Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology

Koristka, Stefanie; Kegler, Alexandra; Bergmann, Ralf; Arndt, Claudia; Feldmann, Anja; Albert, Susann; Cartellieri, Marc; Ehninger, Armin; Ehninger, Gerhard; Middeke, Jan Moritz; Bornhäuser, Martin; Schmitz, Marc; Pietzsch, Jens; Akgün, Katja; Ziemssen, Tjalf; Steinbach, Jörg; Bachmann, Michael

doi:10.1016/j.jaut.2018.02.006

Cited by 66 publications

(54 citation statements)

References 57 publications

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“…Currently, several mechanisms were reported to reveal why Treg cell increased after T‐cell infusion. Engrafting Treg cells with chimeric antigen receptor were supposed to be a promising strategy for autoimmunity disease, nevertheless CAR‐expressing Treg cells were impeded the proliferation and responsiveness of effect T cells. In this case, CART‐19 cells were generated in both CD3 + CD8 + and Treg cells; these artificial CAR‐expressing Treg cells could infiltrate and accumulate in TME.…”

Section: Discussionmentioning

confidence: 99%

The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

Xia

Wang

et al. 2019

Cancer Medicine

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Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). Richter syndrome is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. Currently, there is no effective treatment for it. As a novel cellular‐based immune therapy, chimeric antigen receptor‐modified T (CART) cells treatment is gradually used in treating hematological malignancies, especially in CD19+ B‐cell malignancy. Therefore, CD19‐directed chimeric antigen receptor‐modified T cells (CART‐19) treatment is promising to be used as a new method for RS patients. In our study, one RS patient expressing high level of CD19 molecule was enrolled in clinical trial; he has received a series of treatments but did not achieve a satisfactory therapeutic effect. The patient totally received 3.55 × 108 autologous CART‐19 cells infusion. After CART‐19 infusion, the mainly clinical side effect was repeated fever. The maximal duration period was 24 days and the highest temperature was 40.1°C. Pancytopenia and significantly serum cytokines level rise were observed, including IFN‐γ, IL‐6, and IL‐10. Before discharge, the level of cytokines reduced to normal levels. In addition, we detected the serum biochemical indices as like K+, Ca2+, creatinine, and glutamic‐pyruvic transaminase, all of these indices were normal. This showed that there was no tumor necrosis syndrome after treatment. The proportion of B cells in patient's peripheral blood decreased from 72% to 40.2% after infusion, co‐occurring with reduction in lymph nodes and hematopoietic reconstitution. Based on the recent revolution in the therapeutic landscape for hematological malignancies including B‐cell lymphomas, CART‐CD19 cell therapy as a new therapeutic option for RS might be available in the coming years. It aims to reduce patient's tumor burden, prolong their survival time, and provide opportunities for other sequential therapy such as chemotherapy and bone marrow transplantation.

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Section: Discussionmentioning

confidence: 99%

The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

Xia

Wang

et al. 2019

Cancer Medicine

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“…To permanently produce the anti-muCD19 TM, Chinese hamster ovary cells were transduced with the generated lentiviral vector p6NST50_anti-muCD19 as previously described (28,29). Subsequently, the permanently expressed anti-muCD19 TM was purified and analyzed by SDS-PAGE as published before (21,30,31).…”

Section: Construction Expression and Purification Of The Recombinanmentioning

confidence: 99%

“…Over the past years, we have described and established a universal modular Ab-based CAR platform technology (UniCAR) (see also Fig. 1A) (22,27,30,35,(37)(38)(39)(40)(41). As schematically summarized in Fig.…”

Section: Identification and Characterization Of Car Constructs Suitabmentioning

confidence: 99%

Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

Albert

Koristka

Gerbaulet

et al. 2019

The Journal of Immunology

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Long-term survival of adoptively transferred chimeric Ag receptor (CAR) T cells is often limited. Transplantation of hematopoietic stem cells (HSCs) transduced to express CARs could help to overcome this problem as CAR-armed HSCs can continuously deliver CAR+ multicell lineages (e.g., T cells, NK cells). In dependence on the CAR construct, a variable extent of tonic signaling in CAR T cells was reported; thus, effects of CAR-mediated tonic signaling on the hematopoiesis of CAR-armed HSCs is unclear. To assess the effects of tonic signaling, two CAR constructs were established and analyzed 1) a signaling CAR inducing a solid Ag-independent tonic signaling termed CAR-28/ζ and 2) a nonstimulating control CAR construct lacking intracellular signaling domains termed CAR-Stop. Bone marrow cells from immunocompetent mice were isolated, purified for HSC-containing Lin−cKit+ cells or the Lin−cKit+ Sca-1+ subpopulation (Lin−Sca-1+cKit+), and transduced with both CAR constructs. Subsequently, modified bone marrow cells were transferred into irradiated mice, in which they successfully engrafted and differentiated into hematopoietic progenitors. HSCs expressing the CAR-Stop sustained normal hematopoiesis. In contrast, expression of the CAR-28/ζ led to elimination of mature CAR+ T and B cells, suggesting that the CAR-mediated tonic signaling mimics autorecognition via the newly recombined immune receptors in the developing lymphocytes.

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“…159 In mice, CEA-specific CAR-Tregs have been shown to preferentially accumulate in the lungs and spleen and control asthma better than unmodified Tregs; these findings hold great relevance to the field of lung transplantation and may be a way of controlling alloimmunity without global immunosuppression. 161 While the CAR-and UniCAR-Treg technology has yet to be applied to other solid organ transplants, it holds tremendous potential and warrants investigation in preclinical animal models. Human UniCAR-Tregs have already been developed and demonstrated to be capable of antigen-specific immunosuppression to a degree even greater than that of unmodified Tregs.…”

Section: Future D Irec Ti On Smentioning

confidence: 99%

“…Human UniCAR-Tregs have already been developed and demonstrated to be capable of antigen-specific immunosuppression to a degree even greater than that of unmodified Tregs. 161 While the CAR-and UniCAR-Treg technology has yet to be applied to other solid organ transplants, it holds tremendous potential and warrants investigation in preclinical animal models.…”

Section: Future D Irec Ti On Smentioning

confidence: 99%

The emerging role of regulatory T cells following lung transplantation

Gauthier

Harrison

Krupnick

et al. 2019

Immunological Reviews

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Regulatory T cells (Treg) have proven to be a powerful immunologic force in nearly every organ system and hold therapeutic potential for a wide range of diseases. Insights gained from non‐transplant pathologies, such as infection, cancer, and autoimmunity, are now being translated to the field of solid organ transplantation, particularly for livers and kidneys. Recent insights from animal models of lung transplantation have established that Tregs play a vital role in suppressing rejection and facilitating tolerance of lung allografts, and such discoveries are being validated in human studies and preclinical trials. Given that long‐term outcomes following lung transplantation remain profoundly limited by chronic rejection, Treg therapy holds the potential to significantly improve patient outcomes and should be aggressively investigated.

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Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology

Cited by 66 publications

References 57 publications

The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

The emerging role of regulatory T cells following lung transplantation

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