Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes

Mous, Rogier; Savage, Philip; Remmerswaal, Ester B. M.; Lier, R. A. W. Van; Eldering, Eric; Oers, Marinus H. J. van

doi:10.1038/sj.leu.2404185

Cited by 18 publications

(19 citation statements)

References 30 publications

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“…If we now consider the potential of this type of immunotherapy for clinical use, it should not be difficult to identify, in the majority of cancer patients to be treated, a robust T-cell memory against an endemic virus, such as EBV, CMV, or influenza, for which immunodominant viral peptides have been identified, as shown by a very recent study of B-chronic lymphocytic leukemia leukemia, in which the patients' anti-CMV T cells were redirected in vitro against leukemic cells by the use of a streptavidin-fused anti-CD20 ScFv antibody fragment in combination with biotinylated MHC class I molecules (46). The TAA most expressed on the tumor cells, such as HER2, CEA, CA125 (47), or PSMA (ref.…”

Section: Discussionmentioning

confidence: 99%

Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody × MHC/Viral Peptide Conjugates

Cesson¹,

Stirnemann²,

Robert³

et al. 2006

Clinical Cancer Research

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Purpose:To redirect an ongoing antiviralT-cell response against tumor cells in vivo, we evaluated conjugates consisting of antitumor antibody fragments coupled to class I MHC molecules loaded with immunodominant viral peptides. Experimental Design: First, lymphochoriomeningitis virus (LCMV)^infected C57BL/6 mice were s.c. grafted on the right flank with carcinoembryonic antigen (CEA)^transfected MC38 colon carcinoma cells precoated with anti-CEA Â H-2D b /GP33 LCMV peptide conjugate and on the left flank with the same cells precoated with control anti-CEA F(ab ¶) 2 fragments. Second, influenza virus^infected mice were injected i.v., to induce lung metastases, with HER2-transfected B16F10 cells, coated with either anti-HER2 Â H-2D b /NP366 influenza peptide conjugates, or anti-HER2 F(ab ¶) 2 fragments alone, or intact anti-HER2 monoclonal antibody. Third, systemic injections of anti-CEA Â H-2D b conjugates with covalently cross-linked GP33 peptides were tested for the growth inhibition of MC38-CEA + cells, s.c. grafted in LCMV-infected mice.Results: In the LCMV-infected mice, five of the six grafts with conjugate-precoated MC38-CEA + cells did not develop into tumors, whereas all grafts with F(ab ¶) 2 -precoated MC38-CEA + cells did so (P = 0.0022). In influenza virus^infected mice, the group injected with cells precoated with specific conjugate had seven times less lung metastases than control groups (P = 0.0022 and P = 0.013). Most importantly, systemic injection in LCMV-infected mice of anti-CEA Â H-2D b /cross-linked GP33 conjugates completely abolished tumor growth in four of five mice, whereas the same tumor grew in all five control mice (P = 0.016). Conclusion:The results show that a physiologic T-cell antiviral response in immunocompetent mice can be redirected against tumor cells by the use of antitumor antibody Â MHC/viral peptide conjugates.In recent years, a major effort has been dedicated to the development of active vaccination protocols for immunotherapy of cancer patients, using newly discovered tumor-specific or differentiation antigens (1 -3). Successful induction of specific T-cell responses and tumor infiltration by T lymphocytes were well documented, but the number of tumor remissions remained low (4,5). It is hard to understand the reasons for the relatively poor antitumor activity of the induced specific T lymphocytes, given that such effector cells are known to be so efficient in the elimination of virus-infected cells and in allograft rejection. Three major explanations have been given for the inefficiency of the T-cell antitumor response: the poor antigenicity of autologous tumor antigens, the low expression or absence of MHC molecules on the tumor cell surface, or some functional defects in their antigen-processing machinery (6, 7).Here, we present a new immunotherapeutic strategy that has the potential to overcome these obstacles. We coupled an antitumor antibody fragment to an MHC molecule loaded with an immunodominant viral peptide and showed that tumor cells coated with the...

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Section: Discussionmentioning

confidence: 99%

Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody × MHC/Viral Peptide Conjugates

Cesson¹,

Stirnemann²,

Robert³

et al. 2006

Clinical Cancer Research

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“…CLL cells coated with this targeting complex (TC) were lysed by autologous CMV-specific CTLs with efficiency similar to that of CLL cells directly loaded with CMV peptide. 37 Furthermore, we demonstrated that TC-coated CLL induced both proliferation and production of IFN-␥, tumor necrosis factor alpha (TNF-␣), and macrophage inflammatory protein-1␤ in CMV-specific CD8 ϩ T cells. 37 CMV-specific CD8 ϩ cells are promising effector cells for use in clinical cellular immunotherapy studies.…”

Section: Improving T-cell Function and Activationmentioning

confidence: 98%

“…37 Furthermore, we demonstrated that TC-coated CLL induced both proliferation and production of IFN-␥, tumor necrosis factor alpha (TNF-␣), and macrophage inflammatory protein-1␤ in CMV-specific CD8 ϩ T cells. 37 CMV-specific CD8 ϩ cells are promising effector cells for use in clinical cellular immunotherapy studies. They are proven to be cytotoxic, not autoreactive and capable of homing in a broad variety of tissues.…”

Section: Improving T-cell Function and Activationmentioning

confidence: 98%

“…Indeed, it has been shown that host immune responses against adenoviral vectors include the production of proinflammatory cytokines such as IFN-␥ 48 and the expansion of (adenoviral-specific) CTLs. 49 Although an in vivo antiadenoviral response could have contributed to the clinical effects of both studies, enzyme-linked immunospot (ELISPOT) assays and autologous mixed lymphocyte reactions (MLRs) indicated that the infusion of Ad-CD154-CLL cells also increased the numbers of T cells that produce IFN-␥ in vitro in response to 36 Mous et al 37 autologous CLL cells. 31 These in vitro studies used CD40-activated CLL stimulator cells that were not infected with Ad, indicating that infusion of Ad-CD154-CLL cells induced immune responses against leukemia cells independent of Ad antigens.…”

Section: Improving the Capacity Of Cll To Function As Effective Antigmentioning

confidence: 99%

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Cellular immune therapy for chronic lymphocytic leukemia

Kater

Oers

Kipps

2007

Blood

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Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapyresistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CLL. IntroductionChronic lymphocytic leukemia (CLL) is a CD5 ϩ B-cell malignancy that is considered incurable. Historically, the first-line treatment consisted of alkylating agents, which resulted in response rates in up to 70% of patients, but did not improve survival. 1 Treatment regimens with the nucleoside (purine) analogs, such as fludarabine monophosphate (F-ara-A) or pentostatin, were found to yield higher response rates and to provide for longer progression-free survival, 2 especially in combination with cyclophosphamide. 3 However, despite effecting increased complete response rates, treatment with purine analogs alone does not appear to improve survival. 2 Newer treatment combinations have incorporated use of monoclonal antibodies to chemotherapy. 4,5 Although treatment with such combinations might provide for a first-time-observed survival benefit, 6 such therapy still is not considered curative.Although most patients initially respond to these chemotherapeutic approaches, many develop therapy-resistant disease with repeated therapy. Patients with refractory disease more frequently have leukemia cells that harbor deletions in the short arm of chromosome 17 (17pϪ), which often is associated with loss of functional p53, or in the long arm of chromosome 11 (11qϪ) in and/or around the gene encoding the ataxia telangectasia (ATM), which is a kinase required for p53 function. 7,8 Moreover, many chemotherapy-refractory patients have leukemia cells that have lost functional p53. Because the cytoreductive activity of most chemotherapy agents requires functional p53, 9,10 loss of p53 is ...

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“…However, these constructs were lacking FcRn-binding properties and as a consequence were rapidly cleared and had short in vivo half-lives. An alternative was to generate the pMHCI complex and the antibody separately and fuse both of them by chemical conjugation or by biotin-streptavidin coupling (14,22,(41)(42)(43)(44)(45). Chemical conjugation is technically laborious especially at a larger scale and sitespecific conjugation is not fully developed yet.…”

Section: Discussionmentioning

confidence: 99%

A New Class of Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules to Redirect CD8 T Cells

Schmittnaegel¹,

Hoffmann²,

Imhof-Jung³

et al. 2016

Molecular Cancer Therapeutics

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Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes

Cited by 18 publications

References 30 publications

Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody × MHC/Viral Peptide Conjugates

Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody × MHC/Viral Peptide Conjugates

Cellular immune therapy for chronic lymphocytic leukemia

A New Class of Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules to Redirect CD8 T Cells

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