Antibody-targeted MHC complex–directed expansion of HIV-1– and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination

Stebbing, Justin; Gazzard, Brian; Patterson, Steve; Bower, Mark; Perumal, Dhayaneethie; Nelson, Mark; McMichael, Andrew J.; Ogg, Graham S.; Epenetos, Agamemnon A.; Gotch, Frances; Savage, Philip

doi:10.1182/blood-2003-09-3023

Cited by 13 publications

(10 citation statements)

References 41 publications

(38 reference statements)

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“…17 Its protective effects have also been shown to result in a decreased incidence of AIDS-defining malignancies, such as NHL 39 and Kaposi sarcoma, 20 with PI-and NNRTI-based HAART demonstrating equivalent efficacies. Here, we observed that protease inhibitors significantly enhanced neutropenia induced by infusional CDE chemotherapy in patients with ARL, evidenced by statistically significant decreases in day-10 and day-14 neutrophil counts in patients receiving PI-containing HAART compared with those who received HAART that did not contain PIs.…”

Section: Lymphoma Outcomementioning

confidence: 99%

Protease inhibitors potentiate chemotherapy-induced neutropenia

Bower

McCall-Peat

Ryan

et al. 2004

Blood

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109

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Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDSrelated non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicinetoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (MannWhitney U test; P ‫؍‬ .012) and day-14 (P ‫؍‬ .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colonystimulating factor (G-CSF) administered between groups (P ‫؍‬ .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART ( 2 test; P ‫؍‬ .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.

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Section: Lymphoma Outcomementioning

confidence: 99%

Protease inhibitors potentiate chemotherapy-induced neutropenia

Bower

McCall-Peat

Ryan

et al. 2004

Blood

Self Cite

109

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“…Our data on T-cell proliferation and cytokine production induced by TC-coated B-CLL are in line with a recent study showing that human immunodeficiency virus (HIV) and Karposi sarcoma antigen-containing HLA complexes induce expansion and activation of autologous HIV and Karposi sarcoma-specific CTL. 24 This emphasizes the potential of antibody-targeted MHC complexes as a new approach for therapeutic vaccination. In our study, intracellular staining revealed antigen-triggered production of IFN-g, TNF-a and MIP-1b in CD8-positive T cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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B-cell chronic lymphocytic leukaemia (B-CLL) is a slowly progressing malignancy of CD5 þ B cells, for which at present no curative treatment is available. In our current study, we apply a novel bridging reagent to redirect cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTL) to target B-CLL. A streptavidin-fused anti-CD20 single-chain variable fragment (scFv) is used in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CTL with similar efficiency as B-CLL cells directly loaded with CMV peptide. Killing is HLA restricted and occurs at scFv CD20 concentrations of X100 ng ml À1 and HLA/CMV concentrations of X20 ng ml À1. Furthermore, complex-coated B-CLL cells induce both proliferation and cytokine production (interferon c, tumour necrosis factor a and macrophage inflammatory proteinÀ1 b) in CMV-specific CD8 þ T cells. Hereby, a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B-cell malignancies is constituted.

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“…This local induction of CTLmediated tumor cell lysis may trigger the recruitment, crosspriming, and full activation of the T cells induced by active vaccination and additionally kill the resistant clones with low MHC expression. Indeed, it has been shown that soluble MHC class I, loaded with specific peptides, can act as powerful antigens (49). In the second case, when treatment with the classic antitumor mAbs, such as anti-HER2, anti -epidermal growth factor receptor, or anti-CD20, have induced significant tumor remission, but tumor cells are still present, an additional injection with the antibody-MHC conjugate loaded with viral peptide may add the necessary local CTL targeting to eliminate the tumor cells resistant to the action of antibody alone.…”

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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Antibody-targeted MHC complex–directed expansion of HIV-1– and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination

Cited by 13 publications

References 41 publications

Protease inhibitors potentiate chemotherapy-induced neutropenia

Protease inhibitors potentiate chemotherapy-induced neutropenia

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

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

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