Monoclonal T-Cell Receptors: New Reagents for Cancer Therapy

Stauss, Hans J.; Cesco-Gaspere, Michela; Thomas, Sharyn; Hart, Daniel P.; Xue, Shao-An; Holler, Angelika; Wright, G. Payling; Perro, Mario; Little, Ann‐Margaret; Pospori, C; King, James P.; Morris, Emma

doi:10.1038/sj.mt.6300216

Cited by 54 publications

(49 citation statements)

References 71 publications

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“…42 Irrespective of the putative benefits to CAR-mediated killing that result from the costimulation that CAR-modified CTLs will obtain during native ␣␤TCR engagement, expression of a CAR by CTLs rather than by an activated but otherwise undefined T-cell population ensures that we do not generate a product that also contains undesirable populations such as alloreactive or T regulatory cells. 43 Inclusion of such cells may increase the risk of GVHD in the case of alloreactive cells or limit the ability of the CTLs to control malignant disease through a similar expansion and activation of T regulatory cells. Such unwanted components should be absent from virus-specific CTLs.…”

Section: Discussionmentioning

confidence: 99%

Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation

Micklethwaite¹,

Savoldo

Hanley³

et al. 2010

Blood

101

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IntroductionInfections, malignant relapse, and graft-versus-host disease (GVHD), continue to cause significant morbidity and mortality after hematopoietic stem cell (HSC) or cord blood (CB) transplantation. Virus infections such as cytomegalovirus (CMV), EpsteinBarr virus (EBV), and adenovirus (AdV) are particularly problematic and remain difficult to treat, especially after umbilical CB transplantation. [1][2][3][4][5] Although ganciclovir/foscarnet may help prevent or treat CMV 6 and CD20-specific antibody may control EBV-associated lymphoproliferation, 7 these drugs are expensive and are often toxic or ineffective due to primary or secondary resistance. 6 Moreover, AdV infections are increasingly common and effective treatments are not currently available. 8 The other major cause of morbidity and mortality is relapse, occurring in more than 30% of transplant recipients with B-cell acute lymphoblastic leukemia (B-ALL), [9][10][11][12] with few appealing therapeutic options and less than 10% long-term survival. 13,14 Although donor lymphocyte infusions can be used after HSC transplantation to treat both viral infections and leukemia relapse, these are associated with potentially life-threatening GVHD, 15 have a low success rate in relapsed B-ALL, 15,16 and are unavailable for CB transplant recipients. An alternative for viral infections is the adoptive transfer of cytotoxic T lymphocytes (CTLs) directed to CMV, 17,18 EBV,19,20 and, more recently, AdV, 21,22 which can rapidly reconstitute antiviral immunity after HSC transplantation without causing GVHD. Infusion of peripheral blood-derived T-lymphocyte lines enriched in cells simultaneously recognizing CMV, EBV, and AdV (multivirus-specific CTLs [MV-CTLs]) reproducibly controls infections due to all 3 viruses after allogeneic HSC transplantation. 21 Importantly, functional CMV-, EBV-, and AdV-specific CTLs can now also be generated from naive T cells isolated from CB units. 23 It is also possible to infuse leukemia-specific CTLs into patients after HSC transplantation 24,25 ; these can be generated by stimulating peripheral blood mononuclear cells with apoptotic leukemic blasts. 25,26 Unfortunately, however, the paucity of antigen-specific CTL precursors and the need to separate graft-versus-tumor from the graft-versus-host effect may require extensive culture to generate sufficient numbers of cells for adoptive T-cell therapy. 25,26 To overcome this difficulty, investigators have used T lymphocytes engineered to express chimeric antigen receptors (CARs) directed to self-antigens expressed by tumor cells. 27,28 For example, T cells expressing a CAR specific for the CD19 molecule 29,30 may be able to prevent or treat leukemia relapse in B-ALL patients as these cells almost invariably express CD19.It would be appealing to combine these approaches to prepare a single product containing CTLs that were virus specific (through The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge paym...

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Section: Discussionmentioning

confidence: 99%

Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation

Micklethwaite¹,

Savoldo

Hanley³

et al. 2010

Blood

101

View full text Add to dashboard Cite

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“…Furthermore, we assumed that CMV Ag-specific T cells can be engineered by CMV-TCR transfer independent of the HLA restriction of the TCRs, although up to now mainly transfer of HLA-A*0201-restricted tumor-specific TCRs has been studied (17). To verify these assumptions, we isolated, characterized, and cloned several CMV-specific TCRs that recognize different epitopes from pp65 restricted through various HLA allotypes.…”

Section: Cd8mentioning

confidence: 99%

CMV-Specific TCR-Transgenic T Cells for Immunotherapy

Schub

Schuster

Hammerschmidt

et al. 2009

The Journal of Immunology

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Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN-γ and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.

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“…The latter are highly polar and constitute one face of the Ca domain, which can form weak interactions with the bottom sheet, suggesting a mobility that may allow interactions with the CD3 heterodimers (34). Regardless of potential direct interactions with CD3 components, an improved TCR chain pairing ability has been suggested to enhance the association with CD3 components (39,40), which is supported by our previous finding using murinized TCRs (23). Efforts are under way to better characterize those interactions looking at the relative stability of murine/human chimeric C regions with CD3 components.…”

Section: Discussionmentioning

confidence: 99%