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. Author manuscript; available in PMC: 2021 May 12.
Published in final edited form as: Bone Marrow Transplant. 2019 Aug;54(Suppl 2):759–764. doi: 10.1038/s41409-019-0614-1

Therapeutic Advantages Provided by Banked Virus-Specific T-cells of Defined HLA-Restriction

Richard J O'Reilly 1, Susan Prockop 1, Aisha Hasan 1, Ekaterina Doubrovina 1
PMCID: PMC8115858  NIHMSID: NIHMS1690979  PMID: 31431697

Abstract

We have developed banks of EBV and CMV-specific T-cell lines generated from healthy seropositive 3rd party donors and characterized them as to their HLA type, virus specificity, lack of alloreactivity and HLA restriction. We here summarize results of studies employing these immediately accessible, broadly-applicable 3rd party virus-specific T-cells for adoptive therapy of EBV lymphomas and CMV infections in allo-HCT recipients. We describe the characteristics contributing to their safety. We also discuss several distinctive advantages of banked 3rd party virus-specific T-cells selected on the basis of their HLA restriction, particularly in the treatment of Rituximab-non-responsive EBV+ lymphomas and drug refractory CMV infections complicating HLA non-identical transplants.

Clinical Overview

Following initial demonstrations of the potential of transplant donor-derived unselected and virus-specific T-cells to prevent and treat CMV infections and EBV lymphomas developing after allogeneic hematopoietic cell transplants (HCT), (1–3) trials reported from several centers have recorded clearance of CMV and complete or partial remission of EBV+ lymphomas in 50–88% (4, 5) and 70–90% of patients treated (6, 7) respectively. However, broad application of transplant donor-derived virus-specific T-cells has been limited, due, in large part, to the logistical challenges and time required to isolate and/or generate T-cell populations of the size and virus-specificity required to reverse the rapid progression of CMV infections failing standard antiviral drugs or EBV+ lymphomas progressing despite treatment with Rituximab or chemotherapy. In addition, if the HCT donor is not immune, it is often very difficult to generate virus-specific T-cells. This is particularly an issue for CMV infections, since cord blood grafts and 40–50% of potential HCT donors have not been sensitized to the virus and are not immune (8, 9).

To address these constraints, we and others have been exploring the use of banked, virus-specific T-cells generated from HLA-partially matched healthy seropositive donors other than the HCT donor (10–18). This approach was initially introduced by Haque et al (10) in 2002, as a treatment for patients developing PTLDs after solid organ transplants. In 2010, we used this approach to treat 2 patients who developed monoclonal EBV+ lymphomas as a complication of either a cord blood or T-cell depleted PBSC transplant. Both patients achieved a durable CR (11). Currently, our banks of GMP grade virus-specific T-cells include 330 lines of EBV-specific cytotoxic T-cells and 135 lines specific for CMVpp65. Each line is derived from a healthy HCT donor who has provided separate, specific consent for use of the T-cells in a patient other than the recipient of that donor’s HCT. Each of these T-cell lines is virus-specific and is extensively depleted of alloreactive T-cells. Each of the T-cell lines is HLA typed at high resolution and characterized as to the HLA restrictions of its virus-specific T-cells. In addition, for each of the CMVpp65-specific T-cells and a large proportion of the EBVCTL, the epitope specificity is also defined. With these banks we have been able to identify a suitable HLA-restricted EBV or CMV-specific T-cell matched with the patient for ≥ 2/10 HLA alleles for > 98% and > 94 % of patients referred for search.

We have treated 33 allogeneic HCT recipients with biopsy proven and Rituxan refractory EBV+ lymphomas of whom 68% have achieved CR or durable (>2->7 years) partial remission. In addition, of the 50 HCT recipients who received CMVpp65-specific T-cells as treatment for CMV-induced organ disease or a persistent viremia that has failed to respond to antiviral drugs, 64% have achieved a complete response or a partial response defined as ≥ 2log10 decrease in CMV DNA, quantified by PCR as well as resolution of all symptoms (14, 19, 20).

These results are quite comparable to those we and others have reported for HCT donor-derived virus-specific T-cells (3–7, 12). However, in addition to the obvious advantages of having virus specific T-cells that are immediately accessible “off the shelf” immune cells for adoptive therapy, our studies indicate that these banked 3rd party donor-derived EBV-specific and CMVpp65-specific T-cells also exhibit a striking degree of safety and by virtue of the ascertainment of their lack of alloreactivity, virus-specificity and HLA restrictions prior to use, can provide additional advantages over HCT donor-derived T-cells that are of potential therapeutic significance, particularly in the treatment of patients who have received HLA non-identical or fully haplotype disparate HCT.

In this focused summary, we will describe characteristics of these 3rd party virus-specific T-cells that contribute to their safety, and the therapeutic advantages that can be derived from the use of banked, 3rd party donor-derived virus-specific T-cells of known HLA restriction and epitope specificity both in HLA-matched and HLA disparate hosts.

Safety

A striking feature of the third party EBV-specific and CMVpp65-specific T-cells in our banks has been their safety. Over 5 years, between January 2011 and December 2015, we treated a total of 93 patients with EBV+ lymphomas or other EBV-associated malignancies and 72 immunocompromised patients with CMV infections or persistent viremia who failed antiviral drug treatment. Infusions have been well tolerated with minimal toxicities. Furthermore, in no instance was a cytokine release syndrome observed. Furthermore, of the 33 HCT recipients treated for EBV lymphomas, only 1 developed a transient acute GVHD of grade 1 severity and only 1 of 50 HCT patients treated with CMVpp65 specific T-cells developed GVHD that was possibly related to the T-cell infusions (21). These low incidences of GVHD have also been observed by Leen et al (13, 15).

The absence of cytokine release syndrome (CRS) in patients treated with EBV-specific T-cells, including patients with large EBV+ lymphoma burdens, as well as in patients with other B-cell lymphomas and leukemias treated with virus-specific T-cells modified to express a CD19-specific CAR (22), is striking and as yet unexplained. Recently, Giavridis et al, (23) have shown that in SCID-beige immunodeficient mice bearing human B cell lymphomas, an acute disorder with the hallmarks of CRS can be induced by infusions of CD3/CD28 activated T-cells transduced to express a CD19 specific CAR. In this model, the IL-6, IL-1 and nitric oxide inducing the CRS were found to be derived from murine macrophages of the host that were recruited and activated in response to the CAR T-cells upon engagement of the lymphoma xenograft. The CRS resulted in marked weight loss and death, but could be abrogated by inhibition of iNOS generation by macrophages or by IL-6 or IL-1 blockade. Furthermore, while CAR T-cells expressing an IL-1 receptor antagonist prevented CRS, they retained their antitumor activity. Similarly, in humanized NSG mice that had been irradiated and reconstituted with cord blood-derived CD34+ cells, Norelli et al (24) showed that human T-cells from these mice, transduced to express a CD19-specific CAR, could also cause CRS while a human ALL xenograft, and that the IL-6 and IL-1 were derived from the human monocytes generated from the CD34+ cord blood graft. In contrast, in NSG mice bearing multiple EBV lymphoma xenografts, we have found that similar doses of EBV specific T-cells selectively migrated to and induced regressions of EBV lymphomas co-expressing the EBVCTLs’ restricting HLA allele, but did not cause a generalized CRS-like reaction. Neither the weight and status of the mice nor the growth of tumors that lacked EBV or the restricting HLA allele were affected (25).

There are clear differences in these preclinical models. However, these pre-clinical studies coupled with the striking lack of CRS in patients treated with 3rd party EBVCTLs or either EBVCTLs or multivirus-specific T-cells expressing a CD19 CAR as compared to patients treated with CD3/CD28 activated, CD19CAR modified T-cells suggest that EBVCTLs as well as CAR-modified virus-specific CTLs, by virtue of the limited specificity of their endogenous TCRS, or their development and functional status after extended culture, are less prone or able to recruit and/or activate macrophages to a degree sufficient to cause CRS.

The risk of GVHD in recipients of allogeneic hematopoietic cell transplants (HCT) who have been treated with in vitro generated transplant donor or third party donor-derived virus-specific T-cells has also been almost negligible (1–7, 12, 21). This finding is consistent with the depletion of alloreactive T-cells that occurs over 28–35 days of in vitro culture of donor T-cells sensitized with virus transformed or virus peptide-loaded autologous antigen-presenting cells. In our studies, we have quantified these alterations by limiting dilution analyses of the frequencies of alloreactive CTL precursors (CTLp) in the T-cell enriched fractions of PBMC immediately prior to in vitro sensitization and after 28–35 days of in vitro sensitization (26). In our assay system, the median frequency of major allogantigen-specific CTLp in unselected donor lymphocytes is 97/106 CD3+ T-cells (i.e. approximately 1/104 CD3+ T-cells). In contrast, after culture, the median frequency of alloreactive CTLps in the EBV-specific T-cells has dropped to 5.6/106 (range 1.28–29/106) (12). This number of alloreactive CTLps transferred in a 106 CD3+ T-cells/kg dose of EBVCTLs is very similar to that administered in CD34 selected, T-cell depleted PBSC graft, which provide doses of CD3+ T-cells ranging from 0.1–8.3 × 104/kg recipient weight (27). The fact that the EBVCTLs, after extended culture contain many fewer naïve T-cells may further contribute to the lower risk of GVHD observed, since naïve T-cells have been particularly implicated in the pathogenesis of GVHD (28, 29).

The Selectively Focused In vivo Activity of HLA-Restricted Virus-Specific T-cells

In order to assess the contributions of different types of virus-specific T-cells to the control or eradication of EBV+ lymphomas in vivo, we established a pre-clinical model in which NSG mice bearing up to 4 human tumors differing in their expression of EBV antigens or the HLA alleles by which the adoptively transferred EBVCTLs are restricted. In this model, the tumors are transduced to express a firefly luciferase permitting ongoing evaluation of their viability and growth, and the T-cells are transduced to express alternative reporters permitting their evaluation by chemiluminescence or by PET or SPECT (25). Using this model, we have reported that EBV-specific CD8+ T-cells restricted by HLA-A0201, selectively accumulate and proliferate in EBV+ BLCL grafts co-expressing HLA A0201. They do not accumulate in allogeneic EBV+ BLCL xenografts that do not express HLA 0201, nor do they accumulate in HLA A0201+ leukemias or lymphomas that are EBV negative (25). Furthermore, only the EBV+ HLA A0201 tumors are eradicated. The growth of the other tumors is not affected even though they are allogeneic to the EBVCTLs. In subsequent studies, we also showed, in the same mouse, distinct accumulations of HLA A0201 restricted EBVCTL expressing an HSVTK reporter in EBV+ tumors expressing HLA A0201 and HLA DRB10401 restricted EBVCTLs expressing a human non-epinephrine reporter in separate EBV+ tumors expressing the class II allele but not HLA A0201 (30). More recent experiments in which the same EBV+ tumor has been modified to either express or not express the EBV antigen targeted by the T-cells or the HLA allele by which the T-cells are restricted, have further underscored the necessity of the virus-specific T-cell to recognize the targeted viral antigen in the context of its restricting allele to achieve complete tumor regression. The ongoing nature of the control exerted by T-cells on EBV transformed cells, even in these mice, is suggested by the fact that the T-cells can still be detected at the sites of former tumors 6 months after complete regression (31).

Comparative evaluation of HCT allograft recipients with EBV+ lymphomas who do or do not respond to EBVCTLs generated from their HCT donors have also provided evidence underlining the importance of the T-cells recognizing their targeted antigens presented by the tumor cells in the context of the T-cells’ restricting HLA allele. In most cases in which EBV+ lymphomas develop following an unmodified or T-cell depleted HCT, the HLA restriction of the HCT’s donor’s EBVCTLs does not affect outcome because the EBV lymphomas develop in HCT donor-derived B-cells transformed by the patient’s endogenous EBV. However, in a significant proportion of patients who have failed to respond to adoptive therapy with EBVCTL, we have found that the EBVCTLs used for treatment that were generated from the donor in response to autologous EBVBLCL transformed by the B95.8 strain of EBV, failed to recognize the HCT donor-derived EBV+ lymphoma cells transformed by the patient’s own EBV strain (12). However, HCT donor T-cells generated in response to the donor-type EBV+ lymphoma cells grown from the patient’s disease, were able to lyse the donor-type EBV+ lymphoma cells grown from the patient as well as the B95.8 EBV-transformed donor-type EBVBLCL used to sensitize the T-cells that were initially used for treatment. These findings provide evidence that the failure of the B95.8 sensitized T-cells to recognize the patient’s tumor was not due to any impairments in antigen processing or presentation that might be caused by EBV-derived evasins (32, 33), but rather to the failure of the B95.8 sensitized EBVCTLs to recognize the patient’s virus. In a similar case, Gottschalk et al (34) found that in a patient who failed to respond to HCT donor-derived T-cells sensitized with autologous B95.8-transformed EBVBLCL, a mutation in the patient’s endogenous EBV strain resulted in the deletion of 2 peptide epitopes of EBNA 3b selectively targeted by the B95.8 sensitized EBVCTLs.

Because up to 20% of the EBV lymphomas occurring following an allogeneic HCT may be of host origin, HCT donor-derived EBVCTLs may also fail if the donor and host are not HLA matched and the donor-derived EBVCTLs are selectively restricted by an HLA allele not shared by the host type EBV lymphoma. We have documented this in 2 patients with host-origin EBV lymphomas in our series (12).

In contrast to EBV, CMV and adenovirus infections emerging after an alloHCT principally affect the cells and tissues of the host. Therefore, in an HLA non-identical HCT recipient, virus-specific T-cells transferred in the graft would be expected to provide effective immunity only if the T-cells are restricted by an HLA allele shared by the host’s diseased tissues. In part, this may contribute to the increased risk of life-threatening CMV infections observed among recipients of HLA non-identical transplants, both unmodified and T-cell depleted (35). Indeed, when we examined the HLA restrictions of CMVpp65-specific T-cells from donors of HLA non-identical HCTs, we found in 38% of cases, the donor’s T-cells were restricted by an HLA allele not shared by the HCT recipient. Furthermore, although the incidence of CMV reactivation was only slightly higher in those patients (66% vs 54%), the incidence of CMV disease or persistent viremia markedly exceeded that observed in recipients of HCT from HLA non-identical donors whose CMVpp65-specific T-cells were restricted by an HLA allele shared by the patient (53% vs 0%).

If virus-specific T-cells generated from the HCT donor are used for adoptive therapy, this limitation can even extend to donor/host pairs differing for only 1–2 HLA alleles, by virtue of the immunodominance of epitopes presented by single HLA alleles. For example, we and others (14, 36, 37) have found that T-cells from donors inheriting certain HLA alleles such as B*0702, when sensitized with overlapping peptides spanning the sequence of CMVpp65, will invariably generate T-cells specific for epitopes presented by this allele, to the exclusion of epitopes presented by other alleles. As a result, if the donor inherits HLA B*0702 but the recipient does not, the CMVpp65-specific T-cells generated from that donor, which will be restricted only by HLA B*0702, will not be effective. Conversely, if the HCT donor and recipient share HLA B*0702, the CMVpp65-specific T-cells can be predicted to be appropriately restricted and active.

Banks of 3rd Party Virus-Specific T-cells can Circumvent Therapeutic Obstacles Imposed by HLA-Restriction and Immunodominance

A bank of 3rd party donor-derived virus-specific T-cells of predetermined HLA restriction offers several advantages over transplant-donor derived virus-specific T-cells in these challenging situations (Table 1). First, in HLA disparate HCT donors/host pairings, 3rd party donor T-cells restricted by an HLA allele shared by both the HCT donor and recipient can be selected. This is an important advantage, particularly when treating an EBV+ lymphoma of undetermined origin. In contrast, an HCT donor may or may not respond to an epitope presented by an allele shared by HCT donor and host unless the T-cells are selected with tetramers or selectively sensitized with an epitope known to be presented by such a shared HLA allele (12).

Table 1:

Advantages of Banked Third Party Derived Virus-Specific T-cells

1. Immediate Access
2. Broad Application: Banks of EBV-specific and CMV-specific T-cells cover 98% and 94% of affected patients, respectively
3. Selection of T-cells based on prior characterization:
 • HLA restriction by an allele shared by patient’s disease
 • Epitope specificity
 • Partial HLA matching to patient and transplant
4. Third party T-cells are safe
5. Third party T-cells induce CRs and durable PRs of:
 • EBV+ lymphomas refractory to Rituxan +/− chemotherapy
 • CMV infections or persistent viremia refractory to antiviral drug
 • Both CRs and PRs are durable
6. Banks permit “switch therapy” for non-responders; i.e. selection of T-cells specific for a different epitope presented by an alternate shared HLA allele
7. Both transferred and endogenous virus-specific T-cells may contribute to the durable responses observed
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The banks of 3rd party donor-derived virus-specific CTLs also provide an approach for circumventing the therapeutic obstacle cited above that is imposed by the immunodominance of epitopes presented by certain HLA alleles, such as the immunodominant TPR and RPHER peptides of CMVpp65 presented by HLA B*0702. In such a case, 3rd party CMVpp65-specific T-cells restricted by an HLA allele other than HLA B*0702 that is shared by the patient and HCT donor can be selected for adoptive transfer, with a high likelihood of a response. In contrast, CMVpp65-specific T-cells generated from an HCT donor inheriting HLA B*0702 would be restricted by that allele and ineffective in an HCT recipient lacking that allele.

The bank of pre-characterized 3rd party donor-derived virus-specific T-cells offers a particular advantage to allograft recipients with EBV+ lymphomas who have failed to respond to their initial course of treatment with virus-specific T-cells. While EBV has evolved a plethora of mechanisms to alter expression of latency III and latency II antigens as well as evasins that can interfere with the presentation of immunogenic epitopes by HLA alleles (32, 33), in our series, antigenic differences between the B95.8 strain of EBV used to sensitize the T-cells and the endogenous strains of EBV detected in the patient’s lymphoma have been the most prevalent virus-associated causes of treatment failure (12). In such cases, we have found that by switching treatment to an EBVCTL line specific for epitope(s) presented by a different HLA allele shared by the patient’s lymphoma can induce complete or durable partial remissions in 60% of cases (19). At this point, the potential of such switch therapy in the treatment of infections caused by CMV or other latent viruses is not known. In contrast to EBV proteins like LMP-1 or EBNA 3C, sequence variation in CMVpp65 from different strands of CMV is very limited (38), while the potential of evasins generated by CMV to disrupt antigen presentation is well documented (39, 40). However, since certain evasins are HLA allele-specific in their activity (41), switching to T-cells of a different restriction may still provide a useful therapeutic option.

In conclusion, banked virus-specific T-cells from healthy 3rd party donors that have been pre-characterized as to their HLA restriction(s) can provide distinct therapeutic advantages not only in terms of immediate accessibility but also accuracy of selection for therapeutic effect and if the initial treatment fails, the potential to switch to an alternate T-cell line specific for a different epitope and restricted by an alternate HLA allele shared by the patient’s disease.

Funding Information:

Publication of this supplement was sponsored Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

DISCLOSURE

Conflicts of Interest: RJO’R received consulting fees and grant support from Atara Biotherapeutics, Starr Cancer Consortium, and POl CA23766. When Atara Biotherapeutics licensed banks of EBV and CMV T-cells, RJO’R received a part of the royalties paid to Memorial Sloan Kettering Cancer Center. MSKCC also has several patents of which RJO’R is an inventor bearing on the T-cells. SP received grant support from Atara Biotherapeutics, Mesoblast, and Janssen Pharmaceuticals. SP was an inventor for patents held by MSK but does not receive royalties or income for the inventions. ANH received grant support from Atara Biotherapeutics, holds patents and received royalties for Virus Specific T cell work with Atara Biotherapeutics. ED received grant support and consulting fees from Atara Biotherapeutics. ED also has patents, of which, the author is a co-inventor bearing on the T-cells and received a part of payments to Memorial Sloan Kettering Cancer Center from Atara Biotherapeutics.

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