Antibody response after third dose of COVID-19 mRNA vaccination in allogeneic hematopoietic stem cell transplant recipients is comparable to that in healthy counterparts.

To determine the efficacy of SARS-CoV-2 mRNA vaccination for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, we measured antibody titer serially in 92 allo-HSCT patients. Among the evaluable 87 patients, median age at vaccination was 53 years (range, 18-75). The average time between allo-HSCT and vaccination was 3.3 years (range, 0.5-15.7). One month after the second dose, 70 patients (80.5%) had a positive response, whereas 17 patients (19.5%) had a negative response (< 20 U/mL). Only patients older than 44 years had a negative response. Low IgM level was the only significant predictor of vaccine failure in elderly patients. When antibody response before and after the third vaccination was examined in 47 patients, antibodies increased significantly from a median of 18.3 U/mL to 312.6 U/mL (P < 0.01). The median antibody titer after the third vaccination of healthy individuals (n = 203) was 426.4 U/mL, which was comparable to that of patients (P = 0.2). The antibody titer after the third mRNA vaccination increased even in patients whose first two mRNA vaccinations failed. These findings suggest that allo-HSCT recipients should receive the mRNA vaccine regularly.

Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study.

Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS ] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut-off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09-61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.

Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells.

Genomic deletion of donor-patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells. To investigate this, we conducted in vitro experiments with T cell receptor-transduced T (TCR-T) cells. The cytotoxic activity of NY-ESO-1-specific TCR-T cells exhibited similarly against K562 cells with low HLA-A*02:01 expression. However, we demonstrated that the cytokine production against low HLA-DPB1*05:01 expression line decreased gradually from the HLA expression level approximately 2-log lower than normal expressors. Using sort-purified leukemia cells before and after HSCT, we applied the next-generation sequencing, and revealed that there were several marked downregulations of HLA-class II alleles which demonstrated consistently low expression from pre-transplantation. The marked downregulation of HLA-class II may lead to decreased antigen recognition ability of antigen-specific T cells and may be one of immune evasion mechanism associated with HLA-class II downregulation.

Predictive value of surveillance cultures for bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales among patients with hematological diseases.

PURPOSE: Due to the increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, empirical therapies with cefepime or piperacillin/tazobactam for hematology patients with febrile neutropenia have become ineffective. Carbapenems should be administered as soon as possible in such patients with ESBL bacteremia. If the surveillance culture results are consistent with the blood culture findings, the time to adequate treatment initiation can be shortened. METHODS: All consecutive patients with Enterobacterales bacteraemia who were admitted from January 2013 to December 2018 at the hematology wards were enrolled in this study. Surveillance rectal swab and blood culture results were compared. RESULTS: In total, 67 patients with Enterobacterales bacteremia underwent surveillance culture prior to the onset of infection. Regarding the presence or absence of ESBL-producing Enterobacterales, 64 (95.5%) patients had surveillance results concordant with blood culture results. The positive predictive value of surveillance culture for bacteremia caused by ESBL-producing Enterobacterales was 95.0%. Moreover, the negative predictive value of surveillance culture for bacteremia caused by non-ESBL-producing Enterobacterales was 95.7%. CONCLUSION: The concordance rate between the surveillance rectal swab and blood cultures was highly acceptable. Surveillance rectal swab cultures are useful for identifying patients at high risk for ESBL bacteremia.

Assessment of cellular response to mitogens in long-term allogeneic hematopoietic stem cell transplantation survivors.

Infection is one of the major causes of death in hematopoietic stem cell transplantation (HSCT) survivors. Precise assessments of immune function after HSCT will be critical in establishing appropriate treatment and prophylaxis, such as re-vaccination. Although several surrogate markers for prediction of clinical outcomes after HSCT have been proposed, definitive markers of immune reconstitution and data on those markers in long-term survivors are lacking. In this study, cellular response to mitogens was assessed and clinical features associated with a poor response to mitogens were investigated in long-term allogeneic HSCT survivors. Age at transplantation and age at the time of mitogen stimulation test were each identified as significant risk factors for poor response to phytohemagglutinin and concanavalin A, respectively (P < 0.001 each). However, time elapsed since transplantation was not found to be correlated with responsiveness to mitogens in this study. Prospective, in-depth studies on immune reconstitution are needed to establish appropriate prophylaxis against infections after HSCT and a schedule for re-vaccination.

Spacer Length Modification Facilitates Discrimination between Normal and Neoplastic Cells and Provides Clinically Relevant CD37 CAR T Cells.

Despite the remarkable initial efficacy of CD19 chimeric Ag receptor T (CAR-T) cell therapy, a high incidence of relapse has been observed. To further increase treatment efficacy and reduce the rate of escape of Ag-negative cells, we need to develop CAR-T cells that target other Ags. Given its restricted expression pattern, CD37 was considered a preferred novel target for immunotherapy in hematopoietic malignancies. Therefore, we designed a CD37-targeting CAR-T (CD37CAR-T) using the single-chain variable fragment of a humanized anti-CD37 Ab, transmembrane and intracellular domains of CD28, and CD3ζ signaling domains. High levels of CD37 expression were confirmed in B cells from human peripheral blood and bone marrow B cell precursors at late developmental stages; by contrast, more limited expression of CD37 was observed in early precursor B cells. Furthermore, we found that human CD37CAR-T cells with longer spacer lengths exhibited high gene transduction efficacy but reduced capacity to proliferate; this may be due to overactivation and fratricide. Spacer length optimization resulted in a modest transduction efficiency together with robust capacity to proliferate. CD37CAR-T cells with optimized spacer length efficiently targeted various CD37+ human tumor cell lines but had no impact on normal leukocytes both in vitro and in vivo. CD37CAR-T cells effectively eradicated Raji cells in xenograft model. Collectively, these results suggested that spacer-optimized CD37CAR-T cells could target CD37-high neoplastic B cells both in vitro and in vivo, with only limited interactions with their normal leukocyte lineages, thereby providing an additional promising therapeutic intervention for patients with B cell malignancies.

Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival.

Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19+ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19+ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.

[Bacillus cereus bacteremia in patients with hematological disorders].

Bacillus cereus bacteremia is an infectious disease that may sometimes be fatal with a rapid clinical course. We performed a retrospective analysis on 12 patients with Bacillus cereus bacteremia recruited from January 2010 to March 2015. The primary diseases were acute leukemia (n=5), myelodysplastic syndromes (n=3), malignant lymphoma (n=3), and hemophagocytic syndrome (n=1). Neutrophil count at the onset of this bacteremia was less than 500 cells/µl in 9 patients. At the onset of bacteremia, we observed neurological symptoms (n=7), gastrointestinal symptoms (n=6), and findings suspected of infection at the venous catheter insertion site (n=6). Vancomycin was administered to all the patients; 10 patients showed improvement whereas 2 died early after allogeneic hematopoietic stem cell transplantation owing to bacteremia. Three patients had sequelae of central nervous system disorders. Neurological and gastrointestinal symptoms with fever may be predictors for this bacteremia, and early administration of appropriate antibacterial drugs may improve the prognosis. Future research should be aimed toward the identification of the clinical features of poor prognosis and establishment of remedies for Bacillus cereus bacteremia.

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin.

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 107/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 109/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation.

Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft-vs-host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.

[Leukemic pulmonary infiltration diagnosed by sputum Giemsa-staining].

A 54-year-old man with acute myeloid leukemia (AML) underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched unrelated donor in nonremission status. Bone marrow aspiration performed on day 14 showed that the patient had achieved complete remission; however, he relapsed on day 28. The patient developed a wet cough, and chest computed tomography performed on day 27 revealed pneumonia. Because pneumonia developed along with the leukemic relapse, we suspected that it was due to pulmonary leukemic infiltration (PLI). Giemsa-stained sputum showed some blast cells and fluorescence in situ hybridization indicated that the patient had monosomy 7, which was also detected in bone marrow blasts. Though we prescribed hydroxycarbamide and decreased tacrolimus rapidly, AML progressed and led to the patient's death on day 45. Histopathological findings of the autopsy performed the next day showed diffuse alveolar damage in both lungs. The blast cells were packed in blood vessels of alveolar septa and were also seen in alveoli. PLI was diagnosed pathologically. In conclusion, our case demonstrates that Giemsa stain of sputum is useful in quick diagnosis of PLI without invasive examination.

Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD.

BACKGROUND: Early tacrolimus (TAC) concentrations correlate with the risk of acute graft-versus-host disease (aGVHD); however, whether the variability of early TAC concentrations after allo-HSCT governs the occurrence of aGVHD remains unknown. Here, we evaluate the correlation between the intrapatient variability (IPV) of initial TAC concentrations and the development of aGVHD. METHODS: We retrospectively assessed 202 patients who underwent allo-HSCT and received standard GVHD prophylaxis by continuous intravenous (iv) infusion of TAC and iv methotrexate. IPV was calculated by using the % coefficient of variation in the initial 4 weeks. RESULTS: With median follow-up duration of 20.7 months, 24 patients were diagnosed with grades II-IV aGVHD. Overall survival (OS) and relapse at 12 months after allo-HSCT were 70.6% (95% confidence interval [CI], 63.7%-76.4%) and 18.9% (95% CI, 13.0%-24.4%), respectively. When IPV was categorized into two groups (high: ≥9.5%; low: <9.5%), the cumulative incidence of grades II-IV aGVHD was greater in the IPV-high group at week 3 (odds ratio: 4.15; 95% CI, 1.37%-12.6%, P = .01). No significant differences were observed in OS and relapse between the two groups. CONCLUSION: We concluded that adjusting early TAC concentration stable may reduce aGVHD after allo-HSCT without affecting the relapse rate.

Donor single nucleotide polymorphism in ACAT1 affects the incidence of graft-versus-host disease after bone marrow transplantation.

Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesteryl esters. A recent in vivo study reported that inhibiting ACAT1 enzyme activity upregulates the membrane cholesterol levels of T cells, enhancing their cytotoxic function. In the present study, we investigated whether the presence of the ACAT1 single nucleotide polymorphism rs11545566 in transplant donors affected the risk of graft-versus-host disease (GVHD) in 116 adult patients who underwent bone marrow transplantation from human leukocyte antigen-identical sibling donors, and who received GVHD prophylaxis with short-term methotrexate and cyclosporine. The frequencies of the AA, AG, and GG genotypes in the donors were 31%, 45%, and 24%, respectively. The cumulative incidences of grade II-IV acute GVHD on day 100 in patients whose donors had AA vs. non-AA genotypes were 6% and 18%, respectively, and those of extensive chronic GVHD at 2 years were 7% and 32%, respectively. Multivariate analyses demonstrated that donor rs11545566 non-AA genotypes showed a trend toward a higher incidence of grade II-IV acute GVHD (P = 0.079), and were significantly associated with a higher incidence of extensive chronic GVHD (P = 0.021). These results suggest that donor ACAT1 rs11545566 genotype may be predictive of GVHD.

Prediction of clinical outcome by controlling nutritional status (CONUT) before allogeneic hematopoietic stem cell transplantation in myeloid malignancies.

Malnutrition before allogeneic hematopoietic cell transplantation (allo-HCT) is associated with poor clinical outcomes. Herein, we evaluated the predictive value of controlling nutritional status (CONUT) in patients undergoing allo-HCT for myeloid malignancies. We retrospectively analyzed 200 patients with myeloid malignancies who underwent allo-HCT for the first time. We evaluated CONUT before the initiation of conditioning and compared malnourished patients (poor CONUT, n = 56) with non-malnourished patients (normal CONUT, n = 144). The cumulative incidence of non-relapse mortality within 100 days (early NRM) was significantly higher in the poor CONUT group than in the normal CONUT group [21.4% (95% CI: 11.8-33.0%) vs. 9.7% (95% CI: 5.6-15.2%); P = 0.025]. In multivariate analysis, poor CONUT was an independent and significant risk factor for early NRM [HR: 2.2 (95% CI: 1.0-4.7); P = 0.048]. The overall 1-year survival rate was significantly lower in the poor CONUT group than in the normal CONUT group [53.3% (95% CI: 39.4-65.4%) vs. 71.0% (95% CI: 62.7-77.7%); P = 0.005]. These findings suggest that CONUT before allo-HCT is a useful predictor of poor outcomes in patients with myeloid malignancies.

Quantitative Assessment of T Cell Clonotypes in Human Acute Graft-versus-Host Disease Tissues.

Owing to the difficulty in isolating T cells from human biopsy samples, the characteristics of T cells that are infiltratinghuman acute graft-versus-host disease (GVHD) tissues remain largely uninvestigated. In the present study, TCR-ß deep sequencing of various GVHD tissue samples and concurrent peripheral blood obtained from transplant recipients was performed in combination with functional assays of tissue-infiltrating T cell clones. The T cell repertoire was more skewed in GVHD tissues than in the peripheral blood. The frequent clonotypes differed from tissue to tissue in the same patient, and the frequent clonotypes in the same tissue differed from patient to patient. Two T cell clones were successfully isolated from GVHD skin of a patient. In a cytotoxicity assay, both Tcell clones lysed patient peripheral blood mononuclear cells, but not donor-derived Epstein-Barr virus-transformed lymphoblastoid cells. Their clonotypes were identical to the most and second most frequent T cell clonotypes in the original GVHD skin and accounted for almost all of the skin-infiltrating T cells. These results suggest that human acute GVHD may result from only a few different alloreactive cytotoxic T cell clones, which differ from tissue to tissue and from patient to patient. The characterization of T cells infiltrating human GVHD tissues should be further investigated.

Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications.

Noninfectious transplantation-related complications (TRCs) such as graft-versus-host disease (GVHD) and endothelial cell damage (TRC-EC) are critical after allogeneic hematopoietic stem cell transplantation. Tacrolimus (TAC) is used to control GVHD. Hypertension and renal failure are common adverse events after TAC treatment. Higher blood concentrations of TAC would be expected to reduce the risk of GVHD but may increase TRC-EC. TRC-EC often develops in patients with GVHD; thus, it is difficult to clinically determine the proper intensity of immunosuppression. We therefore evaluated the impact of weekly mean/peak TAC blood concentrations (PTCs) on TRC-EC occurrence and prognosis. Patients (N = 295) who received TAC as a GVHD prophylaxis at our institute from 2009 to 2016 were eligible for this retrospective study. Forty-three patients were diagnosed with TRC-EC: 8 with sinusoidal obstructive syndrome, 28 with transplant-associated microangiopathy, and 7 with idiopathic pneumonia syndrome. The cumulative incidence of TRC-EC at 12 months was 13.8% (95% confidence interval [CI] 10.1% to 18.1%). After multivariate analysis high PTCs during days 22 to 28 (hazard ratio [HR] 2.47; 95% CI, 1.37 to 4.45; P < .01) and grades II to IV acute GVHD (HR, 5.61; 95% CI, 2.99 to 10.53; P < .01) were associated with TRC-EC occurrence. The probability of overall survival (OS) at 12 months was 67.7% (95% CI, 61.7% to 73.0%). After multivariate analysis TRC-EC diagnosis (HR, 2.47, 95% CI, 1.59 to 3.83; P < .01) and high-risk disease (HR, 1.75; 95% CI, 1.17 to 2.61; P < .01) were significantly associated with poor OS. In conclusion, higher PTC during days 22 to 28 increased the risk of TRC-EC. TRC-EC development was associated with poor OS.

Introduction of Genetically Modified CD3ζ Improves Proliferation and Persistence of Antigen-Specific CTLs.

The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-T) is related to the in vivo persistence of the T cells. To improve persistence without modifying TCR affinity, we instead modified intracellular signaling, using artificial T cell-activating adapter molecules (ATAM), generated by inserting the intracellular domain (ICD) of activating T-cell signaling moieties into CD3ζ. ATAMs with the ICD of either CD28 or 4-1BB were generated, assembled into the TCR complex as a part of CD3ζ, and enhanced downstream signaling from the supramolecular activation cluster. ATAMs were retrovirally introduced into human CMV-specific or NY-ESO-1-specific TCR-transduced CD8+ T lymphocytes, and downstream functionality was then examined. ATAM-transduced NY-ESO-1 TCR-T cells were also investigated using the U266-xenograft mouse model. ATAMs were successfully transduced and localized to the cell membrane. ATAM-transduced CMV-specific T cells retained their cytotoxic activity and cytokine production against peptide-pulsed target cells without altering antigen-specificity and showed resistance to activation-induced cell death. Upon both single and repeated stimulation, CD3ζ/4-1BB-transduced T cells had superior proliferation to the CD3ζ-transduced T cells in both the CMV-specific and the NY-ESO-1 TCR-T models and significantly improved antitumor activity compared with untransduced T cells both in vitro and in a mouse xenograft model. ATAM-transduced TCR-T cells demonstrated improved proliferation and persistence in vitro and in vivo This strategy to control the intracellular signaling of TCR-T cells by ATAM transduction in combination with various tumor-specific TCRs may improve the efficacy of TCR-T therapy. Cancer Immunol Res; 6(6); 733-44. ©2018 AACR.