Immunotherapy for transplantation-associated viral infections

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%–90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus-specific T cells to patients after HSCT.

A number of considerations help guide appropriate use of VSTs in post-HSCT patients. Prophylactic therapy poses several challenges: it will expose some patients to unnecessary therapy with the attendant risks of T cell alloreactivity and GVHD, it may not be feasible from a health economics perspective because of a costly cell manufacture process, and it is not yet clear whether the absence of antigenic stimulation from replicating virus may compromise engraftment/expansion of VSTs in vivo.

Preemptive therapy based on PCR-directed surveillance will reduce overtreatment. Concerns mainly relate to deliverability and, in particular, whether good manufacturing practice–compliant (GMP-compliant) technology can generate VSTs at the tempo required for effective clinical application (25). The majority of published clinical studies describe prophylactic or preemptive therapy. Outcomes have been encouraging, but comparisons between studies are difficult because of both the heterogeneous composition of the cell products (namely CD4/CD8 ratio, total cell dose, and range of CMV-target specificities) and the highly variable study design (timing of infusion, preemptive versus prophylactic administration, patient CMV risk group) (33–37). See Table 1 for an overview of clinical studies of CMV-specific T cells after HSCT and Figure 1 for a schematic illustration of different methods of VST manufacture, including direct selection methodology.

Figure 1

VST manufacture and direct selection methodology. VSTs can be generated by coculture of virus-derived peptides, proteins, or viral lysates with antigen-presenting cells (APCs) and T cells. However, these techniques are time-consuming and difficult to reproduce to good manufacturing practice (GMP) standards. Recently developed coculture methods include the use of gene-modified APCs that are engineered to present immunogenic viral peptides to T cells. This may allow for the generation of virus-reactive T cells from virus-naive donors. Direct selection techniques can permit rapid generation of VSTs to GMP standards and are now being used in clinical trials. Selection is delivered through IFN-γ capture or through multimer-based selection. LCL, lymphoblastoid cell lines; MoDC, monocyte-derived dendritic cell; LDA, limiting dilution assay.

Table 1

Clinical studies of donor-derived CMV-specific T cells

CMV-specific T cell clones. Initial clinical studies used CMV-specific T cell clones to reduce the potential risk of GVHD. In one study, large numbers of donor-derived CD8 T cell clones expanded for over 8 weeks in vitro by repeated restimulation were infused at day 30–40 after HSCT into low-risk patients. Encouragingly, CD8 T cell expansion was observed, but was not maintained in the absence of CD4 help, and the logistics of this prolonged manufacture were costly and nonscalable (38). A similar study of CMV-reactive CD4 T cell clones in the haploidentical HSCT setting resulted in detectable CD4 and CD8 CMV-specific responses in treated patients (39). This early work confirmed the potential of adoptive therapy for CMV after HSCT without apparent complication by GVHD, but highlights some of the challenges of manufacture.

CMV-specific T cell lines. An alternative to CMV-specific T cell clones is the use of CMV-specific T cell lines. Oligo- or polyclonal CMV-reactive T cell cultures are enriched for CMV-reactivity by coculture with CMV lysate, proteins, or peptides pulsed onto antigen-presenting cells (APCs), either peripheral blood mononuclear cells (PBMCs) (36) or monocyte-derived dendritic cells (MoDCs) (35). MoDCs have some distinct advantages in this role by virtue of their ability to cross-present via MHC class I to CD8 T cells, though their inclusion adds a further manufacturing step.

One clinical study of a single infusion of mainly CD4 CMV-specific T cells (1 × 10⁷/m²) in patients with persistent CMV DNAemia at 4 weeks after pharmacotherapy showed plasma CMV clearance in 63% of patients. Critics of this study argue that viral loads were modest in half of the patients, that most patients were responding to antiviral pharmacotherapy, and that endogenous reconstitution was likely to contribute to the responses observed (36). In a separate study of preemptive intervention following detection of CMV DNAemia by PCR, T cells cocultured over 3 weeks with MoDCs pulsed with CMV lysate were infused into patients after HSCT. Outcomes were promising: no cases of CMV disease or GVHD were reported, 50% of all treated patients cleared the virus without antiviral pharmacotherapy, and despite very low cell doses (<1 × 10³ CMV T cells/kg), massive in vivo expansion of transferred cells was observed several days after infusion (34).

The HLA-A2–restricted pp65 peptide NLVPMVATV (NLV) can be used in lieu of CMV lysate, and in T cell/MoDC coculture NLV yields a product highly enriched for CMV-reactive CD8 T cells (62% NLV-specific T cells) compared with CMV lysate/MoDCs (0.2%–6.5% CMV-specific CD8 T cells) (37). A potential disadvantage of this manufacturing process is that the final cell product largely comprises terminally differentiated CD8 T cells, and a clinical study of this product demonstrated relatively poor expansion and a short duration of persistence in vivo (40). Sensitization of allogeneic T cells in vitro to a pool of 15-mer peptides spanning pp65 was demonstrated to generate oligoclonal CMV-specific T cells to three different peptides. Seventeen patients were infused, and in 15 cases CMV viremia was cleared, with oligoclonal CMV-specific T cells persisting for up to 2 years in some cases (41). A major disadvantage of the HLA-A2–restricted NLV peptide approach is the restriction of benefit to HLA-A2⁺ patients only.

This work broadly confirms that generation of CMV-specific cell lines is feasible and that infusion is not associated with a significant risk of GVHD. There are compelling data to suggest that virus-specific transferred T cells can engraft and expand and have the potential to mediate clinical responses.

Multispecific T cell lines. Multi-VST lines represent an interesting option to target multiple viral infections using one adoptive cell product. Such lines can be manufactured either with APC systems similar to those described in the preceding section (using overlapping peptide pools from multiple viruses), or with gene transfer approaches. The latter are exemplified by the use of an adenoviral vector encoding the CMV-associated pp65 antigen to transduce APCs (MoDCs and EBV-transformed lymphoblastoid cell lines [LCLs]) before coculture with PBMCs or naive cord blood. This method delivers both MHC class I–dependent processing and expansion of CMV-reactive CD8 T cells, and MHC class II–dependent processing and presentation of adenovirus/EBV/CMV–associated peptides to drive expansion of virus-specific CD4 T cells.

The adenoviral transfer vector promotes antiadenoviral T cell specificity (bispecific cytotoxic T lymphocytes [CTLs]) (42), and if EBV-transformed B cells are used in lieu of MoDCs, then additional EBV-specificity is generated (trispecific CTLs) (43). The relative benefits of trispecific antiviral T cells produced in this way must be weighed against the significantly longer in vitro manufacturing process required to generate them (44). A clinical study of trispecific CTLs administered prophylactically after HSCT in the absence of immunosuppression demonstrated CMV-specific reactivity in 70% of patients, and 40% of patients had detectable circulating T cells to pp65-specific HLA pentamers with no increase in the incidence of GVHD. In this study, CMV- and EBV-specific T cell numbers rose in the absence of viral reactivation, but adenoviral-CTL expansion was only observed in the context of adenoviral infection (43). Bispecific CTLs generated by coculture with adenovirus-transduced MoDCs that were infused 28 days after HSCT delivered similar outcomes to those described above. All treated patients showed CMV-specific immunity, and 5 of 12 had T cells detectable by pp65-specific HLA pentamer analysis (42).

More recent studies have used nucleofection to introduce DNA plasmids encoding multiple immunogenic antigens from CMV, EBV, and adenovirus into APCs (45), or have used viral antigen–derived 15-mer peptide libraries (pepmix) with APCs to deliver a product with a broader CMV-reactive T cell repertoire (46). Extending the scope of antiviral adoptive cell transfer to simultaneously target three viruses has been shown to deliver sustainable responses in patients, and the main reason for therapeutic failure is donor seronegativity (7). Table 2 summarizes some of the clinical trials of multi-VSTs in the post-HSCT setting.

Table 2

Clinical studies using donor-derived multi-VSTs

Direct selection techniques. In generating novel immunotherapies for viral infection after HSCT, the two greatest clinical priorities are the prevention of toxicity and the augmentation of clinical responses. For these reasons, direct selection of CMV-specific T cells from donor samples is an attractive option when they are present at sufficiently high frequencies. Given the high frequencies of circulating CMV-reactive T cells in seropositive individuals, direct selection is likely to yield sufficient starting material for ex vivo manufacture. Direct selection is a rapid process resulting in an enriched starting material. This helps to avoid or reduce ex vivo culture, which may translate into a more cost-effective and GMP-compatible manufacturing process.

Direct CMV-reactive T cell selection can be performed in one of two ways: binding of class I HLA–peptide multimers (47, 48), or selection according to induction of cytokine secretion (often IFN-γ) in response to viral proteins/peptides (49). Alternative approaches target surface antigens upregulated following presentation of viral antigen on some form of APC. The resulting cellular composition will differ between methods such that class I HLA multimers will select only CD8 T cells, whereas IFN-γ catch (also known as gamma catch) technology will deliver a CD4 T cell–skewed product.

Multimer-based selection. Multimer-based T cell selection is currently limited to donors who have one of a restricted number of HLA-restricting alleles and detectable responses to specific immunodominant epitopes. As the technology grows, multimers using an increasing number of alleles and epitopes will become available. Their mode of action is to display peptide-loaded recombinant HLA complexes to T cells, selecting out those with T cell receptors (TCRs) of the correct specificity. There are a number of cell selection reagents available, including tetramers, pentamers, and streptamers. Similar frequencies of multimer-positive T cells can be detected following selection using all three techniques, but tetramers possess the lowest background signal and can potentially deliver the purest product (50).

The first study to demonstrate the feasibility of tetramer-based selection of highly purified CMV peptide–specific CD8 T cells from the blood of CMV-seropositive donors delivered a therapeutic product to nine HSCT patients within 4 hours of cell selection. A median dose of 8.6 × 10³ CMV-specific CD8 T cells/kg at a median purity of 95.6% was infused, and transferred cells remained detectable in all patients at 10 days. Four of seven patients treated preemptively did not require concomitant antiviral pharmacotherapy. Notably, one patient with antiviral drug–resistant CMV achieved disease control within 8 days of infusion (51).

Streptamers possess one major advantage over other forms of selection: they bind target reversibly. Reversible target binding is achieved through monomeric Strep-tagging of MHC molecules loaded with a selected target peptide to which reactive CD8 T cells bind with low affinity. Streptamer multimerization at the T cell surface through binding of the Strep-Tactin backbone increases binding avidity to T cell targets before selection. The subsequent addition of biotin, which competitively binds Strep-Tactin with higher affinity, displaces Strep-Tactin multimers from the Strep-tagged MHC molecules bound to CMV-reactive CD8 T cells. In this monomeric format, Strep-tagged MHC spontaneously dissociates from the selected CD8 T cells as a result of the low-affinity singular bond (48, 52). Two prospective randomized studies using these products have been reported in abstract form: CMV-ACE/ASPECT (NCT01220895, ClinicalTrials.gov) and CMV-IMPACT (NCT01077908) (53, 54). Initial results suggest that they may enhance the tempo of immune reconstitution compared with an untreated control group, and that they may reduce subsequent CMV reactivation rates.

IFN-γ catch. Direct selection of antigen-specific cells can be performed by IFN-γ catch, whereby short-term antigen stimulation ex vivo induces T cell recall responses. IFN-γ–secreting T cells then undergo magnetic selection following labeling with an IFN-γ–targeted mAb conjugated to a leukocyte-specific (CD45) mAb. The resulting cellular product comprises CD4 and CD8 T cells recognizing multiple viral epitopes selected independently of HLA-specificity (unlike multimer-based selections). One clinical study evaluated 18 patients with drug-refractory CMV viremia after HSCT who had no prior history of GVHD. The mean T cell dose achieved in this study was 21.3 × 10³/kg (albeit the dose did not correlate with in vivo expansion), and the CD4/CD8 ratio was 2:1. GVHD occurred in only 1 patient, and 15 of 18 patients had at least 1 log reduction in CMV DNA. In 12 evaluable patients, CMV-reactive T cells expanded in vivo, and in a subgroup, cells were still detectable at 6 months. In all 12 cases, there was either clearance or a significant reduction in CMV viremia (55).

A phase I/II study of IFN-γ catch technology generated pp65-specific T cells for 25 patients after HSCT. Sibling donor PBMCs were coincubated with recombinant pp65 or overlapping pp65 peptides and were selected by immunomagnetic IFN-γ catch technology before administration in the prophylactic/preemptive setting. Products were generated for 25 patients, but were not infused in seven patients because of the presence of grade 1 or greater GVHD prior to infusion. In the prophylactic cohort, patients did not require antiviral pharmacotherapy over 6 months of follow-up. Of 11 patients treated preemptively, two required no antiviral pharmacotherapy and seven required only a single course of treatment. GVHD (greater than grade 1) arose de novo in 3 of 18 patients, but this was not associated with product purity. Predictably, the predominant circulating CMV-reactive T cells at 4 weeks after infusion were effector memory and terminally differentiated effector cells (56).

Both multimer-based and IFN-γ catch–based selection processes offer rapid GMP-compatible manufacture and scalability. Enrichment for virus-specificity may also limit the potential risks of alloimmunity. Potential limitations include the need for additional donor leukapheresis to collect sufficient starting material, which can be burdensome, particularly in the unrelated donor setting. Additionally, this method has a requirement for circulating VSTs, and is therefore not available to virus-naive donors or CMV-seropositive donors who do not respond to pp65 or IE-1 stimulation (57).

Third-party VSTs. In cases in which the donor graft is CMV-naive, manufacture of VSTs is more challenging. In this setting, third-party VSTs collected from virus-immune subjects with common HLA types represent a potential therapeutic option. Biobanks of cryopreserved VSTs can be swiftly accessed, and published data suggest that despite the degree of mismatch inherent in this strategy, it is feasible, is associated with significant clinical responses, and does not precipitate high GVHD rates (58–61). In one clinical study, patients failing 7 days of viral pharmacotherapy for CMV reactivation after HSCT were eligible to receive an initial dose of up to 2 × 10⁷ viral-specific T cells/m², followed by 2 weekly infusions thereafter in the event of a response. Seventeen of 19 evaluable patients achieved a response (9 complete, 8 partial), 10 patients demonstrated expansion of CMV-reactive T cells in the blood, and de novo GVHD occurred in only 2 patients (60). This approach clearly represents an important development — firstly for patients who lack donor-derived VST options, and secondly for those who require urgent therapy and for whom the delays inherent in GMP manufacture of an individualized product are clinically inappropriate. The trade-off comes by virtue of the degree of mismatch and the consequent possibility of shorter persistence and/or risks of alloimmunity, although the latter is not borne out by early studies.

T cells derived from virus-naive donors or cord blood are now being used as starting material to generate CMV-specific T cells in vitro with antigen presentation delivered through donor-derived pp65-transduced PBMCs or LCLs, or APCs incubated with pepmixes. Interestingly, epitope mapping reveals that CMV-reactive T cells generated in this way recognize different epitopes from those recognized by seropositive adult donors, but they still appear to be able to elicit a clinical response and confer protection (62, 63).

Gene modification of T cells by retroviral transduction with a synthetic CMV-specific TCR could offer an alternative option for patients with uncontrolled CMV infection and a CMV-seronegative donor (64). CMV-specific TCR-transduced T cells offer the potential advantages of a targeted therapy with a relatively rapid manufacture process using naive starting material, but the disadvantages include high costs, feasibility issues, increased regulatory complexity, and the risk of viral immune escape by virtue of targeting of a single epitope.

It is often the case that viral reactivation after HSCT arises in patients with GVHD receiving treatment with systemic immunosuppression. The efficacy and persistence of CMV-specific T cells have been shown to be compromised by corticosteroids (29), and for this reason, strategies to facilitate CMV-specific T cell resistance to commonly used immunosuppressive agents, and in particular corticosteroids, may be of critical importance to the field (65, 66).

EBV is a human herpesvirus with a seroprevalence of 95% in adults. Primary infection manifests as infectious mononucleosis, but following clinical recovery, EBV persists in latent form, predominantly in B cells. In the post-HSCT setting, gross impairment of T cell function liberates EBV-infected B cells (usually donor-derived) to outgrow, causing post-transplant lymphoproliferative disorder (PTLD). PTLD risk is particularly high in patients receiving enhanced immune suppression for the treatment of GVHD, and in those receiving anti-thymocyte globulin (57, 67).

The advent of PCR-based EBV monitoring, preemptive therapy, and prompt administration of rituximab has made a huge impact on the mortality associated with PTLD after HSCT, although part of this reduction is attributable to ascertainment bias, and intervention in many who may have spontaneously cleared the virus. Despite these measures, up to one-third of patients with clinically apparent PTLD will succumb to uncontrolled disease, such that cellular therapeutic options are of great clinical relevance (68).

In considering potential immunotherapeutic approaches for PTLD, an understanding of the replicative cycle of EBV and latency-associated antigen expression is critical. Most healthy EBV-seropositive subjects have a broad repertoire of EBV-reactive T cells that mainly target the early-cycle lytic antigens. In the immunocompromised patient after HSCT, highly immunogenic type 3 latency viral antigens such as Epstein-Barr nuclear antigen-2 (EBNA-2), EBNA-3a, EBNA-3b, EBNA-3c, and EBNA-LP are seen in addition to type 1 latency antigens (EBNA-1) and type 2 latency antigens (latent membrane proteins 1 and 2 [LMP1 and LMP2]).

The first clinical studies of immunotherapy for PTLD used unmanipulated donor lymphocyte infusions. Clinical responses were observed, but at the cost of significant toxicity from GVHD (69). The generation of a more virus-specific, less alloreactive therapy, EBV-specific T cells (EBVSTs), has followed similar strategies to those outlined for CMV. Initial studies using the B95-8 laboratory strain of EBV to develop LCLs demonstrated that these potent APCs can successfully expand EBVSTs ex vivo; administration of these cells induced clinical responses in patients. However, the use of live virus to generate patient products brings with it regulatory challenges (57, 70, 71). One further disadvantage of this method, particularly where there is urgent clinical need, is the long in vitro process (up to 3 months). Interestingly, the long culture period does not adversely affect EBVST persistence in vivo (72) and is also purported to reduce alloreactivity in vitro. In fact, any residual alloreactivity identified by in vitro assessment has not been shown to confer an increased risk of GVHD (73). Alternative methods to generate EBVSTs include use of whole viral proteins such as EBNA-1 to expand EBNA-1–specific VSTs, and this has been the subject of a phase I trial of PTLD after HSCT (74). To address the issues of prolonged in vitro processing, novel methods using direct cell selection via multimer binding and IFN-γ capture (EBNA-1–based stimulation) are also being explored (74).

Clinical responses to EBVSTs. There have been multiple clinical studies of EBVSTs generated by coculture with EBV-transformed LCLs for prophylaxis or treatment of PTLD. Across two major centers (St. Jude Children’s Research Hospital and Baylor College of Medicine), 114 patients received EBVSTs. The outcomes were impressive: of 101 treated patients receiving prophylaxis with EBVSTs, 0% developed PTLD compared with 11.5% in the control group. In a cohort with established PTLD, 11 of 13 treated patients achieved sustained complete response to treatment. Importantly, there were few short-term and no long-term toxicities associated with treatment: only 8 of 114 total treated patients experienced a recurrence of GVHD after EBVST treatment (70–72, 75). Similar response rates were observed in a cohort of patients with PTLD at the Memorial Sloan Kettering Cancer Center (MSKCC), where complete response was achieved in 10 of 14 treated patients (76). Notably, the Pavia group reported responses even in patients who had failed rituximab (77).

There is a minority of patients who fail to respond or lose their responses to EBVSTs. In some cases, EBV variants possess deletions in immunodominant epitopes, such that EBVSTs generated against the WT epitope are unable to recognize and bind the variant epitope. The MSKCC group reported 3 patients who did not respond to EBVSTs: the transferred donor T cells recognized the B95-8–transformed LCLs, but not the EBV strain expressed on patient tumors. For one PTLD patient whose tumor derived from recipient (not donor) B cells, the fact that the synthesized donor EBVSTs skewed toward a donor-specific HLA antigen (A11011) that was not present on the recipient cells resulted in immune evasion. This patient subsequently responded to a third-party cell line (76). This case demonstrates the value of determining the origin of the tumor. See Table 3 for clinical trials of donor-derived EBVSTs and Table 2 for a summary of clinical studies of multi-VSTs.

Table 3

Clinical studies using donor-derived EBV-specific T cells

EBV: off-the-shelf third-party cells. PTLD is an aggressive fast-paced tumor that requires urgent treatment, and this must be central to decision making about the source and manufacture methods used to generate EBVSTs. Banks of HLA-matched EBVSTs derived from healthy EBV-seropositive subjects are available where cells are needed urgently. However, shorter persistence of these cells due to mismatching at one or more loci and alloreactivity are both risks. Published data suggest that the concept is feasible, that clinical responses are possible or likely, and that GVHD does not occur at higher rates than in the control population (57, 59, 76).

An early study of third-party EBVSTs for PTLD after solid organ transplantation or HSCT screened EBVST donations before administration to confirm specific killing of donor LCLs as a surrogate readout for efficacy (78). Impressive clinical responses were reported: there was a reduction in tumor burden in 64% of treated patients at 5 weeks, which was maintained in 52% at 6 months of follow-up. There was no reported increase in the incidence of GVHD (59). Further, using the same technology at another center, MSKCC observed clinical responses in 4 of 5 PTLD patients after HSCT (76, 79).

Overall response rates using third-party EBVSTs for PTLD (50%–70% responses) are slightly lower than that observed with donor-derived EBVSTs, but they nonetheless remain a therapeutic option for a subgroup of PTLD patients. Multiple infusions or repeat dosing may be required because of the shorter persistence of these cells in vivo.

EBV: new directions. The high seroprevalence of EBV (greater than 95%) reminds us that strategies to manufacture EBVSTs from EBV-naive donors are less critical than strategies for CMV, whose population prevalence is as low as 50%. However, it is important to be able to manipulate cord blood for this purpose, and adenoviral transfer vector–based transduction of APCs (including LCLs) can be used to generate de novo EBVSTs from cord blood grafts.

Other potential developments in EBV immunotherapy include gene modification of T cells by retroviral transduction with a synthetic EBV-specific TCR. This could potentially offer an alternative option for patients with PTLD and an EBV-seronegative donor (80).

CMV and EBV primary infection and reactivation after HSCT can be formidable clinical problems for which effective pharmacotherapeutics have substantial limitations. Accelerated reconstitution of antiviral immunity through adoptive cellular immunotherapy offers a more physiological solution.

In the setting of EBV-associated PTLD, clinical responses to EBVSTs are reported in 70%–90% of patients with minimal toxicity, and third-party cell banks now permit rapid administration in urgent cases. There is an expanding literature on CMV-specific T cell therapies that suggests their safety and efficacy, but without the robust confirmation of a phase III clinical study (as yet) to support this.

Strategies to select virus-specific cells to high purity have major implications for scalability and deliverability to a wider range of patients than can presently be treated using these methods. Novel developments that provide antiviral adoptive cell transfer options for HSCT patients with seronegative grafts also address an area of significant unmet clinical need.

It is clear that VSTs can potentially deliver clinical benefit and possess an acceptable safety profile. In order to move this technology into the mainstream, optimized GMP-grade delivery and infrastructure must be supported and developed. Work to transition antiviral T cell therapies from academic centers to commercial entities will help to facilitate broader implementation and improve accessibility of these therapies to patients and clinicians. This will also facilitate the larger randomized studies that are required to confirm efficacy, and to establish how these cellular therapies integrate with the newer antiviral pharmacotherapies. In this respect, studies of both HLA multimer–selected and third-party cells have been executed or initiated, the results of which will be crucial to establishing a more robust evidence base, particularly with regard to appropriate control groups. A greater focus on health care economics and reimbursement pathways will also be critical to the final positioning of these therapies in the overall treatment strategies for viral infections. Further analysis, characterization, and comparison of the phenotype and function of VSTs generated by different methods are also key, particularly given paradigm shifts in other T cell manufacturing processes to promote expansion, function, and persistence.

KSP receives funding from Cancer Research UK, Bloodwise, and the Medical Research Council UK. He is the Scientific Director of the National Institute for Health Research (NIHR) NHS Blood and Transplant Research Unit for Stem Cells and Immunotherapy. CR receives funding from the NIHR and the University College London Hospital Biomedical Research Centre.

Address correspondence to: Karl S. Peggs, Department of Haematology, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, United Kingdom. Phone: 44.0.20.7679.2000; Email: k.peggs@cancer.ucl.ac.uk.

Conflict of interest: K.S. Peggs is a founder member of and shareholder in Achilles Therapeutics, and a consultant for Autolus.

Reference information:J Clin Invest. 2017;127(7):2513–2522.https://doi.org/10.1172/JCI90599.

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