Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy

Shah, Nirali N.; Qin, Haiying; Yates, Bonnie; Su, Ling; Shalabi, Haneen; Raffeld, Mark; Ahlman, Mark A.; Stetler‐Stevenson, Maryalice; Yuan, Constance; Guo, Shuang; Liu, Siyuan; Hughes, Stephen H.; Fry, Terry J.; Wu, Xiaolin

doi:10.1182/bloodadvances.2019000219

Cited by 95 publications

(70 citation statements)

References 31 publications

(36 reference statements)

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“…Almost no genotoxic effects from gene transfer into differentiated cells, including T cells, are known. Only a few cases of virus-mediated transformation in patients treated with genetically modified T cells have been reported so far [65][66][67]. A lentiviral vector-mediated insertion of the CAR transgene was observed in a CLL patient treated with CD19-specific CART cells, leading to a disruption of the methylcytosine dioxygenase TET2 gene [65].…”

Section: Viral Transductionmentioning

confidence: 99%

“…Although insertional mutagenesis is undesirable, the described TET2 modification could be used for an optimization of CART cell therapy. An additional case of clonal expansion was seen in a patient that was treated with CD22-specific CART cells caused by lentiviral vector-mediated integration in the CBL gene that is important for the regulation of T cell responses [66]. Furthermore, insertional mutagenesis led to tumor escape in a patient relapsing after treatment with CD19-specific CART cells with a CD19-negative leukemia [67].…”

Section: Viral Transductionmentioning

confidence: 99%

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Optimizing Manufacturing Protocols of Chimeric Antigen Receptor T Cells for Improved Anticancer Immunotherapy

Stock

Schmitt

Sellner

2019

IJMS

101

106

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Chimeric antigen receptor (CAR) T cell therapy can achieve outstanding response rates in heavily pretreated patients with hematological malignancies. However, relapses occur and they limit the efficacy of this promising treatment approach. The cellular composition and immunophenotype of the administered CART cells play a crucial role for therapeutic success. Less differentiated CART cells are associated with improved expansion, long-term in vivo persistence, and prolonged anti-tumor control. Furthermore, the ratio between CD4+ and CD8+ T cells has an effect on the anti-tumor activity of CART cells. The composition of the final cell product is not only influenced by the CART cell construct, but also by the culturing conditions during ex vivo T cell expansion. This includes different T cell activation strategies, cytokine supplementation, and specific pathway inhibition for the differentiation blockade. The optimal production process is not yet defined. In this review, we will discuss the use of different CART cell production strategies and the molecular background for the generation of improved CART cells in detail.

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Section: Viral Transductionmentioning

confidence: 99%

Section: Viral Transductionmentioning

confidence: 99%

Optimizing Manufacturing Protocols of Chimeric Antigen Receptor T Cells for Improved Anticancer Immunotherapy

Stock

Schmitt

Sellner

2019

IJMS

101

106

View full text Add to dashboard Cite

show abstract

“…Similarly, vector insertions in CAR T cells might trigger clonal expansions of genetically modified cells, showing dramatic in vivo expansion of a single clone. As documented in CAR T cell trials using viral vectors, vector insertion within the CBL oncogene and disruption of the normal TET2 allele were reported(56,57). Despite a recent study has suggested that vector insertions might promote CAR T clonal expansion which correlates with positive outcome (58), we did not find any evidence that SB insertions in our trial have triggered any clonal dominance, no selection of genes targeted by CIS which have been associated with potential leukemogenic insertional events in preclinical and clinical gene therapy.…”

mentioning

confidence: 91%

Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

Magnani¹,

Gaipa²,

Lussana³

et al. 2020

Journal of Clinical Investigation

123

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Background. Chimeric antigen receptor (CAR) T cell immunotherapy has achieved complete remission and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. Methods. We reported the early results of a phase I/II trial in B-cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine induced killer cells (CIK). Results. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were two grade I and a grade II cytokine release syndrome (CRS) cases at the highest dose, in the absence of graftversus-host disease (GvHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients, receiving the highest doses, achieved CR and CRi at day 28. Five out of 6 patients in CR were also minimal residual disease (MRD)-negative. Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. Conclusion. SB-engineered CAR T cells expand and persist in pediatric and adult BALL patients relapsed after HSCT. Anti-leukemic activity was achieved without severe toxicities. Trial registration. clinicaltrials.gov NCT03389035.

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“…Another study points out that the lentivirus used to establish anti CD22 CAR-T cells was associated with clonal expansion of cells harboring provirus insertion in the CBL (casitas B-lineage lymphoma) proto-oncogene, though the patients’ ALL resolved and the CAR-T cells ceased the expansion. A subsequent CD22-negative relapse suggests a mechanism independent of CAR-T cell function [ 120 ]. This indicates, so far, that insertional mutagenesis can generate relevant functional data indicating genome locations where CAR insertion impacts T cell expansion.…”

Section: New Routes For Gene Transfer: Bringing the Car To The Celmentioning

confidence: 99%

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

Chicaybam

Bonamino

Invitti

et al. 2020

Cancers

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Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990’s, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen receptors (CAR-T cells) has met with clear success and holds great promise for the future treatment of cancer. We detail a series of considerations for the improvement of the CAR-T cell approach, including the design of the CAR, routes of gene transfer, introduction of CARs in natural killer and other cell types, combining the CAR approach with checkpoint blockade or oncolytic viruses, improving pre-clinical models as well as means for reducing cost and, thus, making this technology more widely available. While CAR-T cells serve as a prime example of translating novel ideas into effective treatments, certainly the lessons learned will serve to accelerate the current and future development of gene therapy drugs.

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Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy

Abstract: Key Points Reexpansion of CAR T cells led to further investigations which confirmed the clonal nature of this expansion.

Cited by 95 publications

References 31 publications

Optimizing Manufacturing Protocols of Chimeric Antigen Receptor T Cells for Improved Anticancer Immunotherapy

Optimizing Manufacturing Protocols of Chimeric Antigen Receptor T Cells for Improved Anticancer Immunotherapy

Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

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