WO2000044893A9 - In vitro activated gamma delta lymphocytes - Google Patents
In vitro activated gamma delta lymphocytesInfo
- Publication number
- WO2000044893A9 WO2000044893A9 PCT/US2000/001867 US0001867W WO0044893A9 WO 2000044893 A9 WO2000044893 A9 WO 2000044893A9 US 0001867 W US0001867 W US 0001867W WO 0044893 A9 WO0044893 A9 WO 0044893A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cells
- leukemia
- cell
- donor
- graft
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
Definitions
- Allogeneic bone marrow transplantation provides a potentially curative treatment for leukemias that are refractory to conventional therapy.
- BMT offers an adoptive immunotherapy effect (graft-versus-leukemia-GvL) that can be beneficial in the elimination of residual leukemia.
- TCD T cell depletion
- GvHD graft-versus-host disease
- relapse rates in high-risk patients can be as high as 70% (2). Therefore, further improvement in disease- free survival is likely to depend on the antileukemic effectiveness of the transplant, i.e. maximizing the GvL effect.
- GvL effectors are predominantly T cells that can either recognize allospecific molecules expressed on both normal and neoplastic hematopoietic cells or recognize cell surface molecules that are either unique to or preferentially expressed by the leukemia (3-7).
- Identification of specific cell populations that are important antileukemic effectors is an essential first step to successful GvL graft engineering and cellular immunotherapy.
- ⁇ + T cells may not be important primary effectors of GvHD (8-12), few have addressed the GvL potential of ⁇ + T cells.
- Essiin (13) noted that in vitro activated ⁇ + T cells can mediate broadly-based non-MHC restricted cytolytic activity to selected human tumor cell lines.
- High-dose chemo/radiotherapy followed by bone marrow rescue provides a potentially curative treatment for a variety of leukemias and solid tumors that are refractory to conventional therapy.
- An alloreactive response mediated by donor immunocompetent cells in the graft and directed against normal cells and tissues in the recipient can result in the development of graft-versus-host disease (GvHD).
- GvHD can occur in up to 50% of patients receiving unmodified, HLA-identical marrow, indicating that minor histocompatibility differences, not detected by conventional HLA matching techniques, can initiate this reaction (22,23).
- Alternative donors include the HLA-phenotypically matched unrelated donor (MUD), a partially mismatched related donor (PMRD) or a cord blood donor (CBD), who can be a phenotypically matched or mismatched related or unrelated donor (1).
- MUD HLA-phenotypically matched unrelated donor
- PMRD partially mismatched related donor
- CBD cord blood donor
- Graft engineering, T cell depletion, and graft-host interactions Initial attempts to use non-manipulated marrow from MUDs and PMRDs have resulted in severe or fatal GvHD (24,25). This stimulated the development of methods to remove the suspected mediators of GvHD (T lymphocytes) from the marrow ex vivo prior to infusion (26).
- pan- TCD aggressive ex vivo pan- TCD was felt not to be optimal in facilitating PMRD BMT, and subsequent studies have explored the use of a modified pan-T cell depletion that leaves more T cells in the graft.
- Another option is the use of a more selective or targeted type of TCD often combined with post-transplant immune suppression (11-13).
- TCD T cell depletion
- GvL graft-versus- leukemia
- GvL The GvL reaction is through to be most effective in chronic phase CML (34,35), although there is also evidence for a GvL effect in the acute leukemias (36). It is generally thought that T lymphocytes recognize and eliminate residual leukemia through both MHC restricted and non- restricted pathways (37). Targets for GvL may include minor and/or major mismatched histocompatibility antigens and/or leukemia-specific antigens (38,39). Every allogeneic BMT patient potentially could benefit from the alloreactive response, although the extent of this benefit varies depending on whether the leukemia expresses allogeneic antigens to a degree that triggers recognition and killing.
- T cell recognition of leukemia-associated antigens is also through to be a potentially important means by which immunocompetent cells may recognize and eliminate residual leukemia. It is known that leukemia-reactive clones can be generated (15). Specific targets for leukemia-reactive clones remain the topic of intense investigation, and some potential leukemia-associated antigens have been identified (3,16-19) and are discussed below. The ability to identify and stimulate a GvL effect via either or both of these mechanisms may be of therapeutic importance in reducing the risk of relapse in patients who have received TCD grafts.
- ⁇ + T lymphocytes Five to ten percent of T cells in normal peripheral blood bear the y ⁇ receptor (42), although this number may be slightly higher in Asians and Blacks.
- ⁇ + T cells play a substantially different role in the immune system than that of ⁇ + T cells.
- One of the most obvious differences is that most ⁇ + T cells usually do not co-express CD4 or CD8, and therefore may develop normally in the absence of MHC class II molecules (43) since positive selection may not be required.
- MHC class II molecules 423 since positive selection may not be required.
- it is difficult to elicit a response of ⁇ + T cells against allogeneic MHC class I or II antigens and when it has been possible to obtain ⁇ + T cell clones against peptide antigens, recognition of these peptides is usually not restricted by classical MHC molecules (44).
- ⁇ + T cells tend to recognize intact rather than processed polypeptide (44).
- ⁇ + T cells do not require presentation of antigens in the context of the MHC Class I or Class II molecules for activation (45), however, they probably require CD28-mediated co-stimulation, and, following activation, show autocrine IL-2 production (46). They can also be activated by anti-CD2 antibodies (47).
- ⁇ + T cells which express CD25 have also been shown to adhere to fibronectin-coated plates via the VLA-4 receptor with subsequent expansion, and cross linking of VLA-4 and VLA-5 receptors result in co-stimulated expansion induced by an anti pan- ⁇ monoclonal antibody (48). Recent evidence has also suggested that certain subtypes of ⁇ + T cells, predominantly the ⁇ + CD8 ⁇ + homodimer population, may be resistant to Cyclosporin A (49).
- TCR- ⁇ + T lymphocytes Potential role of TCR- ⁇ + T lymphocytes in allogenic BMT: While activation mechanisms for ⁇ + T cells are just being elucidated, even less is known about the role of these cells in graft-host interactions. Ellison (50) reported an increase in peripheral ⁇ + T cells in murine studies of acute GvHD following allogeneic non-TCD BMT (50). In that study, depletion of ⁇ + T cells resulted in a significant decrease in GvHD-related mortality. Blazar (51) also has shown that murine ⁇ + T cells can play a role in rejection, alloengraftment, and GvHD through recognition of the "nonclassical" MHC class lb antigens. Studies in humans have to this point been in conflict with murine studies.
- ⁇ + T cells have been found in one (study to be associated with viral and fungal infections during the first year following TCD BMT in patients receiving either PMRD or MUD grafts (12).
- increases in ⁇ + T cells were not found to be associated with GvHD.
- Esslin 13
- in vitro activated peripheral blood ⁇ + T cells posses cytolytic activity to selected human tumor cell lines when compared to similarly activated ⁇ + T cells. This reactivity was not MHC restricted, but was dependent on interaction with LFA-1b/ICAM1 rather than the y ⁇ receptor.
- V ⁇ 3/V ⁇ 1 form of the T cell receptor preferentially expressed the V ⁇ 3/V ⁇ 1 form of the T cell receptor.
- V ⁇ 1+ cell activation has also been reported in response to EBV-transformed B cells (14,53), EBV-infected Burkitt lymphoma cells (53), and Daudi lymphoma cells (54).
- EBV-transformed B cells (14,53)
- EBV-infected Burkitt lymphoma cells 53
- Daudi lymphoma cells 54
- one recent report has shown cytotoxic anti-leukemic activity in a patient against B cell ALL by ⁇ + T cells expressing the V ⁇ 1 form of the T cell receptor (19).
- Donor mononuclear cells were depleted of CD4+/CD8+ T cells, and expanded on a combination of immobilized pan- ⁇ monoclonal antibody and irradiated recipient B cell leukemia. After initial culture and re-stimulation, the cultures expanded rapidly and contained almost exclusively V ⁇ 1+ ⁇ + T cells which expressed CD3, CD25, and CD69, but were CD4- and CD8- which are cytolytic to recipient leukemia and K562 cells but are minimally cytolytic to self MNC and third party leukemia.
- FIG. 1 shows the expansion of donor ⁇ + T cells in culture.
- Fig. 2 shows the phenotypic analysis of proliferating ⁇ + T cells from cultures on pan- ⁇ MAb with blasts.
- Fig. 3 shows the phenotypic analysis of proliferating ⁇ + T cells from cultures on pan- ⁇ MAb without blasts.
- Fig. 4 shows the phenotype of ⁇ + T cells from Patient #1.
- Fig. 5 shows the flow cytometric binding assay depicting the binding of activated donor ⁇ + T cells to recipient leukemic CD19+ blasts.
- Fig. 6 shows the cytotoxicity of donor ⁇ + T cells.
- Fig. 7 shows the cytotoxicity of expanded ⁇ + T cells against various cell lines.
- Fig. 8 shows the cytotoxic effects of expanded ⁇ + T cells against other cell lines.
- Fig. 9 shows the mRNA and surface expression of V ⁇ subtypes. DESCRIPTION OF THE PREFERRED EMBODIMENTS EXPERIMENTAL PROTOCOLS
- Donor/recipient pairs Three patients who presented for BMT with relapsed acute lymphoblastic leukemia or induction failure and their HLA-partially mismatched related donors were enrolled in this study.
- the cells were then cryopreserved at a concentration of 20 x 10 6 /ml in AIM-5 medium (Gibco) with 15% fetal bovine serum (Gibco) and 10% DMSO and stored in liquid nitrogen until donor selection was complete. Up to 50 ml of peripheral blood was then obtained from the corresponding partially mismatched related donor. These donor- derived ⁇ + T cells were purified in the MNC layer by negative selection using CD4+ and CD8+ immunomagnetic microspheres (Dynal) at a ratio of 5 microspheresxell. Removal of CD4+ and CD8+ cells from peripheral blood effectively depleted >95% of ⁇ + T cells.
- the number of ⁇ + T cells in the preparation and the effectiveness of the ⁇ + T cell depletion was monitored by flow cytometry as described below using fluorochrome- conjugated antibodies to TCR- ⁇ , TCR- ⁇ , CD4, CD8, and CD3 (Becton-Dickinson Immunocytometry Systems-BDIS; San Jose, CA).
- ⁇ + T cells were generated from donor-recipient pairs as follows: Tissue culture-treated 24 well plates were coated with 10 ⁇ g TCR- ⁇ 1 pan- ⁇ monoclonal antibody (Endogen; Woburn, MA) in 300 ⁇ g PBS for 24h at 4°C to facilitate initial activation and expansion of ⁇ + T cells as described by Esslin (13). Irradiated (50Gy) primary leukemic blasts that were obtained and cryopreserved prior to BMT were thawed, washed x 3, and re-suspended in AIM-5 Media with 15% FBS and 25IU of IL-2 at a concentration of 1.0 x 10 6 cells/ml.
- Endogen Woburn, MA
- Flow cytometry Expanded/activated ⁇ + T cells were analyzed by four color flow cytometry for expression of CD45, CD3, CD4, CD8, CD19, CD56, CD25, HLA-DR, CD69 (Becton Dickinson Immunocytometry Systems; San Jose, CA-BDIS), and V ⁇ 1 (Endogen, Woburn, MA), TCR- ⁇ , CD57, CD94, and V ⁇ 1-V ⁇ 3 (Coulter Immunotech; Miami, FL) using monoclonal antibodies conjugated with fluorescein isothiocyanate (FITC), phycoerythrin (PE), peridinin chlorophyll protein (PerCP), or allophycocyanan (APC).
- FITC fluorescein isothiocyanate
- PE phycoerythrin
- PerCP peridinin chlorophyll protein
- API allophycocyanan
- Recipient primary B cell leukemias were analyzed for expression of CD19, CD10, CD45, CD7, CD20, CD23, slgG ⁇ , slgG ⁇ , HLA-ABC, and HLA-DR (all from BDIS). At least 50,000 ungated events were collected in a list mode file and cell subpopulations in the lymphocyte CD45/side scatter gate and CD3/side scatter gate are quantitated and expressed as a percentage of the total lymphocyte population. Analysis was performed on a FACS Calibur flow cytometer using CellQuest software (BDIS).
- Flow cytometric binding assays Binding of donor ⁇ + T cells to specific targets was examined by flow cytometry.
- Donor ⁇ + T cells were incubated in AIM-5 Media with 15% FBS for 30 minutes at 37°C, centrifuged, and resuspended in phosphate-buffered saline.
- the cell suspension was labeled with one MAb specific for the leukemia but not expressed on ⁇ + T cells (CD19) and anti-TCR ⁇ , which is not expressed on the leukemia.
- the cell preparation was incubated at 4°C for 30 min, washed x 3, and analyzed by flow cytometry as detailed above.
- Cytotoxicity assays Third-party mononuclear cells, K562 erythroleukemia cells, and recipient primary leukemia were used as targets. Aliquots of target cells were labeled overnight with 3,3'-dioctadecyloxacarbocyanine (DiOC décor) (Molecular Probes, Eugene, OR). The cells were then washed in phosphate buffered saline (PBS) and resuspended in RPMI-1640 with 10% fetal bovine serum (FBS) at a concentration of 2 x 10* cells/ml. Control MNC and expanded ⁇ + T cells were suspended in RPMI-1640 and diluted to yield E:T ratios of 40:1-2.5:1 and added to the target cells.
- PBS phosphate buffered saline
- FBS fetal bovine serum
- ⁇ T cell Receptor Characterization The clonal heterogeneity of ⁇ + T cells determined by flow cytometry was further evaluated using molecular approaches to assess ⁇ TCR variable gene expression using peripheral blood mononuclear cells (PBMC) collected from the BMT donors and the expanded ⁇ + T cells from derived from culture on the pan- ⁇ MAb and co-culture with the recipient ALL.
- PBMC peripheral blood mononuclear cells
- Total RNA was extracted from MNC or cultured cells by the acid-phenol guanidinium thiocyanate method (55) and reverse transcribed according to the GeneAmp RNA PCR protocol (Perkin-Elmer Cetus, Norwalk, CT).
- the cDNA product served as template for PCR amplifications utilizing ⁇ TCR gene family- specific primers according to established methods (56).
- PCR amplification products were analyzed by agarose gel electrophoresis in order to determine the number and identity of ⁇ TCR V gene families expressed in each sample. This analysis was facilitated by DNA blot hybridization with corresponding TCR C ⁇ - or C ⁇ -horseradish peroxidase (HRP) conjugated oligonucleotide probes followed by chemiluminescent detection (23). Amplified products were resolved on 4% sequencing gels and detected, due to the incorporation of fluorescent primers during amplification, using the Hitachi FMBIO-100 Fluorescent Imager or the ABI 377 (Perkin-Elmer) automated sequencer using GenescanTM software. This method (known as TCR spectratyping) provides a more refined assessment of ⁇ TCR clonal diversity in the specimens. RESULTS
- Immobilized pan- ⁇ MAb alone and with and leukemic blasts stimulate ⁇ + T cells.
- ⁇ + T cells strongly proliferated in response to immobilized pan- ⁇ MAb alone and a combination of immobilized pan- ⁇ MAb and blasts.
- Leukemic blasts alone did not support sustained proliferation of ⁇ + T cells. It should be noted, however, that in one experiment ⁇ + T cell proliferation occurred later in the culture than in the other two experiments. Immunophenotypic analysis of proliferating ⁇ + T cell cultures.
- Phenotypic analysis revealed that proliferating ⁇ + T cells from cultures on pan- ⁇ MAb with blasts preferentially expressed V ⁇ 1 ( Figure 2) while ⁇ + T cells proliferating on pan- ⁇ MAb without blasts preferentially expressed V ⁇ 2 (Figure 3).
- the ⁇ + T cell cultures were predominantly CD3+CD4-CD8- and expressed activation-associated antigens CD69, CD25, and HLA-DR regardless of culture conditions ( Figure 4).
- Functional analysis of ⁇ + T cell cultures Cultured donor-derived ⁇ + T cells from both culture methods were tested for their ability to bind and to lyse primary leukemia from the corresponding BMT recipient. Figure 5 shows that indeed donor ⁇ + T cells will bind recipient leukemia.
- Donor ⁇ + T cells were highly cytotoxic to recipient leukemia as well as the NK sensitive target cell line K562 (Figure 6). In one experiment, mild nonspecific cytotoxicity was seen against third party MNC. Different lytic profiles were seen which correlated with culture method and predominant V ⁇ gene usage ( Figures 7 & 8). V ⁇ 1+ cells cultured on immobilized pan- ⁇ MAb and recipient blasts lysed primary ALL from the recipient and K562 cells as well as lymphoid cell lines, but had essentially no activity against myeloid cell lines. In contrast, V ⁇ 2 clones from cultures expanded on pan- ⁇ MAb alone showed cytotoxic activity against all targets. TCR repertoire analysis of ⁇ + T cells.
- Interleukin 2 prevents graft- versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells.
- Tsuji S Char D, bucy RP, Simonsen M, Chen C, Cooper MD. + T- cells are secondary participants in acute graft-versus-host reactions initiated by
- Esslin A Formby B. Comparison of cytolytic and proliferative activities of human and T-cells from peripheral blood against various human tumor cell lines. Journal of the National Cancer Institute 83:1564, 1994. 14. Orsini DL, VanGils M, Kooy YMC, Struyk L, Klein G, van den Elsen P, Koning F. Functional and molecular characterization of B-cell-responsive V 1 + T-cells. European Journal of Immunology 24:3199, 1994.
Abstract
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CA002360046A CA2360046A1 (en) | 1999-01-28 | 2000-01-27 | In vitro activated gamma delta lymphocytes |
AU34728/00A AU771710B2 (en) | 1999-01-28 | 2000-01-27 | In vitro activated gamma delta lymphocytes |
JP2000596135A JP2002535002A (en) | 1999-01-28 | 2000-01-27 | In vitro activated gamma delta lymphocytes |
IL14433900A IL144339A0 (en) | 1999-01-28 | 2000-01-27 | A cell line containing gamma delta lymphocytes and pharmaceutical compositions containing the same |
EP00913249A EP1147186A4 (en) | 1999-01-28 | 2000-01-27 | In vitro activated gamma delta lymphocytes |
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CA2926859A1 (en) * | 2013-10-25 | 2015-04-30 | Board Of Regents, The University Of Texas System | Polyclonal gamma delta t cells for immunotherapy |
AU2015287456A1 (en) * | 2014-07-09 | 2017-02-02 | Tc Biopharm Ltd | Gamma delta T cells and uses thereof |
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US20220031744A1 (en) * | 2018-09-19 | 2022-02-03 | FUJIFILM Cellular Dynamics, Inc. | Protein l for activation and expansion of chimeric antigen receptor-modified immune cells |
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