A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy

Philip, Brian; Kokalaki, Evangelia; Mekkaoui, Leila; Thomas, Simon; Straathof, Karin; Flutter, Barry; Marin, Virna; Marafioti, Teresa; Chakraverty, Ronjon; Linch, David C.; Quezada, Sergio A.; Peggs, Karl S.; Pulé, Martin

doi:10.1182/blood-2014-01-545020

Cited by 329 publications

(304 citation statements)

References 33 publications

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“…In previous studies, we have shown that RQR8-transduced cells are effectively depleted from mice with rituximab. 32 Others have shown that elimination of redirected T cells based on suicide genes may protect against side effects in patients. 44 The TCRs studied herein were derived from CD4 C Th cells, but are still functional in CD8…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that administration of the anti-CD20 antibody rituximab mediates effective deletion of RQR8-exopressing T cells in vitro and in vivo. 32 …”

Section: Selection Of Two Dp-4 Restricted T-cell Clones For Molecularmentioning

confidence: 99%

“…The sorting process effectively purified the fraction of TCR-C13/RQR8 and TCR-D71/RQR8 expressing T cells (data not shown), as previously reported for other constructs incorporating RQR8. 32 It is further desirable to obtain TCR-transduced T cells that can be propagated in vitro and used for functional assays. Such cell lines are not generally available, as T-cell lines like SupT1 are functionally impaired.…”

Section: Tcr/rqr8 Expression In Transduced Supt1 Cells and Binding Tomentioning

confidence: 99%

“…31,32 Briefly, PBMC transductions were performed as follows: PBMCs were isolated by Ficoll (GE Healthcare) gradient centrifugation and stimulated with phytohemagglutinin at 5 mg/mL. Interleukin-2 (IL-2) stimulation (100 IU/mL) was added following overnight stimulation.…”

Section: Tcr Expression and T-cell Redirectionmentioning

confidence: 99%

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T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

et al. 2016

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We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4 C Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted Tcell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNg, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4C and CD8 C T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…We have previously reported that administration of the anti-CD20 antibody rituximab mediates effective deletion of RQR8-exopressing T cells in vitro and in vivo. 32 …”

Section: Selection Of Two Dp-4 Restricted T-cell Clones For Molecularmentioning

confidence: 99%

Section: Tcr/rqr8 Expression In Transduced Supt1 Cells and Binding Tomentioning

confidence: 99%

Section: Tcr Expression and T-cell Redirectionmentioning

confidence: 99%

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T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

et al. 2016

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“…For instance, the truncated EGFR, co-expressed with the CAR by the same T cell, can be targeted by the antibody cetuximab which efficiently eliminates those marked cells [117]. Efforts are also being undertaken to coexpress the targetable epitope within the extracellular part of the CAR, thereby making the CAR itself a target of a depleting antibody [118]. An anti-idiotypic antibody directed against the scFv of the CAR itself may be used for depleting CAR T cells as well [119].…”

Section: (V) Car T Cell Eliminationmentioning

confidence: 99%

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

Holzinger¹,

Abken²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Adoptive therapy of malignant diseases by chimeric antigen receptor (CAR) redirected T cells takes advantage of the patient's own immune system to recognize and destroy cancer cells. This is impressively demonstrated by the induction of complete and lasting remissions of leukemia with CAR-engineered T cells in early phase trials. Recent developments in optimizing the CAR design, in the recognition of target cells and the production of modified cells for clinical use, have paved the path for a broader application than currently explored. The chapter reviews the differences in CAR design, the success in the treatment of hematologic malignancies, the challenges in treating solid cancer, the treatment-related toxicities, and strategies to improve safety of CAR T cell therapy. Challenges for future applications are discussed.

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Cancer Gene Therapy

Tashiro

Brenner

2017

Holland‐Frei Cancer Medicine

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Overview Gene therapy of cancer has shown increasingly encouraging results and now is ready to enter mainstream oncological practice. Gene transfer can modify the cellular phenotype and behavior of malignant cells or host immune cells in order to modulate tumor responses. In this chapter, we discuss both of the above approaches and describe the vector systems that are able to produce the intended genetic modifications. We describe current clinical successes of gene therapy and outline the challenges it has yet to overcome. The success of either approach depends on efficient, safe gene transfer with vectors that can either integrate (e.g., retroviral, lentiviral, or adeno‐associated viral, or transposons) or not integrate (e.g., adenoviral, herpesviral, or nonviral) into the human genome. To date, reversing the phenotype of all stem cells within a cancer has not proven feasible, and infectious cytolytic viral therapy has not yet had a significant impact in the clinic. Enhancement of active cancer immunotherapy with forced expression of antigens and cytokines or the enhancement of adoptive immunotherapy by engineering T lymphocytes with specific T‐cell receptors and chimeric antigen receptors shows greater immediate promise, although ultimately a combination of multiple approaches will prove optimal.

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A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy

Abstract: Key Points Marker genes enable detection and selection of T cells, whereas suicide genes enable selective destruction of T cells in case of toxicity. RQR8 is a 136-amino-acid epitope-based marker/suicide gene that enables clinical selection, cell tracking, and deletion in case of toxicity.

Cited by 329 publications

References 33 publications

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

Cancer Gene Therapy

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