CAR T cell infusion(s) of the same product due to recurrent malignancy or early loss of BCA. The clinical outcomes with a focus on disease response to CAR T cell therapy ( 22 , 23 ), carHLH ( 18 ), and epigenetic reprograming of CAR T cells ( 24 ), have been reported elsewhere for a subset of these patients.…”

Section: Resultsmentioning

confidence: 99%

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

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Section: Resultsmentioning

confidence: 99%

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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“…In addition to permitting the study of primary antigen-specific Treg and Tconv responses, of importance for in vitro modeling of autoimmunity and cancer (70), our combination treatment approach also has relevant clinical implications for autologous adoptive cellular therapies (45). Studies in the delivery of chimeric antigen receptor (CAR) T cells in cancer (71, 72) and CAR Tregs in inflammatory models (73) have clearly shown that therapeutic success is reliant on dampening of memory acquisition and hindering the development of cellular exhaustion. CAR Tregs, while proposed for treatment of autoimmunity, likewise require methodological fine-tuning for prevention of exhaustion and loss of lineage stability (74).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Shapiro

Peters

Brown

et al. 2022

Preprint

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IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes (T1D) progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1R was elevated on murine memory and human naïve Treg subsets. IL-2 and IGF1 promoted murine PI3K/Akt and human STAT5 signaling in Tregs. IL-2 and IGF1 treatment expanded Tregs beyond either agent alone in NOD mice. Incubation of naïve human CD4+T cells with IL-2 and IGF1 enhanced Treg proliferationin vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2Rα expression on naïve Tregs, in contrast to intermediate-affinity IL-2Rβ and IL-2Rγ subunit enhancement on naïve conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2Rγ-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naïve Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive T cell expansions bothin vitroandin vivofor cellular therapeutics and genetic modifications.

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“…Zebley et al . [ 209 ] performed DNA methylation profiling using serial clinical samples from patients with acute lymphoblastic leukemia (ALL) and found that post‐infusion CD8 and CD19 CAR‐T cells undergo DNA methylation reprogramming that drives cell differentiation toward exhaustion. It was also demonstrated that low‐dose DAC‐treated CD19 CAR‐T cells have stronger anti‐lymphoma, proliferation and cytokine‐releasing capacities, which is associated with less exhaustion and maintenance of memory phenotype and effector function [ 43 ].…”

Section: Advances Of Epi‐cell Therapy For Solid and Hematological Can...mentioning

confidence: 99%

Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

Liu

et al. 2022

Cancer Communications

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Over the last two decades, several epi‐drugs, immune checkpoint inhibitors (ICIs) and adoptive cell therapies have received clinical approval for use in certain types of cancer. However, monotherapy with epi‐drugs or ICIs has shown limited efficacy in most cancer patients. Epigenetic agents have been shown to regulate the crosstalk between the tumor and host immunity to alleviate immune evasion, suggesting that epi‐drugs can potentially synergize with immunotherapy. In this review, we discuss recent insights into the rationales of incorporating epigenetic therapy into immunotherapy, called epi‐immunotherapy, and focus on an update of current clinical trials in both hematological and solid malignancies. Furthermore, we outline the future challenges and strategies in the field of cancer epi‐immunotherapy.

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CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia

Cited by 62 publications

References 55 publications

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

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