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  • 1
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    Adoptive Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides of the CMV-pp65 Protein for the Treatment of Persistent CMV Antigenemia Following Allogeneic Hematopoietic Stem Cell Transplants
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 351-351
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 351-351
    Abstract: Abstract 351 We have generated donor-derived T-cell lines specific for CMVpp65 peptides for use in a phase I, dose escalation trial of adoptive immunotherapy. T-cells were sensitized by autologous monocyte-derived DCs loaded with a pool of 138 pentadecapeptides (15-mers), with 11 amino acid overlaps spanning the entire 561 amino acid sequence of the CMV protein pp65. The 138 pentadecapeptides were synthesized and the T-cells were sensitized under GMP conditions. In preclinical studies we have been able to generate CMVpp65 specific T-cell lines from each seropositive donor tested, irrespective of HLA genotype. During the culture period of 21–35 days, populations of T-cells specific for CMV-pp65 selectively expanded 200–300 fold, while T cells reactive against major or minor alloantigens were depleted. Thirteen pts with persistent CMV viremia, refractory to at least 2 weeks of therapeutic doses of ganciclovir or foscarnet, have been enrolled: 3 pts at a T cell dose of 5×105/kg, 3 pts at 1×106 T cells/kg, and 7 pts at 2×106 T cells/kg. CMV specific cytototoxic T lymphocytes (CTLs) were generated from HLA-identical unrelated donors (3 pts) or from HLA-identical siblings (10 pts). Two pts received conventional transplants after non-myeloablative conditioning; 11 pts received myeloablative conditioning and T-cell depleted transplants. Pts were eligible if they had persistent CMV viremia despite 2 weeks' treatment with antiviral drugs or had toxicities precluding further treatment with antiviral agents. Prior to infusion, T cell specificity against CMV was confirmed by cytotoxicity, intracellular interferon gamma (IFN-g) production, and MHC-tetramer staining (if available). The HLA-restrictions, epitope specificities, and TCR Vβ repertoires of the T-cell lines were also characterized before infusion. Cells were also assayed to establish lack of alloreactivity, microbiological sterility, and low endotoxin levels. All CTLs demonstrated cytolytic activity against peptide-loaded autologous PHA blasts but no cytotoxicity against non-pulsed HLA-matched or peptide-pulsed HLA-mismatched target cells. The proportion of CMVpp65-specific CD8+ cells in the infused T-cells, measured by intracellular IFN-g or MHC tetramers, ranged from 2 – 20 % or 4 – 70%, respectively. Post infusion, an increase in the absolute lymphocyte count correlated with an increase in CMV-specific T-cell frequencies to levels as high as 14% of CD8+ cells. In one pt, the CTLs were monitored and persisted for more than 2 years (10% of CD8+ cells) after the infusion. Notably, the same pp65-derived epitopes and HLA-restrictions which characterized the infused CTLs were detected in the pt specimens post infusion. The same TCR Vβ repertoires of the CMVpp65-specific CTLs infused were also detected post infusion. Donors for three of the treated pts expressed HLA-A*0201 and HLA-B*0701 alleles. Epitope-specific T cells for the HLA-A*0201-restricted NLVPMVATV peptide and the B*0701-restricted RPHERNGFTV peptide were detected and monitored in pre and post infusion T-cell populations in these three pts. In all three pts, the B*0701 restricted RPHERNGFTV emerged as the dominant T-cell population. All 13 pts tolerated the infusions well without acute toxicities. None developed symptoms of GvHD at the dose levels tested. Twelve of the 13 pts cleared CMV viremia by 2–8 weeks following the CTL infusions. One of the pts died six weeks after the CTL infusion of respiratory failure despite clearing CMV from blood and bronchial aspirates. Another pt who initially remained viremic following the CTL infusion was restarted on oral valganciclovir and subsequently cleared CMV viremia. Only one pt had persistent viremia and died of pneumonia 31 days after CTL infusion. The results from this trial demonstrate that donor T cells, sensitized with this pool of overlapping CMV pp65 pentadecapeptides, are safe and clear CMV viremia resistant to standard therapy. A larger phase II trial for the treatment of persistent CMV viremia and CMV infections is currently ongoing at MSKCC. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.351.351
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    Two Chemotherapy-Based Conditioning Regimens Compared To TBI-Based Conditioning Secure Consistent Engraftment Of T-Cell Depleted Allogeneic HSCT, Similarly Low Incidences Of Gvhd and Favorable Rates Of Disease-Free Survival (DFS)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 546-546
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 546-546
    Abstract: To ascertain the therapeutic potential of non-TBI-based conditioning for CD34+ HPC-selected , T cell-depleted allografts, we conducted a trial comparing our standard regimen, arm (A) 1375cGy HFTBI+ thiotepa,5 mg/kg/day x 2 days + cyclophosphamide 60 mg/kg/day x 2 days vs. arm (B) Busulfex 0.8 mg/kg/6h x12 (dose adjusted) + melphalan 70 mg/kg/day x 2 + fludarabine 25 mg/m2/day x5 and arm (C) Clofarabine 20 mg/m2/day x 5 + melphalan 70 mg/m2/day x 2 + thiotepa 5 mg/kg/day x2, as preparation for T-cell depleted CD34+ PBSC transplants from GCSF-mobilized leukocytes fractionated with the CliniMACS device. Primary endpoints were engraftment, GVHD, transplant-related mortality (TRM) and 2 yr OS and DFS (Confer Table). Stratification of pts to arms A (standard), B or C was based on the patient’s disease, disease stage and clinical factors such as age, prior therapy or comorbidities enhancing risks of TBI. Arm B was the non-TBI arm predominantly used for myeloid and Arm C for lymphoid malignancies. Prior to transplant, recipients of HLA-matched or non-identical transplants received rabbit thymoglobulin at 2.5 mg/kg/day x2 or 3 days respectively, to prevent graft failure. No GVHD drug prophylaxis was given post transplant. A total of 181 consecutive patients, accrued between 5/13/2010 and 6/12/2013, were analyzed (81 in arm A, 78 in arm B, 22 in arm C). These pts have been followed for a median of 12.1 months. Donors were related or unrelated and HLA-matched for 74% of the patients and 1-2 HLA allele disparate for 26%. Median age for the entire group was 50.5 years, with older pts predominating in the non-TBI groups (medians arm A ,31.9 yrs; arm B , 61.9 yrs; arm C, 44.6 yrs). The CD34+ PBSC transplants provided a mean dose of 9.7x106 CD34+ progenitors/Kg (range 1.4-89.7) and 4.5x103 CD3+ T-cells/Kg (range 0.6-25.3). All pts engrafted; but 2 pts (2.5%) in arm B experienced late graft failure, one of whom was reconstituted after a secondary graft. Overall the incidence of grade II-IV acute GVHD was 18%, and 14% for recipients of HLA-matched grafts. TRM at 1 year was 10% in Arm A, and 15% in Arms B and C. Two year OS and DFS for each arm are: arm A, 66.7% and 58.4%; arm B 62.3% and 59.5%; arm C 52% and 53%. For the 101 pts who received standard risk transplants (i.e., pts with high risk forms of AML, ALL or NHL in 1o CR, AML in 2o CR, MDS RA/RCMD, CML in 1o CP or MM in CR1, VGPR or first PR ), 2 year OS and DFS are: arm A 68% and 62%; arm B 67% and 66%; arm C 86% and 86%, with relapse rates at 2 yrs of: arm A 23%, arm B 15%, and arm C 14%. These results thus identify two non-TBI-based conditioning regimens that secure consistent engraftment of rigorously T-cell depleted allogeneic HSCT and can yield favorable long-term DFS and OS with low incidences of GVHD and relapse. Table 1 Overall Results Graft 1 Year Acute GVHD II – IV 2 Year PTs ENG Failure TRM ALL HLA-Matched O.S. DFS ARM A 81 81 0 10% 23% 17% 66.7% 58.4% ARM B 78 78 2 15% 12.3% 13% 62.3% 59.5% ARM C 22 22 0 15% 27% 20% 52% 53% Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.546.546
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-09-08)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-09-08)
    Abstract: Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion ( p  = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg ( p  = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion ( p   〈  0.01, p   〈  0.01, and p  = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-32491-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 4
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    Third Party CMV-Specific Cytotoxic T Cells for Treatment of Antiviral Resistant CMV Infection after Hematopoietic Stem Cell Transplant
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 61-61
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 61-61
    Abstract: Adoptive immunotherapy with transplant donor derived virus specific T cells is an effective strategy for the treatment of CMV viremia and disease arising after an allogeneic hematopoietic stem cell (HSCT). This approach is not readily applicable if the donor is seronegative or not available to provide lymphocytes for in vitro expansion for CMV specific cytotoxic T lymphocytes (CMV-CTL) lines or if the CMV CTL lines derived from non-identical donors are restricted by non-shared HLA alleles. We and others have previously presented results indicating that treatment with in vitro expanded CMV-CTLs derived from an HLA partially matched third party donors can effectively treat CMV infections in the post-transplant setting. However, the patient population most likely to benefit from this approach has not been well defined. Patients at especially high risk of succumbing to CMV infection include those who acquire resistance to antiviral therapy. We now present results of treatment with banked off-the-shelf third party CMVpp65 specific CTLs in patients with genetically defined mutations in the UL54 DNA polymerase and UL97 kinase CMV genes predicting resistance to antiviral agents. Fifteen recipients of HSCT with mutations defined prior to the start of cell therapy were treated. All 15 had mutations associated with resistance to ganciclovir. Overall 5 had resistance to ganciclovir, foscarnet and cidofovir, 5 had resistance to ganciclovir and foscarnet, one had resistance to ganciclovir and cidofovir and 4 had resistance to ganciclovir alone. Third party CMV-CTLs were selected on the basis of HLA matching at high resolution at a minimum of 2/8 recipient alleles and HLA restriction of the T cells by one or more HLA alleles present in the patient. CMV-CTLS were selected from a bank of 132 lines generated under GMP conditions from normal HSCT donors specifically consented for use of their T cells in patients other than the designated transplant recipient. These 15 patients had a median age of 60.5 (7.4-70.1) years and started therapy with CMV-CTLs a median of 157 (70-564) days after reactivation of CMV. Four of these patients had CMV disease while 11 were treated for viremia alone. Prior therapy in this cohort included foscarnet (N=15) ganciclovir and/or valganciclovir (N=14) and cidofovir and/or brincidofovir (N=9). Each cycle of CMV-CTLs consisted of 3 weekly infusions of 1x106 T-cells/kg/infusion. These 15 patients received a median of 2 (1-3) cycles of CMV-CTLs. CMV-CTLs were well tolerated and there were limited toxicities. Six patients experienced AEs of which one grade 3 and one grade 4 AE were deemed possibly related to infusions with CMV-CTLs. Overall 11/15 (73.3%) patients responded to CMV-CTL therapy including 2 patients with disease with 6 CRs and 5 PRs. Overall survival at 6 months in the 11 responders and 4 non-responders was 72.7% and 25.0% respectively. Within the 6 month follow-up one of the 11 responding patients died of CMV while 3 of the 4 non-responding patients died of CMV. These results indicate that third party donor derived "off-the-shelf" CMV-CTLs can effectively treat CMV viremia or disease in patients not responding to antiviral therapy with demonstrated genetic resistance to antiviral agents. Figure 1. Figure 1. Disclosures Doubrovina: Atara Biotherapeutics: Consultancy, Research Funding. Hasan:Atara Biotherapeutics: Consultancy, Research Funding. Koehne:Atara Biotherapeutics: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.61.61
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
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    Dual-Sensitized T-Cells Responding to EBV Blcl and Either CMVpp65 or WT-1 Peptide Pools Have Distinct or Shared HLA Restrictions That May Depend on the Presenting HLA Alleles
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4596-4596
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4596-4596
    Abstract: Adoptive Immunotherapy with virus-specific T-cells generated from transplant or third party donors can induce durable remissions of severe infections or EBV lymphomas post-transplant. T-cells sensitized with antigens from multiple viruses have also shown promise. However, in any individual donor, immunogenic peptides from different viruses might be expected to elicit T-cell responses restricted by different HLA alleles. In HLA non-identical patients, the efficacy of T-cells reactive against any one virus would be eliminated if the T-cells specific for that virus are restricted by an HLA allele not shared by the patient. To examine this hypothesis, we evaluated the HLA restrictions of T-cells generated from 42 healthy donors after dual sensitization with either autologous EBV-transformed B-cells (EBVBLCL) loaded with a pool of overlapping 15-mer peptides spanning the sequence of CMVpp65 (n=20) or autologous EBVBLCL loaded with a pool of 15-mers spanning the oncofetal protein WT-1 (n=22). The HLA restrictions of the CMVpp65-specific and WT1 specific T cells were assessed by their cytotoxic activity against a panel of Cr51 labeled dendritic cells sharing a single HLA allele with the T cells donor. The EBV restrictions of the dual sensitized EBV CTLs were identified by their cytotoxic activity against EBV BLCLs sharing the same single HLA alleles derived from the same donors. In 13/20 CMVpp65/EBV sensitized T cells (65%) and 17/22 WT1/EBV sensitized T cells (77%) the CMV or WT1 specific T cell lines were restricted by single HLA alleles. In 10 of the 20 (50%) lines sensitized with EBV BLCL and CMVpp65, CMVpp65 specific T cells were restricted by an HLA allele that was also one of the restricting alleles for EBV CTLs in the same line. However, in the other 10(50%) the CMVpp65 T cells were restricted by an HLA allele different from that of the EBV CTLs. In the 22 lines co-sensitized with EBV and WT1, WT1 specific T cells were restricted by an allele different from those of the EBV CTLs in 13 (59%) lines. Comparison of EBVCTLs from dual sensitized T cell lines with EBVCTLs contemporaneously generated from the same donors but sensitized with EBV BLCL alone revealed that in 2/4 CMVpp65/EBV lines and 2/5 WT1/EBV lines in which the HLA restriction of CMVpp65 or WT1 specific T cells differed from that of EBV T cells in the same culture, the HLA allele differentially presenting the CMV or WT1 antigen but not an EBV antigen in the dual sensitized cultures was a prominent restricting allele of T cells sensitized with an autologous EBV BLCL alone. In our bank of 135 CMVpp65-specific T-cells sensitized with autologous APCs loaded with the same pool of overlapping CMVpp65 peptides, T-cells specific for epitopes presented by HLA B0702 were dominant in 33/34 donors inheriting this allele. Furthermore, for T-cell lines generated from 50 donors inheriting HLA A0201, HLA A0201 restricted T-cells specific for the NLV peptide of CMVpp65 were dominant for all lines except those 13 that co-inherited HLA B0702. Disclosures Doubrovina: Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Hasan:GlaxoSmithKline: Employment. Prockop:Atara Biotherapeutics: Research Funding; Mesoblast: Research Funding. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-119001
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 6
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    Safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794) in advanced myxoid/round cell liposarcoma (MRCLS) following high lymphodepletion (Cohort 2): Interim analysis.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 11521-11521
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 11521-11521
    Abstract: 11521 Background: Cancer testis antigen NY-ESO-1 is expressed in multiple tumor types, including 80‒90% of MRCLS [1,2]. Overall response rates (ORRs) to MRCLS treatment are low (1L, 〈 20%; 2L, 〈 10%) [2]. Lete-cel, an autologous T-cell therapy, targets NY-ESO-1/LAGE-1a+ tumors using a genetically modified, high-affinity T-cell receptor. High-dose lymphodepletion (LD) was linked with better responses in synovial sarcoma [3] ; the current study tested this hypothesis in MRCLS. Methods: This open label, pilot study evaluates lete-cel efficacy and safety in advanced MRCLS following low-dose (Cohort 1 [C1]; 30 mg/m 2 fludarabine [flu] x 3d + 600 mg/m 2 cyclophosphamide [cy] x 3d) or high-dose (Cohort 2 [C2] ; 30 mg/m 2 flu x 4d + 900 mg/m 2 cy x 3d; initiated based on C1 data) LD. Key eligibility: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced high-grade NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline; measurable disease; specified washouts; and active/chronic/intercurrent illness restrictions. Stages include screening, leukapheresis, lete-cel manufacture, LD, lete-cel infusion (1– 8 × 10 9 transduced T cells), follow-up. Response is assessed at wk 4, 8, 12, and 24, then every 3 mo to disease progression/death/withdrawal. The primary efficacy endpoint is investigator-assessed ORR by RECIST v1.1. In C1 (n=10 patients [pts]), lete-cel was well tolerated and linked with 2 confirmed partial responses (PR; ORR, 20%) and stable disease (SD) in 8 pts. Planned interim analysis for C2, shown here, was done once all 10 treated pts had ≥3 post-baseline disease assessments or progressed/died/withdrew. Efficacy data will be correlated with transduced cell kinetics and pharmacodynamics marker profiles. Results: Durable (1.0–7.8 mo) PR (4/10 pts [ORR, 40%] ; 2 ongoing) and prolonged (2.7–10.6 mo) SD (5/10 pts; 3 ongoing) with tumor regression were observed. Treatment-emergent cytopenias occurred in all pts. All experienced T-cell related cytokine release syndrome (5 serious adverse events; 30% Grade 3), with onset ≤5d of infusion and median duration 7.5d. Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, pancytopenia, or aplastic anemia were not reported. Conclusions: A single lete-cel infusion after high LD showed antitumor activity in advanced MRCLS and a manageable safety profile consistent with other lete-cel studies. The trial is active but no longer recruiting (NCT02992743). MRCLS is included in a separate, ongoing lete-cel study (NCT03967223). References: 1. D’Angelo SP, et al. J Clin Oncol 2018;36:15_suppl, 3005. 2. Pollack SM, et al. Cancer Med 2020;9(13):4593–602. 3. D’Angelo SP, et al. J Immunother Cancer 2020;8:P298. Funding: GSK (208469; NCT02992743). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Clinical trial information: NCT02992743.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.11521
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 7
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    Open-label pilot study of genetically engineered NY-ESO-1–specific t cells (GSK3377794) alone or in combination with pembrolizumab in relapsed/refractory multiple myeloma.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. TPS8555-TPS8555
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. TPS8555-TPS8555
    Abstract: TPS8555 Background: Adoptive cellular therapy may be practice-changing in relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A*02. GSK3377794 has shown clinical activity in synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and MM after autologous stem cell transplant. NY-ESO-1 and LAGE-1a are cancer/testis antigens frequently overexpressed in MM and linked to poor clinical outcome. PD-1 expression on CD8 T cells, which has been observed in MM patients previously treated with GSK3377794 as well as with CD19 CAR T-cell therapy, can limit adaptive immune response. We hypothesize that GSK3377794 alone, or in combination with the anti-PD-1 inhibitor pembrolizumab, may result in an antitumor effect in MM. Methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients with relapsed/refractory MM positive for HLA-A*02:01, HLA-A*02:05, ± HLA-A*02:06 and NY-ESO-1/LAGE-1a. Patients (n = 20) who have received ≥3 prior therapies containing ≥1 immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, or glucocorticoid will be assigned to either single-infusion GSK3377794 (Arm 1, n = 10) or single-infusion GSK3377794 + pembrolizumab 200 mg IV every 3 weeks (Arm 2, n = 10). Arm 1 enrollment will be completed first. In Arm 2, pembrolizumab will begin in Week 3 (Week 6 if precluded by toxicity). Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x10 9 transduced T cells). Primary and secondary objectives are to assess safety/tolerability and antitumor activity, respectively, of GSK3377794 (± pembrolizumab). Arm 2 enrollment will pause for a 3-week safety review after 3 patients have received a first dose of pembrolizumab. Efficacy, safety, and biomarkers will be assessed every visit. The treatment phase will last 108 weeks, or until disease progression; follow-up will last ≤15 years. As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470) Clinical trial information: NCT03168438 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.TPS8555
    RVK:
    XA 52760
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    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 8
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    Dominant epitopes presented by prevalent HLA alleles permit wide use of banked CMVpp65 T cells in adoptive therapy
    American Society of Hematology ; 2022
    In:  Blood Advances Vol. 6, No. 16 ( 2022-08-23), p. 4859-4872
    Details
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 16 ( 2022-08-23), p. 4859-4872
    Abstract: We established and characterized a bank of 138 CMVpp65 peptide-specific T-cell (CMVpp65CTLs) lines from healthy marrow transplant donors who consented to their use for treatment of individuals other than their transplant recipient. CMVpp65CTL lines included 131 containing predominantly CD8+ T cells and 7 CD4+ T cells. CD8+ CMVpp65CTLs were specific for 1 to 3 epitopes each presented by one of only 34 of the 148 class I alleles in the bank. Similarly, the 7 predominantly CD4+ CMVpp65CTL lines were each specific for epitopes presented by 14 of 40 HLA DR alleles in the bank. Although the number of HLA alleles presenting CMV epitopes is low, their prevalence is high, permitting selection of CMVpp65CTLs restricted by an HLA allele shared by transplant recipient and hematopoietic cell transplant donor for & gt;90% of an ethnogeographically diverse population of hematopoietic cell transplant recipients. Within individuals, responses to CMVpp65 peptides presented by different HLA alleles are hierarchical. Furthermore, within groups, epitopes presented by HLA B*07:02 and HLA A*02:01 consistently elicit immunodominant CMVpp65CTLs, irrespective of other HLA alleles inherited. All dominant CMVpp65CTLs exhibited HLA-restricted cytotoxicity against epitope loaded targets and usually cleared CMV infections. However, immunodominant CMVpp65CTLs responding to epitopes presented by certain HLA B*35 alleles were ineffective in lysing CMV-infected cells in vitro or controlling CMV infections post adoptive therapy. Analysis of the hierarchy of T-cell responses to CMVpp65, the HLA alleles presenting immunodominant CMVpp65 epitopes, and the responses they induce may lead to detailed algorithms for optimal choice of third-party CMVpp65CTLs for effective adoptive therapy.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2022007005
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 9
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    Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma
    Elsevier BV ; 2020
    In:  Biology of Blood and Marrow Transplantation Vol. 26, No. 3 ( 2020-03), p. S269-S270
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 3 ( 2020-03), p. S269-S270
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2019.12.437
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    detail.hit.zdb_id: 2057605-5
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    Abstract 4978: Adoptively transferred CMV-specific T-cells recognizing dominant and sub-dominant pp65 epitopes demonstrate improved in vivo inhibition of tumor xenografts in combination with PD-1 inhibition
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4978-4978
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4978-4978
    Abstract: Adoptive transfer of transplant donor or third party donor derived CMV-specific T cells (CMV-CTL) can effectively treat CMV infections in HSCT recipients. In clinical trials, infusion of partially matched third party CMV-CTLs, has demonstrated high response rates against persistent CMV infection. T-cells (TC) generated in vitro or directly selected in vivo demonstrate a striking preponderance of specificity for 1-2 immunodominant (ID) epitopes presented by specific HLA alleles. ID epitopes elicit higher TC functional activity in vivo, compared to sub-dominant (SD) epitopes. The relative clinical efficacy of TC directed against ID versus SD epitopes in vivo remains undefined. Agents augmenting activity of TC responsive to SD epitopes are unexplored. When these alleles are co-inherited in humans, epitopes of CMVpp65 presented by HLA A*02:01 are ID over HLA A*24:02 presented epitopes. We describe an in vivo model to assess efficacy of CMV-CTLs using colon carcinoma cells (coca)transduced to express CMVpp65, as a surrogate system. HLA A*02:01 + and A*24:02 + human coca cells were transduced to express CMVpp65 and GFP-firefly luciferase (cocapp65). CMV-CTLs responding to either the A*0201 presented ID NLV epitope (A2-NLV) or the A*24:02 presented SD QYD epitope (A24-QYD) were generated from donors co-inheriting HLA A*02:01 and A*24:02 by in vitro stimulation using NIH 3T3 artificial antigen presenting cells, expressing HLA A*02:01 or A*24:02, B7.1, LFA-3, and ICAM1. Tumor cells (105 cells) were injected subcutaneously into groups of 5-6 NSG mice on the R flank, and 105 cells from a pp65 expressing melanoma cell line (melpp65), lacking expression of HLA A*02:01 or A*24:02 were injected on the L shoulder as control. 2 Groups each received 106 of tetramer+ A2-NLV or A24-QYD CMV-CTLs i.v per mouse; one of each CMV-CTL treated group also received 2 i.v doses ( 200µg /dose) of anti-PD1 antibody (Nivolumab-BMS) at day 2 and 7 post CTL infusion. Control groups received IL-2, with or without anti-PD1, or HLA mismatched CMV-CTLs. Tumor growth was monitored by bioluminescent imaging. CMV-CTLs responsive to SD A24-QYD epitope induced significant cocapp65 growth suppression compared to controls, but did not eradicate tumors in any animal. Combined treatment of A24-QYD CMV-CTLs with anti-PD-1 Ab induced complete cocapp65 eradication in 2 of 5 mice, with minute residual tumors in 3 mice. Treatment with ID A2-NLV CMV-CTLs induced complete cocapp65 eradication in 2 of 5 mice, and smaller residual tumors compared to SD A24-QYD CTL treatment. Combined treatment with anti-PD-1 and A2-NLV CMV-CTLs led to complete cocapp65 eradication in 3 of 5 mice, with minute tumors in 2 mice. Taken together, these data provide evidence that blocking the PD-1/PD-L1 interaction may significantly augment the antiviral activity of both ID and SD CMV-CTLs. Citation Format: Aisha N. Hasan, Annamalai Selvakumar, Tzu-Yun Kuo, Richard J. O'Reilly. Adoptively transferred CMV-specific T-cells recognizing dominant and sub-dominant pp65 epitopes demonstrate improved in vivo inhibition of tumor xenografts in combination with PD-1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4978. doi:10.1158/1538-7445.AM2017-4978
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-4978
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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