Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

Melenhorst, J. Joseph; Chen, Gregory M.; Wang, Meng; Porter, David L.; Chen, Changya; Collins, McKensie; Gao, Peng; Bandyopadhyay, Shovik; Sun, Hongmin; Zhao, Ziran; Lundh, Stefan; Pruteanu-Malinici, Iulian; Nobles, Christopher L.; Maji, Sayantan; Frey, Noelle V.; Gill, Saar; Loren, Alison W.; Tian, Lifeng; Kulikovskaya, Irina; Gupta, Minnal; Ambrose, David E; Davis, Megan M.; Fraietta, Joseph A.; Brogdon, Jennifer L.; Young, Regina M.; Chew, Anne; Levine, Bruce L.; Siegel, Donald L.; Alanio, Cécile; Wherry, E. John; Bushman, Frederic D.; Lacey, Simon F.; Tan, Kai; June, Carl H.

doi:10.1038/s41586-021-04390-6

Cited by 453 publications

(372 citation statements)

References 25 publications

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“…Recent studies suggest that long-term persistence of the infused CAR T cells is crucial for sustained response. Moreover, Melenhorst and colleagues recently reported in a seminal paper a highly activated CD4 + population dominating the CAR T cell population at the later time points in two CLL patients with a decade-long remission post CAR T treatment [ 48 ]. These data speak for the importance of CD4 + CAR T counterpart for long-term cytotoxicity against CD19-expressing cells and support our findings suggesting that CD4 + CAR T cells may be less prone to exhaustion compared with CD8 + cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Beider

Itzhaki

Schachter

et al. 2022

Cells

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Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Beider

Itzhaki

Schachter

et al. 2022

Cells

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“…In fact, the presence of a stochastically recombined and highly polyclonal TCR repertoire, allowing HLA-unrestricted recognition of stress-induced molecules 8 , may also counteracts tumor immune evasion (via CAR antigen loss or HLA downregulation, for example). Moreover, the "trophic" (homeostatic) signals received through  TCR binding to butyrophilins constitutively expressed in multiple tissues 54 may be beneficial for in vivo persistence, and may underlie the recent description of a striking V1  T cell-associated CD19CAR-T cell expansion (from a very low initial frequency), over 10 years in a disease-free CLL patient 55 . Furthermore, although allogeneic CD19-directed CAR-NK cells have recently shown promising clinical results 56 , their "off-the-shelf" implementation may be difficult due to the reported substantial decrease in viability after the freezing/thawing process 57,58 , which contrasts with the robustness we observed with CD123CAR-DOTs.…”

Section: Discussionmentioning

confidence: 99%

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Martinez

Tirado

Mensurado

et al. 2022

Preprint

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Chimeric Antigen Receptor (CAR)-T cells have emerged as a breakthrough treatment for relapse/refractory (r/r) hematological tumors, showing impressive complete remission rates in B-cell malignancies. However, around 50% of the patients relapse before 1-year post-treatment. T-cell fitness is critical to prolong the persistence and activity of the adoptively transferred product. Allogeneic T cells from healthy donors are less dysfunctional or exhausted than autologous patient-derived T cells, enabling a very attractive and cost-effective off-the-shelf therapy option. In this context, Delta One T cells (DOTs), a recently described cellular product based on MHC/HLA-independent Vd1+ gd T cells generated from the peripheral blood of healthy donors, represent a robust platform of allogeneic effector T cells. Here we generated and pre-clinically validated 4-1BB-based CAR-DOTs directed against the IL-3a; chain receptor (CD123), a target antigen widely expressed on acute myeloid leukemia (AML) blasts. CD123CAR-DOTs showed vigorous, superior to control DOTs, cytotoxicity against AML cell lines and primary samples both in vitro and in vivo. Continuous administration of IL-15 supported the long-term persistence of a single-dose CD123CAR-DOTs in patient-derived xenograft models, sustaining their anti-leukemic efficacy as demonstrated in a re-challenge assay in vivo. Our results provide proof-of-concept for an allogeneic next-generation therapy based on CD123CAR-DOTs for r/r AML patients.

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“…CAR T-cell therapy introduces synthetic T-cell receptors into T-cells, which confer the ability to recognize tumor-specific surface antigens and initiate an MHC-independent immune response [ 39 , 40 , 41 ]. CAR T-cell therapy has had great efficacy in hematogenous malignancies but has been difficult to implement in solid tumors due to the immunosuppressive environment of the TME [ 2 , 40 ]. Moreover, solid tumors lack highly specific surface antigens, which can lead to numerous off-target effects when using CAR T-cell therapy.…”

Section: Current Immunotherapy Options and Developmentsmentioning

confidence: 99%

“…A recent promising advancement has been an immunotherapeutic approach, which may involve either antagonizing the tumor′s inherent immune-suppressive properties or, conversely, inducing a glioma-specific immune response using either exogenous or endogenous agents. Immunotherapy has recently been popularized by the impressive outcomes in hematogenous malignancies [ 2 ]. However, for immunotherapy to be successful in solid tumors such as GBM, it must overcome tumor heterogeneity and the physical barriers imposed by the BBB and the tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers

Lechpammer

Rao

Shah

et al. 2022

Cancers

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Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.

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Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

Cited by 453 publications

References 25 publications

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers

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