Artificial Antigen Presenting Cells That Express Prevalent HLA Alleles: A Step Towards the Broad Application of Antigen-Specific Adoptive Cell Therapies
Abstract: The artificial antigen-presenting cells (AAPCs) described in this review were generated to facilitate the production of virus-specific T-cells for the treatment of infections in patients after bone marrow transplant. These AAPCs consist of murine 3T3 cells genetically modified to express critical human molecules needed for T-cell stimulation, such as the co-stimulatory molecules B7.1, ICAM-1, and LFA-3 and one of a series of 6 common HLA class I alleles. When T-cells were sensitized against cytomegalovirus (CMV) using AAPCs that express a shared HLA allele or using autologous antigen-presenting cells (APCs) loaded with the CMVpp65 antigen, they were activated and expanded to become HLA-restricted CMVpp65-specific T-cells. These T-cells demonstrated functional activity in vitro against CMV by producing IFNγ and inducing CMVpp65-specific cytotoxicity. T-cells sensitized with AAPCs recognized antigenic epitopes presented by each HLA allele known to be immunogenic in Man. Sensitization with AAPCs also permitted expansion of IFNγ+ cytotoxic T-cells against subdominant epitopes that were not effectively recognized by T-cells sensitized with autologous APCs. This panel of AAPCs provides a source of immediately accessible, standardizable, and replenishable "off the shelf" cellular reagents with the potential to make adoptive immunotherapy widely available for the treatment of lethal infections, cancer, and autoimmune diseases.
Therapeutic infusion of T-cells cultured and activated in vitro under specific conditions that empower them to attack and kill virally infected cells or cancer cells is known as adoptive immunotherapy. This type of immune cellular therapy has emerged as an effective approach for the prevention and/or treatment of potentially lethal infections caused by cytomegalovirus (CMV) and Epstein-Barr virus (EBV) that often affect patients during their prolonged immuno-suppressed state after allogeneic hematopoietic stem cell (HSCT) or organ transplants (Walter et al., 1995; Rooney et al., 1998; Einsele et al., 2002; Haque et al., 2002; O’Reilly et al., 2007). Clinical trials using adoptive transfer of T-cells from cancer patients that are activated and expanded ex vivo have also demonstrated that tumor specific T-cells expanded in vitro from the blood of cancer bearing hosts possess anti-cancer activity as shown by regression of metastatic tumors after infusion of the expanded T-cells (Dudley et al., 2002; Hunder et al., 2008). Currently, clinical studies of adoptive transfer of T-cells directed against specific alloantigens (Rooney et al., 1998) or oncofetal proteins differentially expressed by host tumors are also being explored (Bonnet et al., 1999; Marijt et al., 2003; Kloosterboer et al., 2004).
However, translation of cell based therapies into a standardized, reproducible, and exportable therapy remains challenging for several reasons.
Activation of T-cells: The Critical Interaction Between the T-cell Receptor and Antigen-presenting Cell
In order to generate T-cells directed against a particular virus or cancer cell, the T-cells need to be sensitized using antigen-presenting cells (APCs) such as dendritic cells (DCs) that present immunogenic peptides on HLA (MHC) alleles shared by the donor and diseased host tissues. Figure 1 demonstrates the complex mechanism involved in the presentation of peptide antigens by APCs and the engagement of the T-cell receptor (TCR) with HLA-peptide complex on the surface of the APCs leading to the activation and expansion of T-cells.
As shown in Figure 1A, protein antigens are broken down and processed into antigenic peptide epitopes in the cytosol of the cell via the ubiquitin proteasome system, then transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) where the appropriate peptide epitope is loaded onto the specific peptide binding groove within the HLA molecule with the help of chaperone proteins, following which the HLA-peptide complex is transported through the Golgi peptide complex on the APC (Figure 1B). This interaction is stabilized and potentiated by additional co-stimulatory molecules on the APC (B7.1, LFA-3, ICAM-1) that bind to CD28, CD2, and LFA-1, respectively, on the T-cell surface, leading to T-cell activation, cytokine release, and T-cell expansion. If the cell presenting the antigenic peptide fails to express these costimulatory molecules, the T-cell may be rendered anergic, that is, incapable of generating an effective response. Indeed, the lack of expression of costimulatory molecules on tumor cells constitutes one mechanism whereby tumors can evade T-cell immune mechanisms (Cavallo et al., 1995). Tumors also secrete soluble immunosuppressive factors such as IL-10, TGFβ, PGE2, and VEGF that inhibit DC differentiation and maturation. These immature DCs have abnormally low expression of MHC-II and low or undetectable levels of costimulatory molecules, whereby they are unable to process and present antigens and cannot induce an effective immune response against the tumor (Bronte et al., 2001). Furthermore, certain tumors may induce the patients’ own APC to express other costimulatory molecules, like B7.H1, that preferentially stimulate regulatory T-cells to suppress responses (Curiel et al., 2003).
Therefore, presentation of specific antigenic epitopes by the HLA molecule expressed on professional APCs coexpressing activating costimulatory molecules is a critical component in the process of T-cell activation and expansion.
Limitations of Current Techniques for Expansion of Antigen-specific T-cells
The generation of antigen-specific CD8+ and CD4+ T-cells for adoptive immunotherapy classically entails extended in vitro culture of the T-cells with autologous dendritic cells that are either loaded with peptide epitopes of the antigenic protein or genetically engineered by transduction with a recombinant viral vector or transfection with DNA or an mRNA that directs the expression of the antigenic protein. However, production of dendritic cells from blood monocyte or CD34+ marrow precursors takes up to 10 days. Furthermore, it is often difficult or impossible to generate DCs from heavily treated patients in numbers needed for the repeated sensitizations over extended periods of culture required to expand low frequency T-cells responsive to tumor-associated oncofetal proteins. DCs generated from the blood of tumor-bearing hosts may also express immunomodulating proteins such as B-7H1 which can suppress the generation of functional effector T-cells (Curiel et al., 2003). For patients who have received allogeneic hematopoietic cell transplants, access to secondary blood samples from the transplant donor may also be limited.
The Issue of Immunodominant Epitopes and HLA Restriction of T-cell Response
T-cells respond to antigenic epitopes presented in the context of an HLA allele. Earlier studies in our own laboratory and by other groups have shown that in-vitro sensitization of T-cells with peptide-loaded autologous APCs consistently stimulates the propagation of T-cells specific for only 1-2 epitopes of viral antigens (CMVpp65, EBV, HIV) and restricted by no more than 1-2 of the donor’s HLA alleles. This constitutes the immunodominant T-cell response. The basis for such immunodominance is complex and poorly understood. The in vivo selection of dominant responses is likely influenced by the characteristics of the causative viral pathogen and the stage of infection (van der Most et al., 2003; Vescovini et al., 2007), the host cells that process viral proteins and present potentially immunogenic peptides on specific HLA alleles, the quantity and HLA-binding affinity of the antigenic peptides presented, and the types and affinities of the T-cell responses elicited (Yang et al., 2000; Kedl et al., 2003; van der Most et al., 2003; Pudney et al., 2005; Sylwester et al., 2005; Woodberry et al., 2005; Bihl et al., 2006; Yewdell, 2006; Assarsson et al., 2007; Vescovini et al., 2007). Such immunodominant responses pose a special challenge to the development of effective T-cell immunotherapies for the increasing proportion of patients now receiving transplants from HLA disparate donors. Virus-specific T-cells that are generated from transplant donors by sensitization with autologous APCs presenting viral antigens will be therapeutically active only if the immunodominant T-cells that preferentially expand in vitro are restricted by HLA alleles shared by the transplant recipient, and not by HLA alleles unique to the donor.
Artificial Antigen Presenting Cells
To overcome constraints of time, cost, and limited supply of APCs, several groups have proposed the use of different types of genetically engineered artificial antigen presenting cells (AAPCs) using either cell based (immortalized cell lines of Drosophila, mouse or human origin) or acellular systems (polymer beads or liposomes) (Kim et al., 2004). Artificial antigen presenting cells consist of a cell, bead, or cell membrane that expresses certain co-stimulatory molecules known to interact with molecules on the T-cell surface and provide critical stimulatory signals, such as B7.1, ICAM-1 and LFA-3, for T cell expansion. The cell based AAPCs may also secrete certain cytokines (IL-2, IL-7) that promote T-cell proliferation and Th-1 differentiation. AAPCs expressing a human HLA can be used for the generation and expansion of antigen-specific cytotoxic T-cells (Cai et al., 1996; Latouche and Sadelain, 2000; Papanicolaou et al., 2003; Oelke and Schneck, 2004; Dupont et al., 2005; Sasawatari et al., 2006; Yuan et al., 2006) since the peptide epitope specifically bound to the HLA molecule can interact with T-cells bearing the appropriate TCR selected during T-cell development in the thymus based on the HLA encountered during this process. In contrast, AAPC systems exclusively engineered to express co-stimulatory molecules without an HLA molecule can only be employed to non-specifically stimulate expansion of unselected or antigen-specific T-cells (Levine et al., 2002; Maus et al., 2002; Thomas et al., 2002; Derdak et al., 2006).
To overcome the constraints of immunodominant T-cell response, specifically for patients receiving transplants from HLA disparate donors, we hypothesized that AAPCs engineered to express both an HLA allele and important co-stimulatory molecules can present both immunodominant and subdominant immunogenic viral or tumor antigens on the single expressed HLA allele so as to generate HLA-restricted T-cells of desired specificity. To date there have been no reports of the construction or function of AAPCs expressing HLA alleles other than HLA A 0201. While HLA A0201 is the most commonly inherited class-I allele and AAPCs expressing this allele have provided a useful proof of principle, at least 60% of patients lack this allele (Mori et al., 1997).
Construction of a Panel of AAPC Expressing Prevalent HLA Class-I Alleles
We established a panel of murine 3T3 cell-based AAPCs, each expressing human ICAM-1, B7.1, and LFA-3 as well as β2-microglobulin and a single common HLA class I allele: HLA A0201, A0301, A2402, B0702, B0801, or C0401 to sensitize T-cells against virus specific or tumor selective antigens. These genes were sequentially transduced into the 3T3 cells using retroviral SFG vectors. The resultant cells were then sorted via flow cytometry to isolate and expand the cells expressing high levels of each of the transduced genes. We chose to construct this panel of AAPCs from a murine 3T3 cell line rather than a human cell line such as the human leukemia K562 cell, as proposed by other groups (Maus et al., 2002; Butler et al., 2007), primarily because of concerns that K 562 or other human cells lacking HLA expression could process and present minor alloantigens in the context of a transduced HLA allele, especially hematopoietic minor antigens, that might stimulate donor T-cells capable of inducing graft versus host disease (GVHD. An additional concern was that K 562 cells express MICA and MICB, which, on one hand, can be a significant alloantigen (Gambelunghe et al., 1999; Pellet et al., 1999; Petersdorf et al., 1999), and on the other, can release soluble MICA and MICB, which, by downregulating surface expression of NKG2D on CD8+ T-cells can interfere with T-cell effector functions (Boissel et al., 2006).
Each AAPC in this panel was evaluated for its capacity to sensitize and stimulate the expansion of HLA-restricted T-cell populations specific for peptides of CMVpp65 known to be expressed on CMV infected human cells. We chose to evaluate responses to the CMVpp65 protein because it is the immunodominant antigen that is most frequently targeted by CD8+ cytotoxic T-cells in CMV seropositive donors (Wills et al., 1996) and because a large series of epitopes of CMVpp65 have been identified that can be presented by the HLA alleles in the AAPC panel and can elicit cytotoxic T-cell responses (Gandhi and Khanna, 2004; Kondo et al., 2004).
Generation of CMV-specific T-cells and Assessment of T-cell Responses to CMVpp65
We used a pool of 138 overlapping pentadecapeptides spanning the sequence of CMVpp65 to sensitize T-cells and to determine the specific peptides eliciting T-cell responses as described earlier (Trivedi et al., 2005). T-cells from each donor were sensitized using 3 approaches: (1) AAPC transduced with the entire sequence of CMVpp65 (AAPCclass I-pp65), (2) AAPC loaded with the CMVpp65 peptide pool (PL-AAPCclass I), and (3) Autologous APCs (cytokine activated monocytes) loaded with the CMVpp65 peptide pool (PL-CAM). Antigen-specific T-cells were phenotypically quantitated by the proportion of CD8+ T-cells binding MHC-class-I tetramer complexes for HLA A0201, A2402, and B0702 which bear known epitopes for these HLA alleles. Functional characterization of CMV-specific T-cells was performed by examining interferon gamma production by T-cells in response to specific peptide pools of CMVpp65, and evaluation of their ability to lyse HLA-matched peptide-loaded human target cells in-vitro in a standard chromium release assay.
AAPCs Induce Expansion of Antigen-specific T-lymphocytes
Tetramer analysis of T-cells after 21 days of sensitization using AAPCclass I-pp65 when compared to PL-AAPCclass I demonstrated at least a log fold higher increases (550-1000 vs. 50-200) in antigen specific T-cells. These T-cells were able to bind to tetramers containing known immunogenic epitopes of CMVpp65 presented by the HLA expressed by the AAPC, and were predominantly effector memory cells in phenotype. Among the donors tested, the Vβ chains represented in the TCR of T cells sensitized with AAPCclass I-pp65 were the same as those detected upon sensitization of T-cells with autologous PL-CAM.
T-cells sensitized using AAPC consistently responded to specific epitopes of CMVpp65 known to be presented by the HLA expressed by the AAPC. The T-cells also demonstrated significant cytolytic activity against peptide-loaded human cell targets sharing the HLA expressed by the AAPC, but did not lyse the same targets not loaded with the peptide or HLA mismatched targets. Therefore, T-cells generated using either PL-AAPCclass I or AAPCclass I-pp65 demonstrate functional activity against CMVpp65 that is HLA-restricted and epitope specific.
AAPCs Process and Present Known Immunogenic Epitopes of CMVpp65
We further examined the capacity of AAPCs transduced with CMVpp65 to process and present CMV pp65 epitopes. Specifically, we evaluated if they present epitopes known to be immunogenic in Man and also if they presented other epitopes not normally presented by human APCs. We mapped epitopes recognized by T-cells sensitized with PL-CAM or PL-AAPCclass I and compared them to those elicited in response to AAPCclass I-pp65. All HLA A0201+ and B 0702+ donors sensitized with HLA A0201+ and B0702+ AAPCclass I-pp65 respectively generated T-cells specific for the NLV or the TPR peptide known to be presented by HLA A 0201+ and B0702+, respectively. Five out of 7 HLA A2402+ donors responded to the QYD epitope presented by A2402, while 2 donors responded to newly identified epitopes presented by HLA A2402 when sensitized with either AAPCclass I-pp65 or PL-CAMs. Similarly, 2 of 3 HLA C0401+ donors responded to the QYD nonamer known to be presented by this allele, while the third C0401+ donor responded to another epitope when sensitized with either AAPCclass I-pp65 or autologous PL-CAMs. Taken together, these data provide evidence that the murine 3T3 derived AAPCclass I-pp65 are able to process and present epitopes of CMVpp65 on their expressed HLA alleles that are known to be presented by the same alleles on human APCs.
AAPC Are Capable of Generating Antigen Specific Responses Against Subdominant Epitopes of CMVpp65
In our previous (Trivedi et al., 2005) and current studies, sensitization of T-cells with autologous PL-CAMs selectively induced T-cells specific for 1-2 immunodominant CMVpp65 epitopes. T-cells sensitized with PL-AAPCclass I or AAPCclass I-pp65 expressing HLA alleles presenting immunodominant epitopes regularly elicited responses to the same dominant epitopes. Notably, we could also generate comparable cytotoxic T-cell responses against sub-dominant epitopes using AAPC which were either not produced or only present at low frequencies in T-cells sensitized with autologous APCs. For example, in a donor who bears HLA A0201 and B0702, the immunodominant T-cell response was restricted by the TPR epitope presented by HLA B0702 when sensitized using PL-CAMs. Also in this donor, T-cell responses were successfully generated against the subdominant epitope NLV presented by HLA A0201 using AAPC expressing HLA A0201.
In recent years, the field of artificial antigen presenting cells has undergone tremendous metamorphosis to reach the horizon of clinical applications. Most of the work has been geared towards enhancing T-cell expansion primarily by engineering AAPC systems to optimize co-expression of co-stimulatory molecules such as CD28 and anti-CD3. More recently, using K562 based AAPCs, more efficient and large scale T-cell expansion has been reported when additional co-stimulation of T-cells was provided through expression of the ligand for CD137 (4-1BBL) in addition to CD-28, anti-CD3 (Suhoski et al., 2007; Zhang et al., 2007). Our own studies also demonstrated augmentation of T-cell expansion using 3T3 cells that express 4-1BBL as well as B7.1, LFA-3, and ICAM-1 (Stephan et al., 2007). It remains to be confirmed if the additional expression of 4-1BBL on the surface of our current panel of AAPCs indeed enhances T-cell expansion.
Based on the results summarized here, we are presently proceeding to manufacture a panel of clinical grade AAPCs derived from C-GMP compliant NIH 3T3 fibroblasts. These AAPCs will be used for the generation of antigen-specific T-cells of desired HLA restriction for adoptive immunotherapy of CMV infections and relapsed WT-1 positive leukemias in recipients of HLA mismatched or haploidentical transplants.
Thus far, tumor-specific T-cells adoptively transferred to patients for treatment of cancer have a short duration of survival in the body, and cannot be detected in follow up blood samples from patients within a few months after infusion. It is well known that expansion of T-cells using IL-2 predominantly produces short-lived effector memory (TEM) and effector (TE) CD8+ T cells without expanding the CD62L+ and CCR7+ central memory T cells (TCM), which may persist for long periods of time in vivo. Therefore, we and others are exploring in vitro culture strategies that would potentiate both the expansion and the in-vivo persistence of antigen-specific TCM. To this end, cytokines such as IL-15 and IL-21 are being evaluated for their potential to foster growth of antigen-specific TCM CD8+ T-cells. Studies are also in progress to determine if trans-presentation of IL-15 with its receptor alpha (IL-15Rα) on AAPCs will enhance the stimulatory effects of IL-15 or promote greater expansion of TCM CD8+ T-cells (Hasan et al., 2008; Kokaji et al., 2008; Stonier et al., 2008) which would persist longer in vivo after adoptive transfer.
The studies reported to date have described the generation of HLA class-I restricted CD8+ T-cells via stimulation by AAPCs. However, there is also a need for a panel of AAPCs that express prevalent HLA Class-II alleles. Such a panel would permit selective stimulation and expansion of CD4+ T-cells specific for epitopes presented by HLA class-II alleles.
Sensitization of T-cells from a large pool of donors using this panel of AAPCs and evaluation of T-cell response using the overlapping pentadecapeptide approach provide a distinct opportunity for the rapid definition of antigenic epitopes that can be presented by the shared HLA allele expressed on the surface of the AAPC and the donor T-cell. Comparative studies using this panel of AAPCs may also permit more discriminatory analysis of the potential of specific allelic variants of a given HLA allele to cross-present epitopes to other allelic variants (for example, the potential of specific epitopes presented by an allele such as HLA B3501 to also elicit peptide-specific responses by T-cells expressing another variant such as HLA B3505). Such studies are urgently needed to identify and predict allelic incompatibilities that may impair reconstitution of immunity or the effectiveness of antigen-specific adoptive cell therapies early after transplant.
In conclusion, this panel of AAPCs, stably expressing HLA A0201, A2402, B0702, B0801, or C0401, can each stimulate the generation of significant populations of CMVpp65-specific HLA-restricted T-cells against both dominant and subdominant epitopes of CMVpp65. Our results demonstrate that within 3 weeks in culture, T-cells sensitized with either PL-AAPCclass I or AAPCclass I-pp65 can generate 5 x106 to 1 x 108 epitope specific T-cells, which would provide a sufficient dose of T-cells for adoptive cell therapy for prevention or treatment of CMV infections. These AAPCs would be particularly useful for generating antigen specific T-cells restricted by a desired HLA allele shared by donor and host cells in patients receiving HLA disparate bone marrow transplants. Therefore, this panel of AAPCs provides a source of immediately accessible, standardizable, and replenishable “off the shelf” cellular reagents with the potential to make adoptive cellular therapies more widely available for the treatment of lethal infections, cancer, and autoimmune diseases.
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