Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study

Meij, Pauline; Jedema, Inge; Hoorn, Menno A.W.G. van der; Bongaerts, Rian; Cox, Linda; Wafelman, Amon R.; Marijt, Erik W.A.; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.3324/haematol.2011.053371

Cited by 53 publications

(44 citation statements)

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“…At the end of the culture period (day [10][11][12][13][14], purified virus-specific T cells transduced with the HA-1-TCR were tested for antigen-specific interferon (IFN)-γ production in a standard enzymelinked immunosorbent assay (CLB, Amsterdam, the Netherlands).…”

Section: Functional Analysismentioning

confidence: 99%

“…4 We have recently presented the results of our phase I clinical study in which the toxicity and the potential anti-leukemic effect of treatment with HA-1-specific cytotoxic T lymphocyte lines was examined in three patients with a leukemic relapse following allogeneic SCT. 14 The administration of HA-1-specific T-cell lines was demonstrated to be safe without induction of GvHD. However, HA-1-specific T-cell lines lacked in vivo persistence and in vivo anti-leukemic reactivity.…”

Section: Introductionmentioning

confidence: 99%

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A Good Manufacturing Practice procedure to engineer donor virus-specific T cells into potent anti-leukemic effector cells

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nEBV reactivation or EBV-positive B-cell lymphomas, respectively. This adoptive transfer was demonstrated not only to be effective in preventing or curing the viral diseases but also to be safe without inducing GvHD. In addition, long-term persistence of the virus-specific donor T cells was demonstrated. 26 We hypothesize that in vivo activation of the endogenous TCR by viral antigens can result in both increased numbers of TCR-modified T cells, as well as in increased introduced TCR expression, as T-cell stimulation is followed by increased activation of the retroviral promotor. [30][31][32] Previously, we demonstrated that we could reprogram virus-specific T cells into antileukemic effector T cells using TCR gene transfer without loss of their original anti-virus specificity. 33,34 Another possible advantage of the use of virus-specific T cells is the exclusion of regulatory T cells from the pool of TCR-modified lymphocytes that can possibly disturb the immune reaction. Since virus-specific T-cell populations consist of a restricted TCR repertoire, 35,36 the number of different mixed TCR dimers formed will be limited and from in vivo data this appears a viable strategy to prevent neoreactivity 37 caused by mixed TCR dimers. 37,38 Furthermore, we have modified the HA-1-TCR both to improve cell surface expression of the HA-1-TCR, and to diminish mixed TCR dimer expression with unknown and potentially unwanted reactivity. 38,39 For the clinical study, we will selectively isolate permissive virus-specific T cells that highly express HA-1-TCR after gene transfer (Table 1). 39,40 Recently, Streptamers were used to selectively isolate CMV-specific T cells. 41 CMV-specific T cells were transferred directly after Streptamer-based isolation into patients with CMV reactivation without toxicity, and patients were able to manage CMV virus thereafter. 41 Here, we describe a Good Manufacturing Practice (GMP) procedure to rapidly generate dual-specific, donor virusspecific T cells with high avidity anti-leukemic reactivity. The process of Streptamer-based isolation of pure populations of virus-specific T cells and transduction with GMPgrade retroviral supernatant encoding the HA-1-TCR has been validated with four large-scale test procedures in the cleanroom. All HA-1-TCR-transduced, virus-specific T-cell products met the criteria for in process testing and quality control testing, and were highly reactive against HA-1-positive leukemic cells. Methods Selection and isolation of virus-specific T cellsThis study was approved by the Leiden University Medical Center institutional review board and written informed consent was obtained according to the Declaration of Helsinki. From donor leukocytes from a leukapheresis product or total peripheral blood mononuclear cells either one or two virus-specific T-cell populations were isolated using Streptamers (Table 1) (Stage Therapeutics, Götingen, Germany) according to the manufacturer's instructions. Streptamer-incubated donor le...

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Section: Functional Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Good Manufacturing Practice procedure to engineer donor virus-specific T cells into potent anti-leukemic effector cells

et al. 2013

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“…Six of these studies involved individuals bearing hematological (most often B-cell) malignancies, 80 - 85 especially in settings of post-HSCT relapse 80 , 81 , 83 , 85 . The remaining 4 trials investigated the clinical potential of ACT in patients with neuroblastoma, nasopharyngeal carcinoma, melanoma or recurrent ovarian carcinoma 86 - 89 .…”

Section: Literature Updatementioning

confidence: 99%

Trial Watch

et al. 2013

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Adoptive cell transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic cell-based approaches (which de facto constitute cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of cellular immunotherapy.

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“…4, 5 At least three cell types other than dendritic cells (DCs) have been used as APCs for clinical studies, but individually all have mechanistic or practical limitations that preclude broader use. For example, autologous EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) can induce T-cell responses to subdominant virus-associated tumor antigens such as LMP1 and LMP2 if they are forced to express the target at high level, for example by adenovirus transduction, but they also express strong endogenous antigens.…”

Section: Introductionmentioning

confidence: 99%

Complementation of Antigen-presenting Cells to Generate T Lymphocytes With Broad Target Specificity

Ngo¹,

Ando

Leen

et al. 2014

Journal of Immunotherapy

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Antigen-specific T-cells provide a therapy for cancer that is highly specific, self-replicating and potentially devoid of toxicity. Ideally, tumor-specific T-cells should recognize multiple epitopes on multiple antigens to prevent tumor immune-escape. However the large-scale expansion of such broad-spectrum T-cells has been limited by the availability of potent autologous antigen-presenting cells that can present antigens on the polymorphic array of each patient's HLA allotype. We evaluated a novel antigen-presenting complex (KATpx) in which antigens in the form of peptide libraries can be presented by autologous activated T-cells while co-stimulation is complemented in trans by an HLA-negative K562 cell line genetically modified to express CD80, CD83, CD86 and 4-1BBL (K562cs). The additional co-stimulation provided by K562cs significantly enhanced T-cell expansion in culture over autologous activated T-cells alone while maintaining antigen specificity. We validated this antigen-presenting system by generating Epstein Barr Virus (EBV) antigen-specific T-cells from healthy donors and from patients with EBV-positive malignancies including nasopharyngeal carcinoma (NPC) and multiply relapsed EBV-positive lymphoma. These T-cells were specific for EBNA1, LMP1 and LMP2, the viral antigens expressed in these type 2 latency EBV-associated malignancies. The KATpx system consistently activated and expanded antigen specific T-cells both from healthy donors and from 5 of 6 patients with lymphoma and 6 of 6 with NPC, while simplifying the process for generating APCs by eliminating the need for live virus (EBV) or viral vectors to force expression of transgenic EBV antigens. Hence KATpx provides a robust, reliable, and scalable process to expand tumor-directed T-cells for the treatment of virus-associated cancers.

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Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study

Cited by 53 publications

References 18 publications

A Good Manufacturing Practice procedure to engineer donor virus-specific T cells into potent anti-leukemic effector cells

A Good Manufacturing Practice procedure to engineer donor virus-specific T cells into potent anti-leukemic effector cells

Trial Watch

Complementation of Antigen-presenting Cells to Generate T Lymphocytes With Broad Target Specificity

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