Publications by authors named "Catherine M Bollard"

228 Publications

Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors.

Nat Commun 2021 Nov 18;12(1):6689. Epub 2021 Nov 18.

Center for Cancer and Immunology Research, Children's National Research Institute, Washington, DC, USA.

Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.
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http://dx.doi.org/10.1038/s41467-021-26936-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602676PMC
November 2021

Off the Shelf Third Party Virus Specific T-Cell Therapy to Treat JC Polyomavirus Infection in Hematopoietic Stem Cell Transplant Recipients.

Transplant Cell Ther 2021 Nov 13. Epub 2021 Nov 13.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati OH.

Background: Progressive multifocal leukoencephalopathy (PML) is a progressive and generally fatal demyelinating neurological disease that occurs in profoundly immunocompromised patients due to infection with the human polyomavirus JC virus (JCPyV). Treatment options are limited and are largely focused on restoring T-cell immunity and outcomes are historically poor. Control of JCPyV in the setting of an immunocompromised patient by adoptive transfer of third-party virus specific T-cells (VSTs) has been described in a small number of cases.

Objective: To investigate treatment response and outcomes in recipients of hematopoietic stem cell transplant (HSCT) with PML treated with third-party VSTs directed against BK virus, a highly homologous polyoma virus that shares immunogenic epitopes with JCPyV.

Study Design: Retrospective chart review was performed on four patients who received VSTs for the treatment of PML at Cincinnati Children's Hospital Medical Center since 2019 RESULTS: VSTs were safely administered with no cases of graft-vs-host disease and no infusion reactions. One patient, who was treated almost immediately after diagnosis, was able to clear JCPyV from blood and CSF with resultant stabilization of neurologic decline. Interferon-gamma ELISpot demonstrated virus specific T-cells in the peripheral blood following infusion. Response was maintained through repeat infusions. Three other patients, all of whom had a longer delay between diagnosis and infusion, had progressive neurologic decline despite varying degree of improvement in viral load.

Conclusion: PML is a rare but often fatal complication following HSCT for which few treatment options are available. BK directed, JCPyV cross-reactive VSTs are a safe and viable therapeutic option and prompt administration should be considered after a diagnosis of PML is made. Key points • Virus specific T cells targeting JCPyV virus are safe with no infusional toxicity or de-novo graft versus host disease. • Virus specific T-cells have evidence of efficacy in some cases of PML, but further studies are needed to determine factors that will optimize response.
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http://dx.doi.org/10.1016/j.jtct.2021.11.005DOI Listing
November 2021

Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia.

Mol Ther Methods Clin Dev 2021 Dec 1;23:296-306. Epub 2021 Oct 1.

The George Washington University Cancer Center, Washington, DC 20052, USA.

The synovial sarcoma X breakpoint 2 (SSX2) belongs to a multigene family of cancer-testis antigens and can be found overexpressed in multiple malignancies. Its restricted expression in immune-privileged normal tissues suggest that SSX2 may be a relevant target antigen for chimeric antigen receptor (CAR) therapy. We have developed a T cell receptor (TCR)-like antibody (Fab/3) that binds SSX2 peptide 41-49 (KASEKIFYV) in the context of HLA-A∗-0201. The sequence of Fab/3 was utilized to engineer a CAR with the CD3 zeta intra-cellular domain along with either a CD28 or 4-1BB costimulatory endodomain. Human T cells from HLA-A2 donors were transduced to mediate anti-tumor activity against acute myeloid leukemia (AML) tumor cells. Upon challenge with HLA-A2/SSX2 AML tumor cells, CAR-expressing T cells released interferon-γ and eliminated the tumor cells in a long-term co-culture assay. Using the HLA-A2 T2 cell line, we demonstrated a strong specificity of the single-chain variable fragment (scFv) for SSX2 p41-49 and the closely related SSX3 p41-49, with no response against the others SSX-homologous peptides or unrelated homologous peptides. Since SSX3 has not been observed in tumor cells and expression cannot be induced by pharmacological intervention, SSX2 represents an attractive target for CAR-based cellular therapy to treat multiple types of cancer.
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http://dx.doi.org/10.1016/j.omtm.2021.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526777PMC
December 2021

High risk of relapsed disease in patients with NK/T cell chronic active Epstein-Barr virus disease outside of Asia.

Blood Adv 2021 Oct 20. Epub 2021 Oct 20.

NIH, Bethesda, Maryland, United States.

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or NK cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis (HLH) and/or lymphoma. The disease is more common in Asia than in the United States and Europe. While allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment for the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% v 25%, p<0.01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% v 35%, p=0.1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.
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http://dx.doi.org/10.1182/bloodadvances.2021005291DOI Listing
October 2021

Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial.

J Clin Oncol 2021 Nov 27;39(33):3716-3724. Epub 2021 Sep 27.

Department of Pediatrics, Center for Cancer and Blood Diseases, Children's Hospital Colorado, Aurora, CO.

Purpose: A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents.

Patients And Methods: We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567).

Results: Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically ( = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%).

Conclusion: DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma.
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http://dx.doi.org/10.1200/JCO.21.00920DOI Listing
November 2021

Using Molecular Stratification for Smart Combination Therapies.

J Clin Oncol 2021 Nov 24;39(32):3527-3530. Epub 2021 Sep 24.

Center for Cancer and Immunology Research, Children's National Hospital and The George Washington University, Washington, DC.

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http://dx.doi.org/10.1200/JCO.21.01804DOI Listing
November 2021

Tumor associated antigen specific T cells with nivolumab are safe and persist in vivo in rel/ref Hodgkin Lymphoma.

Blood Adv 2021 Sep 8. Epub 2021 Sep 8.

The George Washington University School of Medicine, United States.

Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-T when given alone or with nivolumab were safe and could elicit anti-tumor effects in vivo in patients with relapsed/refractory (r/r) HL. Ten patients were infused TAA-T (8 autologous; 2 allogeneic) for active HL(n=8) or as adjuvant therapy after hematopoietic stem cell transplant (n=2) at cumulative doses ranging from 0.5 X107 to 4 X107cells/m2. Six patients received nivolumab priming before TAA-T and continued until disease progression or unacceptable toxicity. All 10 products recognized 1 or more TAAs, were polyfunctional and did not demonstrated autoreactivity. Patients were monitored for safety for six weeks following the TAA-T and for response until disease progression. The infusions were safe with no clear dose limiting toxicities. Patients receiving TAA-T as adjuvant therapy remain in continued remission at 2+ years. Of the 8 patients with active disease,1 patient had a complete response and 7 had stable disease at 3 months, 3 of whom remain with stable disease at 1 year. Antigen spreading and long-term persistence of TAA-T in vivo were observed in responding patients. Nivolumab priming impacted the TAA-T recognition and persistence. In conclusion, treatment of r/r HL patients with TAA-T alone or in combination with nivolumab was safe and produced promising results (clinicaltrials.gov NCT022039303 and NCT03843294).
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http://dx.doi.org/10.1182/bloodadvances.2021005343DOI Listing
September 2021

Spike-directed vaccination elicits robust spike-specific T-cell response, including to mutant strains.

Cytotherapy 2021 Sep 2. Epub 2021 Sep 2.

Program for Cell Enhancement and Technologies for Immunotherapy, Children's National Medical Center, Washington, DC, USA. Electronic address:

Although most studies describing coronavirus disease 2019 vaccine responses have focused on antibodies, there is increasing evidence that T cells play a critical role. Here the authors evaluated T-cell responses in seronegative donors before and after vaccination to define responses to the severe acute respiratory syndrome coronavirus 2 reference strain as well as to mutations in the variant strains Alpha/B.1.1.7 and Beta/B.1.351. The authors observed enhanced T-cell responses to reference and variant spike strains post-vaccination.
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http://dx.doi.org/10.1016/j.jcyt.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411349PMC
September 2021

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted.

Blood Adv 2021 09;5(17):3309-3321

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.
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http://dx.doi.org/10.1182/bloodadvances.2021004456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525242PMC
September 2021

EBV+ Lymphoproliferative Diseases: Opportunities for leveraging EBV as a Therapeutic Target.

Blood 2021 Aug 26. Epub 2021 Aug 26.

George Washington University, United States.

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell based immune therapies. In this review, we will describe the EBV-associated lymphoproliferative diseases and will particularly focus on the therapies that target EBV.
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http://dx.doi.org/10.1182/blood.2020005466DOI Listing
August 2021

Flow-based analysis of cell division identifies highly active populations within plasma products during mixed lymphocyte cultures.

Blood Transfus 2021 Nov 14;19(6):456-466. Epub 2021 Jun 14.

Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, United States of America.

Background: Leukoreduction to eliminate mononuclear cells within blood products is necessary to prevent graft-versus-host disease after transfusion. Published reports document low concentrations of mononuclear cells leftover in fresh-frozen plasma products, however the phenotype and the proliferative potential of these cells has not been tested.

Materials And Methods: We investigated residual cellular components contained within fresh and fresh-frozen plasma products and characterised their proliferative potential in co-cultures with unrelated allogeneic cells. We designed a flow-based assay to phenotype cells and quantify cell division by measuring the dilution of fluorescently labeled protein as cells divide. Leukocytes from consenting donors were purified from fresh liquid or fresh-frozen plasma units and cultured for three to seven days with unrelated irradiated allogeneic targets.

Results: We discovered a median of 1.6×10 viable lymphocytes were detectable in fresh plasma units after collection (n=8), comprised of a mixture of CD3+ CD8+ and CD3+ CD4+ cells. Furthermore, we identified a median of 8.4% of live CD3+ plasma lymphocytes divided as early as Day 4 when co-cultured with unrelated allogeneic cells, expanding to a median 88.8% by Day 7 (n=3). Although freezing the plasma product reduced the total number of viable leukocyte cells down to 2.3×10 (n=10), residual naive CD3+ cells were viable and demonstrated division through Day 7 of co-culture.

Discussion: The evidence of viable proliferative lymphocytes in fresh and fresh-frozen plasma products derived from centrifugation suggests that additional leukoreduction measures should be investigated to fully eradicate reactive lymphocytes from centrifuged plasma products.
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http://dx.doi.org/10.2450/2021.0096-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580781PMC
November 2021

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

Ann Hematol 2021 Oct 24;100(10):2529-2539. Epub 2021 Jul 24.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
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http://dx.doi.org/10.1007/s00277-021-04558-0DOI Listing
October 2021

Genomic and clinical characterization of early T-cell precursor lymphoblastic lymphoma.

Blood Adv 2021 07;5(14):2890-2900

ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.

Early T-cell precursor phenotype acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-ALL with a unique immunophenotype and genetic abnormalities distinct from conventional T-ALL. A subset of T lymphoblastic lymphoma (T-LLy) also demonstrates the early T-cell precursor immunophenotype and may be a counterpart of ETP-ALL. Unlike ETP-ALL, the incidence, clinical features, and genomic features of ETP-LLy are unknown. We reviewed the immunophenotyping data of 218 T-LLy patients who enrolled in the Children's Oncology Group AALL0434 clinical trial and identified 9 cases (4%) exhibiting a definitive ETP immunophenotype. We performed single-nucleotide polymorphism array profiling on 9 ETP-LLy and 15 non-ETP T-LLy cases. Compared with non-ETP T-LLy, ETP-LLy showed less frequent deletion of 9p (CKDN2A/B), more frequent deletion of 12p (ETV6) and 1p (RPL22), and more frequent absence of biallelic T-cell receptor γ deletions. Recurrent abnormalities previously described in ETP-ALL such as deletions of 5q and 13q and gain of 6q were not observed in ETP-LLy cases. There were no failures of therapy among the ETP-LLy subtype with a 4-year event-free survival of 100%. Overall, ETP-LLy does not exhibit unifying genetic alterations but shows some distinct genomic features from non-ETP T-LLy suggesting that ETP-LLy may be a distinct entity from non-ETP T-LLy.
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http://dx.doi.org/10.1182/bloodadvances.2021004334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341356PMC
July 2021

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies.

J Exp Med 2021 07 14;218(7). Epub 2021 May 14.

Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY.

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This "participant-derived xenograft" model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.
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http://dx.doi.org/10.1084/jem.20201908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129803PMC
July 2021

Robust Antibody and T Cell Responses to SARS-CoV-2 in Patients with Antibody Deficiency.

J Clin Immunol 2021 08 13;41(6):1146-1153. Epub 2021 May 13.

Center for Cancer and Immunology Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA.

Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.
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http://dx.doi.org/10.1007/s10875-021-01046-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117127PMC
August 2021

Identification of novel HLA-restricted preferentially expressed antigen in melanoma peptides to facilitate off-the-shelf tumor-associated antigen-specific T-cell therapies.

Cytotherapy 2021 08 5;23(8):694-703. Epub 2021 Apr 5.

Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA; GW Cancer Center, George Washington University, Washington, DC, USA; Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, DC, USA. Electronic address:

Background Aims: Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen that is overexpressed in many human malignancies and poorly expressed or absent in healthy tissues, making it a good target for anti-cancer immunotherapy. Development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory solid tumors and hematological malignancies expressing PRAME antigen requires the identification of major histocompatibility complex (MHC) class I and II PRAME antigens recognized by the tumor-associated antigen (TAA) T-cell product. The authors therefore set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized.

Methods: Peptide libraries of 125 overlapping 15-mer peptides spanning the entire PRAME protein sequence were used to identify HLA class I- and II-restricted epitopes. The authors also determined the HLA restriction of the identified epitopes.

Results: PRAME-specific T-cell products were successfully generated from peripheral blood mononuclear cells of 12 healthy donors. Ex vivo-expanded T cells were polyclonal, consisting of both CD4+ and CD8+ T cells, which elicited anti-tumor activity in vitro. Nine MHC class I-restricted PRAME epitopes were identified (seven novel and two previously described). The authors also characterized 16 individual 15-mer peptide sequences confirmed as CD4-restricted epitopes.

Conclusions: TAA T cells derived from healthy donors recognize a broad range of CD4+ and CD8+ HLA-restricted PRAME epitopes, which could be used to select suitable donors for generating off-the-shelf TAA-specific T cells.
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http://dx.doi.org/10.1016/j.jcyt.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316284PMC
August 2021

Chimeric antigen receptor-engineered natural killer cells: a promising cancer immunotherapy.

Expert Rev Clin Immunol 2021 Jun 12;17(6):643-659. Epub 2021 Apr 12.

Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, WA, USA.

:Widespread success of CD19 chimeric antigen receptor (CAR) T cells for the treatment of hematological malignancies have shifted the focus from conventional cancer treatments toward adoptive immunotherapy. There are major efforts to improve CAR constructs and to identify new target antigens. Even though the Food and Drug Administration has approved commercialization of some CD19 CART cell therapies, there are still some limitations that restrict their widespread clinical use. The manufacture of autologous products for individual patients is logistically cumbersome and expensive and allogeneic T cell products may pose an appreciable risk of graft-versus-host disease (GVHD).:Natural killer (NK) cells are an attractive alternative for CART-based immunotherapies. They have the innate ability to detect and eliminate malignant cells and are safer in the 'off-the-shelf' setting. This review discusses the current progress within the CAR NK cell field, including the challenges, and future prospects. Gene engineered NK cells was used as the search term in PubMed and Google Scholar through to December 2020.:CAR NK cell therapies hold promise as an 'off-the-shelf' cell therapy for cancer. It is hoped that an enhanced understanding of their immunobiology and molecular mechanisms of action will improve their in vivo potency.
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http://dx.doi.org/10.1080/1744666X.2021.1911648DOI Listing
June 2021

Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1.

Blood 2021 07;137(26):3595-3603

Center for Cancer and Immunology Research, Department of Pediatrics, Children's National Hospital and The George Washington University, Washington, DC.

Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.
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http://dx.doi.org/10.1182/blood.2020009806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462406PMC
July 2021

T-Cell Therapy for Lymphoma Using Nonengineered Multiantigen-Targeted T Cells Is Safe and Produces Durable Clinical Effects.

J Clin Oncol 2021 05 28;39(13):1415-1425. Epub 2021 Jan 28.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.

Purpose: Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen-specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape.

Patients And Methods: We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 10 cells/m) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment.

Results: Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 10 cells/m) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years).

Conclusion: T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 10 cells/m are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.
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http://dx.doi.org/10.1200/JCO.20.02224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274795PMC
May 2021

SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.

Blood 2020 12;136(25):2905-2917

National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD.

T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.
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http://dx.doi.org/10.1182/blood.2020008488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746091PMC
December 2020

Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma.

Cancers (Basel) 2020 Dec 2;12(12). Epub 2020 Dec 2.

Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Houston, TX 77030, USA.

Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed-Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3-18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.
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http://dx.doi.org/10.3390/cancers12123603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761312PMC
December 2020

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.

Blood Adv 2020 11;4(22):5745-5754

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, OH.

BK polyomavirus (BKPyV) infection is a major complication of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT). Treatment options are limited, poorly effective, and have significant toxicities. Cellular therapy using T cells directed against BKPyV is an emerging therapy, and we report efficacy in controlling BKPyV-associated disease in highly immunocompromised patients. Virus-specific T cells (VSTs) against BKPyV were manufactured using either blood from the patient's stem cell donor (donor-derived VSTs) or from unrelated donors (third-party VSTs). VSTs were used to treat BKPyV in 38 HSCT recipients and 3 SOT recipients between June 2017 and December 2019. Overall response rate was 86% in patients treated for BK viremia, 100% in patients treated for hemorrhagic cystitis, and 87% in patients treated for both BK viremia and hemorrhagic cystitis. No infusional toxicity, de novo graft-versus-host disease, or rejection of the organ occurred attributable to the VST infusion. BKPyV-specific immune responses were demonstrated by interferon-γ production by peripheral blood mononuclear cells postinfusion in response to BKPyV antigens. VSTs are a safe and potentially effective strategy to treat BKPyV and associated symptoms in recipients of HSCT and SOT. Cellular therapy should be considered for all patients with BKPyV and underlying immune suppression at risk of complications. This trial was registered at www.clinicaltrials.gov as #NCT02532452.
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http://dx.doi.org/10.1182/bloodadvances.2020003073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686882PMC
November 2020

Frontiers in cancer immunotherapy-a symposium report.

Ann N Y Acad Sci 2021 04 13;1489(1):30-47. Epub 2020 Nov 13.

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, California.

Cancer immunotherapy has dramatically changed the approach to cancer treatment. The aim of targeting the immune system to recognize and destroy cancer cells has afforded many patients the prospect of achieving deep, long-term remission and potential cures. However, many challenges remain for achieving the goal of effective immunotherapy for all cancer patients. Checkpoint inhibitors have been able to achieve long-term responses in a minority of patients, yet improving response rates with combination therapies increases the possibility of toxicity. Chimeric antigen receptor T cells have demonstrated high response rates in hematological cancers, although most patients experience relapse. In addition, some cancers are notoriously immunologically "cold" and typically are not effective targets for immunotherapy. Overcoming these obstacles will require new strategies to improve upon the efficacy of current agents, identify biomarkers to select appropriate therapies, and discover new modalities to expand the accessibility of immunotherapy to additional tumor types and patient populations.
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http://dx.doi.org/10.1111/nyas.14526DOI Listing
April 2021

T-Cell Therapeutics Targeting Human Parainfluenza Virus 3 Are Broadly Epitope Specific and Are Cross Reactive With Human Parainfluenza Virus 1.

Front Immunol 2020 5;11:575977. Epub 2020 Oct 5.

Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, United States.

Human Parainfluenza Virus-3 (HPIV3) causes severe respiratory illness in immunocompromised patients and lacks approved anti-viral therapies. A phase I study of adoptively transferred virus-specific T-cells (VSTs) targeting HPIV3 following bone marrow transplantation is underway (NCT03180216). We sought to identify immunodominant epitopes within HPIV3 Matrix protein and their cross-reactivity against related viral proteins. VSTs were generated from peripheral blood of healthy donors by ex-vivo expansion after stimulation with a 15-mer peptide library encompassing HPIV3 matrix protein. Epitope mapping was performed using IFN-γ ELIspot with combinatorial peptide pools. Flow cytometry was used to characterize products with intracellular cytokine staining. In 10 VST products tested, we discovered 12 novel immunodominant epitopes. All products recognized an epitope at the C-terminus. On IFN-γ ELISpot, individual peptides eliciting activity demonstrated mean IFN-γ spot forming units per well (SFU)/1x10 cells of 115.5 (range 24.5-247.5). VST products were polyfunctional, releasing IFN-γ and TNF-α in response to identified epitopes, which were primarily HLA Class II restricted. Peptides from Human Parainfluenza Virus-1 corresponding to the HPIV3 epitopes showed cross-reactivity for HPIV1 in 11 of 12 tested epitopes (mean cross reactivity index: 1.19). Characterization of HPIV3 epitopes may enable development of third-party VSTs to treat immune suppressed patients with HPIV infection.
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http://dx.doi.org/10.3389/fimmu.2020.575977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573487PMC
June 2021

Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.

Blood 2021 04;137(13):1777-1791

Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent MAPK pathway activation. Standard-of-care chemotherapies are inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis, and the potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited "exhausted" phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intralesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intralesional regulatory T cells demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses. Whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cells and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment, and they highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.
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http://dx.doi.org/10.1182/blood.2020005867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020265PMC
April 2021

Hematopoietic Cell Transplantation: Practice Predictions for the Year 2023.

Transplant Cell Ther 2021 02 9;27(2):183.e1-183.e7. Epub 2020 Oct 9.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Research priorities are best determined by the most pressing scientific questions, in the context of current knowledge. However, definitive research studies take time, while real-world experience accumulates. Adoption of new practices before adequate comparison with current treatments threatens successful study conduct and may expose patients to what ultimately turns out to be inferior treatment. We conducted a survey to understand the hematopoietic cell transplantation (HCT) community's predictions about future practice trends in the HCT field and results of ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials to gauge how the HCT community views the treatments being studied. The survey was distributed between February and March 2019 to an electronic mailing list of HCT clinicians practicing in the United States maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR). Of 986 clinicians surveyed, 315 responded (32%). They predicted an increase in the number of HCTs performed for malignant hematologic diseases and benign diseases such as sickle cell, autoimmune, and genetic disorders. The majority (63%) predicted that matched related donors will remain the preferred donor source for adult HCT recipients in 2023, but 21% predicted haploidentical (haplo) donors and 17% predicted matched unrelated donors would be the preferred source. Most respondents (65%) predicted a decrease in the use of umbilical cord blood (UCB) as a graft source for HCT. Most respondents also predicted that calcineurin-based graft-versus-host disease (GVHD) prophylaxis would be replaced by post-transplantation cyclophosphamide (PTCy) (55%), biomarker use would become standard practice to guide GVHD therapy (73%), and steroids would be combined with other agents as first-line therapy for newly diagnosed acute (53%) and chronic GVHD (54%). In ongoing BMT CTN trials in which outcomes are not yet known, 60% to 92% of respondents had an opinion about which arm they thought would be superior. However, not all respondents predicted the same outcome, with 44% to 88% choosing the same arm. There was no clear relationship between the proportion predicting the same arm would win and accrual to the trial. Survey respondents were optimistic about an increasing volume of transplantation procedures, and they also expected significant changes in HCT practice over the next few years, including wider adoption of PTCy GVHD prophylaxis, increased use of biomarkers to guide GVHD therapy, and decreased use of UCB HCT. The degree of equipoise in the community about the relative efficacy of therapies being studied did not seem to affect accrual to current BMT CTN trials, but this is an area that needs further investigation.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546661PMC
February 2021

NK Cell Adoptive Immunotherapy of Cancer: Evaluating Recognition Strategies and Overcoming Limitations.

Transplant Cell Ther 2021 01 29;27(1):21-35. Epub 2020 Sep 29.

Program for Cell Enhancement and Technologies for Immunotherapy and Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC; School of Medicine and Health Sciences, George Washington University, Washington, DC. Electronic address:

Natural killer (NK) cells, the primary effector cells of the innate immune system, utilize multiple strategies to recognize tumor cells by (1) detecting the presence of activating receptor ligands, which are often upregulated in cancer; (2) targeting cells that have a loss of major histocompatibility complex (MHC); and (3) binding to antibodies that bind to tumor-specific antigens on the tumor cell surface. All these strategies have been successfully harnessed in adoptive NK cell immunotherapies targeting cancer. In this review, we review the applications of NK cell therapies across different tumor types. Similar to other forms of immunotherapy, tumor-induced immune escape and immune suppression can limit NK cell therapies' efficacy. Therefore, we also discuss how these limitations can be overcome by conferring NK cells with the ability to redirect their tumor-targeting capabilities and survive the immune-suppressive tumor microenvironment. Finally, we also discuss how future iterations can benefit from combination therapies with other immunotherapeutic agents.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043250PMC
January 2021

Engineered Antigen-Specific T Cells Secreting Broadly Neutralizing Antibodies: Combining Innate and Adaptive Immune Response against HIV.

Mol Ther Methods Clin Dev 2020 Dec 21;19:78-88. Epub 2020 Aug 21.

George Washington University Cancer Center, George Washington University, Washington, DC, USA.

While antiretroviral therapy (ART) can completely suppress viremia, it is not a cure for HIV. HIV persists as a latent reservoir of infected cells, able to evade host immunity and re-seed infection following cessation of ART. Two promising immunotherapeutic strategies to eliminate both productively infected cells and reactivated cells of the reservoir are the adoptive transfer of potent HIV-specific T cells and the passive administration of HIV-specific broadly neutralizing antibodies also capable of mediating antibody-dependent cellular cytotoxicity (ADCC). The simultaneous use of both as the basis of a single therapeutic has never been explored. We therefore sought to modify HIV-specific T cells from HIV-naive donors (to allow their use in the context of allotransplant, a promising platform for sterilizing cures) so they are able to secrete a broadly neutralizing antibody (bNAb) directed against the HIV envelope to elicit ADCC. We designed an antibody construct comprising bNAb 10-1074 heavy and light chains, fused to IgG3 Fc to elicit ADCC, with truncated cluster of differentiation 19 (CD19) as a selectable marker. HIV-specific T cells were expanded from HIV-naive donors by priming with antigen-presenting cells expressing overlapping HIV antigens in the presence of cytokines. T cells retained specificity against Gag, Nef, and Pol peptides (218.55 ± 300.14 interferon γ [IFNγ] spot-forming cells [SFC]/1 × 10) following transduction (38.92 ± 25.30) with the 10-1074 antibody constructs. These cells secreted 10-1074 antibodies (139.04 ± 114.42 ng/mL). The HIV-specific T cells maintained T cell function following transduction, and the secreted 10-1074 antibody bound HIV envelope (28.13% ± 19.42%) and displayed ADCC activity (10.47% ± 4.11%). Most critically, the 10-1074 antibody-secreting HIV-specific T cells displayed superior suppression of HIV replication. In summary, HIV-specific T cells can be engineered to produce antibodies mediating ADCC against HIV envelope-expressing cells. This combined innate/adaptive approach allows for synergy between the two immune arms, broadens the target range of the immune therapy, and provides further insight into what defines an effective anti-HIV response.
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http://dx.doi.org/10.1016/j.omtm.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508916PMC
December 2020
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