Letter | Published:

T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant


Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1,2,3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms’ Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein–Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients (NCT01640301). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.

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Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the Fred Hutchinson Cancer Research Center to verify whether the request is subject to any intellectual property confidential obligations. Patient-related data not included in the paper were generated as part of a clinical trial and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a Material Transfer Agreement. PBMC scRNAseq data for patients 10 and 18, as well as the R code to generate the tSNE plots using Seurat software packages, are available at the National Center for Biotechnology Information Gene Expression Omnibus, accession number GSE128933.


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We thank E. Estey and F. Milano for their contribution to the manuscript; the Fred Hutchinson Cancer Research Center Good Manufacturing Practice Cell Processing Facility for generating TTCR-C4; the Immune Monitoring Laboratory for generating tetramers; the Flow Cytometry Facility for providing instruments and assistance in flow cytometry assays; and the Program in Immunology, Immunotherapy Integrated Research Center, Seattle Cancer Care Alliance Immunotherapy Clinic staff and K.-T. Bui for supporting the clinical protocol implementation. We received funding from grant no. P01CA18029-41 (P.G.), grant no. NIH-5K08CA169485 (A.G.C.), the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center (A.G.C.), Damon Runyon (A.G.C.), the Guillot Family ZachAttacksLeukemia Foundation and Juno Therapeutics.

Author information

Conception and design were performed by P.D.G., A.G.C., M.B., G.B.R. and T.M.S. Collection and assembly of data were carried out by A.G.C., D.N.E., M.B., M.S.M., K.G.P., V.V., R.G., M.B., C.C.Y., P.M., H.N.N., L.A.K., L.C., F.W., D.H., M.L., K.C., A.S., M.J.M. and N.D. Data analysis and interpretation were performed by A.G.C., D.N.E., T.M.S., K.G.P., V.V., R.G., M.S.M., T.A.G. and P.D.G. All of the authors contributed to the writing of the manuscript. Final approval of the manuscript was given by all of the authors.

Correspondence to Philip D. Greenberg.

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Competing interests

A.G.C. has received support from Juno Therapeutics. P.D.G. is a consultant, has received support from and had ownership interest in Juno Therapeutics. He consults and has ownership interest in Immune Design Corp, Innate Pharma and FLX Bio. P.D.G., T.M.S., H.N.N. and the Fred Hutchinson Cancer Research Center have intellectual property related to TCRC4. A.G.C. and K.G.P. have received reagents from 10X Genomics. R.G. has received consulting fees from Juno Therapeutics, Takeda Pharmaceuticals and Infotech Soft, and has received support from Johnson and Johnson and Juno Therapeutics. The authors declare no other competing interests.

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Extended data

Extended Data Fig. 1 Flow diagram of patients enrolled on the clinical study.

Follow-up of the 64 patients screened for participation in the study. Patients could either enter the study by being screened/enrolled pre-HCT (49 patients) or after post-HCT relapse (15 patients). Patients with no detectable disease at day ~28 post-HCT were eligible to receive treatment on the prophylactic arm described here, and patients with evidence of relapse post-HCT alternatively received therapy on the treatment arm (not described here). Between 29 April 2013 and 19 October 2016, 29 patient/donor pairs were enrolled pre-HCT. Of these, TCRC4-transduced cells were initiated for 23 patients, and 12 patients who had not relapsed before day 28 received TCRC4-transduced cells on the prophylactic arm. One additional patient was considered not evaluable for response outcomes as this patient received <12% the intended dose and was unable to receive further infusions due an inability to generate additional T cells from the donor.

Extended Data Fig. 2 Treatment plan.

The first patient received 4 escalating doses of TTCR-C4 starting at 109 cells per m2 on day 0, then 3.3 × 109 cells per m2 on day 28 and 1010 cells per m2 on days 56 and 84, followed by low-dose subcutaneous IL-2 (2.5 × 105 IU twice daily) for 14 d (stage 1) administered to enhance the survival of transferred T cells. After safety was established, to increase the likelihood of delivering therapeutic cell doses to patients before disease progression, all remaining patients were planned to receive 2 doses of 1010 cells per m2. The next 11 patients received 1 infusion at doses of 1010 cells per m2 on day 0 and 1010 cells per m2 on day 28 with the latter infusion followed by 14 d of low-dose subcutaneous IL-2. For safety, no subsequent infusion could be administered if persistence of the transfused cells was >3% of total CD8+ cells.

Extended Data Fig. 3 Characteristics of treated and comparative group patients.

Characteristics of treated and comparative group patients. AML risk stratification by genetics was assessed using the European Leukemia Net criteria3. Persistent AML after one induction is associated with unfavorable outcomes60. The post-HCT relapse risk was assessed using published criteria2. NED, no evaluable disease.

Extended Data Fig. 4 Normal count recovery after HCT and TTCR-C4 infusions.

ad, Percentages of hematocrit (a), platelet (b), neutrophil (c) and lymphocyte (d) counts for TTCR-C4-treated (n = 12) and comparative group (n = 70) patients alive at day 80 (2.5 months (mo)). Baseline for TTCR-C4-treated and comparative group patients was their pre-infusion value and their day 80 value, respectively. Box and whiskers plots including range (whiskers), interquartile range (box), median (horizontal line) and all values are shown. Two-sided paired t-tests were used for statistical analysis. Source Data

Extended Data Fig. 5 Adverse events.

One patient experienced NCI-CTCAE v.4.0 grade 3 symptoms (fever, chills, rigors, nausea) commonly associated with cytokine release syndrome after each of 2 infusions, which were managed on the general hospital ward and resolved within 24 h with supportive treatment (fluids, acetaminophen, antihistamines). Five patients experienced a temporary (1–13 d) decrease in lymphocytes, which is a routinely observed, transient side effect of T cell infusions, presumably reflecting T cell margination14. Three patients experienced a hemoglobin drop that returned to pre-infusion levels within 1–4 d, 2 patients experienced a drop in platelets that returned to pre-infusion levels within 1–7 d and 2 patients experienced a drop in absolute neutrophil counts that recovered within 11–23 d; the transient nature of these hematologic events is consistent with cytokine-mediated effects14.

Extended Data Fig. 6 GVHD observed after TTCR-C4 infusions.

aGVHD, acute GVHD; cCVHD, chronic GVHD.

Extended Data Fig. 7 In vivo persistence kinetics and clonotype evolution of transferred TTCR-C4.

a,b, Tetramer+CD8+ T cells per microliter (left y axis) in PBMCs collected after the first infusion for all patients (n = 12) (a), and for selected patients (n = 6) who received a second infusion within 365 d of their first (note: patient 11 received a second infusion 795 d after the first and is not depicted here) (b). Black asterisks indicate timing of TTCR-C4 infusion and blue asterisks indicate that the infusion was followed by low-dose subcutaneous IL-2. c, Graphs to the left, frequency of the first 25 most frequent clonotypes (shaded in color) and remainder of the clonotypes (shaded in gray) expanded and detected at any time-point after infusions (Supplementary Table 1) present in infusion products in selected patients (n = 11). The proportions of the sum of clonotype frequencies present in the infusion product but not detected after infusion are indicated in white (see Supplementary Table 1 for exact numbers relative to each patient). c, Graphs to the right, sum of the percentage of clonotypes detected at designated time-points after infusions (black lines), individual percentage contributions of the most prevalent 25 clonotypes in the infused products (colored lines), sum of the remaining sequences (gray lines), sum of all product clonotypes (black lines) and percentage of multimer+ T cells (open blue circles) for each corresponding patient. Regression was performed on the log of the sum of clonotype frequencies obtained by HTTCS and log percentage tet+ cells (n = 5 data points for patients 3, 10, 11, 12, 13, 18, 24 and 25; n = 4 data points for patients 17, 20 and 21). Goodness of fit was evaluated with R2. Significance of the correlation (R2 and P values) between the sum of the percentage clonotypes and multimer are depicted on the right side of each graph. Source Data

Extended Data Fig. 8 TEM Clonotypes composing TTCR-C4 differentiate into TCM and TTD in vivo.

a, Schematic of differentiation grouping used for assigning subset identity: CD45RA, CCR7+ (TCM); CD45RA, CCR7 (TEM); and CD45RA+, CCR7 (TTD). b, Grouping of TTCR-C4 WT1 tetramer-binding cells into differentiation subsets immediately before infusion (n = 12) and after 7 d (n = 10), ~30 d (n = 9), ~100 d (n = 9) and 200–300 d (n = 9) in vivo. Box and whisker plots include range (whiskers), interquartile range (box), median (horizontal line) and all individual values. Two-sided paired t-tests were used to compare product with in vivo respective subsets and are indicated above each one. c, Venn diagram indicating the number of clonotypes (total clonotypes from patients 10, 11,12 and 24) in each subset. d, Percentage of total WT1-binding clonotypes detected ~100 d after transfer identified in each subset (4 patients combined). Source Data

Extended Data Fig. 9 Identification of PBMC subpopulations.

a, Clusters identified by principal component analysis and visualized with tSNE for both patients combined (n = 18,372, each represented with a dot). bl, Expression patterns of transcripts encoding key genes (http://www.ncbi.nlm.nih.gov/gene), shown above each plot, that assisted in confirmation of cluster identification. Blue color indicates expressed, with darker blue indicating greater expression.

Extended Data Fig. 10 Significantly expressed genes in TTCR-C4.

Expression of transcripts encoding granulysin (GNLY), granzyme K (GZMK) (patients 10 and 18), granzyme H (GZMH), homeodomain protein homeobox (HOPX), inhibitor of DNA binding 2 (ID2) and lymphotoxin B (LTB) (patient 18 only) are compared in endogenous CD8+ effector (CCR7) T cells (red, n = 1,298 (patient 10) and 1,282 (patient 18)) and TTCR-C4 (blue, n = 695 (patient 10) and 327 (patient 18)), shown as violin plots. The shape of the violin displays frequencies of values. All individual values are shown. MAST (see Methods) was used to determine the significance shown below each plot. Significance thresholds were set a priori at a threshold of false discovery rate of 5% and positive or negative fold change > log2(1.3). All significantly differentially expressed genes are shown in this figure.

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Fig. 1: Phenotypic and functional characteristics of EBV-specific donor-derived TTCR-C4.
Fig. 2: Prophylactic effect, kinetics of in vivo persistence and clonotype evolution of TTCR-C4 in vivo.
Fig. 3: Phenotypic, functional characteristics and transcriptome of TTCR-C4 in vivo.
Extended Data Fig. 1: Flow diagram of patients enrolled on the clinical study.
Extended Data Fig. 2: Treatment plan.
Extended Data Fig. 3: Characteristics of treated and comparative group patients.
Extended Data Fig. 4: Normal count recovery after HCT and TTCR-C4 infusions.
Extended Data Fig. 5: Adverse events.
Extended Data Fig. 6: GVHD observed after TTCR-C4 infusions.
Extended Data Fig. 7: In vivo persistence kinetics and clonotype evolution of transferred TTCR-C4.
Extended Data Fig. 8: TEM Clonotypes composing TTCR-C4 differentiate into TCM and TTD in vivo.
Extended Data Fig. 9: Identification of PBMC subpopulations.
Extended Data Fig. 10: Significantly expressed genes in TTCR-C4.