A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia

Enblad, Gunilla; Karlsson, Hannah; Gammelgård, Gustav; Wenthe, Jessica; Lövgren, Tanja; Amini, Rose‐Marie; Wikström, Kristina; Essand, Magnus; Savoldo, Barbara; Hallböök, Heléne; Höglund, Martin; Dotti, Gianpietro; Brenner, Malcolm K.; Hagberg, Hans; Loskog, Angelica

doi:10.1158/1078-0432.ccr-18-0426

Cited by 192 publications

(161 citation statements)

References 29 publications

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“…Moreover, it was shown that the degree of intracellular signaling activity of 3G CART cells was higher than of 2G CART cells and probably resulted in superior cell proliferation . First clinical studies with CD19‐specific 3G CART cells demonstrated efficiency and safety in patients with B cell malignancies . The aim of this study was to further improve the generation of these potentially superior 3G CART cells.…”

Section: Discussionmentioning

confidence: 99%

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

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Übelhart

Schubert

et al. 2019

Intl Journal of Cancer

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Despite encouraging results with chimeric antigen receptor T (CART) cells, outcome can still be improved by optimization of the CART cell generation process. The proportion of less‐differentiated T cells within the transfused product is linked to enhanced in vivo CART cell expansion and long‐term persistence. The clinically approved PI3Kδ inhibitor idelalisib is well established in the treatment of B cell malignancies. Besides B cell receptor pathway inhibition, idelalisib can modulate T cell differentiation and function. Here, detailed longitudinal analysis of idelalisib‐induced effects on T cell phenotype and function was performed during CART cell production. A third generation CD19.CAR.CD28.CD137zeta CAR vector system was used. CART cells were generated from peripheral blood mononuclear cells of healthy donors (HDs) and chronic lymphocytic leukemia (CLL) patients. Idelalisib‐based CART cell generation resulted in an enrichment of less‐differentiated naïve‐like T cells (CD45RA+CCR7+), decreased expression of the exhaustion markers PD‐1 and Tim‐3, as well as upregulation of the lymph node homing marker CD62L. Idelalisib increased transduction efficiency, but did not impair viability and cell expansion. Strikingly, CD4:CD8 ratios that were altered in CART cells from CLL patients were approximated to ratios in HDs by idelalisib. Furthermore, in vivo efficacy of idelalisib‐treated CART cells was validated in a xenograft mouse model. Intracellular TNF‐α and IFN‐γ production decreased in presence of idelalisib. This effect was reversible after resting CART cells without idelalisib. In summary, PI3Kδ inhibition with idelalisib can improve CART cell products, particularly when derived from CLL patients. Further studies with idelalisib‐based CART cell generation protocols are warranted.

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Section: Discussionmentioning

confidence: 99%

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

Stock

Übelhart

Schubert

et al. 2019

Intl Journal of Cancer

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“…In a phase I dose-escalation study, Ramos et al 56 active disease responded to treatment, including three complete responses (CRs). Enblad et al 58 reported the outcomes of 15 patients with r/r B-cell malignancies treated with autologous anti-CD19 CAR T cells incorporating both CD28 and 4-1BB costimulatory domains, four of whom did not receive lymphodepletion before CAR T cell infusion. 56,57 In 10 out of 11 patients with active disease, greater expansion (up to 40-fold) of third-generation CAR T cells compared to second-generation CAR T cells was seen, and third-generation CAR T cells remained detectable at higher levels up to 160 days postinfusion.…”

Section: Combining Costimulatory Domainsmentioning

confidence: 99%

“…One case of severe cytokine release syndrome (CRS) and one case of severe CAR T cell-related encephalopathy syndrome (CRES), also referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), were observed. 36,58,59 Third-generation CAR T cells incorporating the Toll/interleukin-1 receptor (TIR) domain of Tolllike receptor 2 (TLR2), together with the CD3f and CD28 intracellular domains, were administered to three patients with an extramedullary relapse of B-ALL. Moreover, only third-generation CAR T cells expanded significantly when infused to patients in remission after autologous stem cell transplantation, suggesting the third-generation CAR T cells can expand despite minimal CD19 antigen exposure.…”

Section: Combining Costimulatory Domainsmentioning

confidence: 99%

“…73 Moreover, increasing clinical experience in the early recognition and management of CRS and neurotoxicity is likely to reduce the incidence of severe toxicities, the early introduction of anti-IL-6 therapy and corticosteroids being associated with lower rates of life-threatening complications. 53,56,58 However, the number of recipients of third-generation CAR T cells in the published literature is low, and the results of additional trials, including some currently recruiting studies, will be needed to accurately assess toxicity risk (see Figure 4). CRS in particular often occurs during or near the peak of CAR T cell expansion.…”

Section: Safety Considerationsmentioning

confidence: 99%

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Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

et al. 2019

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Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4‐1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti‐CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct‐ and disease‐specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

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“…These second‐generation CAR‐T therapies have been used in the seminal CAR‐T trials in CD19 and/or CD22 expressing malignancies . More recently, investigators have been researching methods to leverage current CAR‐T and increase persistence and/or cytolytic effect by incorporating various combinations of co‐stimulatory molecules including: 4‐IBB, CD27, CD134, and ICOS . The inclusion of suicide genes such as icasp9, surface marker depletions of EGFR and other analogous mechanisms to destroy CAR‐T at a clinically indicated time are also being investigated …”

Section: Efficacy Of Car‐t In Hematologic Malignanciesmentioning

confidence: 99%

Cellular therapy: Immune‐related complications

Oved

Barrett

Teachey

2019

Immunological Reviews

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The advent of chimeric antigen receptor T (CAR‐T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized “living therapy” is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR‐T. The overwhelming release of cytokines and chemokines by activated CAR‐T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti‐IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR‐T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR‐T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR‐T‐related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR‐T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR‐T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.

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A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia

Cited by 192 publications

References 29 publications

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

Cellular therapy: Immune‐related complications

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