Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.
PURPOSE Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083 ) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
The successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment. C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by >80% of AML but is absent on normal HSCs. Here we describe the development and evaluation of CLL-1-specific chimeric antigen receptor T cells (CLL-1.CAR-Ts) and we demonstrate their specific activity against CLL-1 AML cell lines as well as primary AML patient samples in vitro. CLL-1.CAR-Ts selectively reduced leukemic colony formation in primary AML patient peripheral blood mononuclear cells compared to control T cells. In a human xenograft mouse model, CLL-1.CAR-Ts mediated anti-leukemic activity against disseminated AML and significantly extended survival. By contrast, the colony formation of normal progenitor cells remained intact following CLL-1.CAR-T treatment. Although CLL-1.CAR-Ts are cytotoxic to mature normal myeloid cells, the selective sparing of normal hematopoietic progenitor cells should allow full myeloid recovery once CLL-1.CAR-T activity terminates. To enable elective ablation of the CAR-T, we therefore introduced the inducible caspase-9 suicide gene system and we show that exposure to the activating drug rapidly induced a controlled decrease of unwanted CLL-1.CAR-T activity against mature normal myeloid cells.
BackgroundThe adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site.MethodsFirst (1G - CD3ζ) and second generation (2G - 41BB.CD3ζ) MUC1-specific CARs were constructed using the HMFG2 scFv. Following retroviral transduction transgenic expression of the CAR±ICR was assessed by flow cytometry. In vitro CAR/ICR T cell function was measured by assessing cell proliferation and short- and long-term cytotoxic activity using MUC1+ MDA MB 468 cells as targets. In vivo anti-tumor activity was assessed using IL4-producing MDA MB 468 tumor-bearing mice using calipers to assess tumor volume and bioluminescence imaging to track T cells.ResultsIn the IL4-rich tumor milieu, 1G CAR.MUC1 T cells failed to expand or kill MUC1+ tumors and while co-expression of the 4/7ICR promoted T cell expansion, in the absence of co-stimulatory signals the outgrowing cells exhibited an exhausted phenotype characterized by PD-1 and TIM3 upregulation and failed to control tumor growth. However, by co-expressing 2G CAR.MUC1 (signal 1 - activation + signal 2 - co-stimulation) and 4/7ICR (signal 3 - cytokine), transgenic T cells selectively expanded at the tumor site and produced potent and durable tumor control in vitro and in vivo.ConclusionsOur findings demonstrate the feasibility of targeting breast cancer using transgenic T cells equipped to thrive in the suppressive tumor milieu and highlight the importance of providing transgenic T cells with signals that recapitulate physiologic TCR signaling – [activation (signal 1), co-stimulation (signal 2) and cytokine support (signal 3)] - to promote in vivo persistence and memory formation.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0347-5) contains supplementary material, which is available to authorized users.
Chimeric antigen receptor (CAR) T cell therapy for the treatment of acute myeloid leukemia (AML) has the risk of toxicity to normal myeloid cells. CD7 is expressed by the leukemic blasts and malignant progenitor cells of approximately 30% of AML patients but is absent on normal myeloid and erythroid cells. Since CD7 expression by malignant blasts is also linked with chemoresistance and poor outcomes, targeting this antigen may be beneficial for this subset of AML patients. Here, we show that expression of a CD7-directed CAR in CD7 gene-edited (CD7 KO ) T cells effectively eliminates CD7 + AML cell lines, primary CD7 + AML, and colony-forming cells but spares myeloid and erythroid progenitor cells and their progeny. In a xenograft model, CD7 CAR T cells protect mice against systemic leukemia, prolonging survival. Our results support the feasibility of using CD7 KO CD7 CAR T cells for the non-myeloablative treatment of CD7 + AML.
Introduction Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. In the pivotal JULIET trial, 115 patients received tisagenlecleucel treatment; the best overall response rate (ORR) was 54% and complete response (CR) rate was 40%. At a median follow-up of 24 months, the median duration of response was not reached. Grade 3 or higher cytokine release syndrome (CRS) (UPenn scale) and neurotoxicity within the first 8 weeks after infusion occurred in 22.6% and 11.3%, respectively (Bachanova et. al. Hematol Oncol. Abstr 2019). CIBMTR CT Registry was developed to collect long-term safety and efficacy information on recipients of cellular immunotherapies and it is utilized for a post marketing study of tisagenlecleucel in the real-world setting. Methods Clinical data from the registry were analyzed for baseline information. Efficacy and safety data were collected from patients with a minimum of 3 months follow-up. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported as per the consensus ASTCT criteria. Important manufacturing product characteristics of tisagenlecleucel were compared to clinical outcomes obtained by the CIBMTR CT registry. The association of number of cells administered, cell viability, potency, and transduction efficiency to overall response, CRS and ICANS grade was performed using descriptive summaries and univariate logistic regression analyses. Tisagenlecleucel cell product characterization by immunophenotyping was also compared to clinical outcomes in the CIBMTR Registry. Results Twenty-six centers contributed data for relapsed/refractory DLBCL patients through the CIBMTR CT registry as of May 31, 2019. Baseline information was available in 70 patients while outcomes ≥ 3 months post-infusion was available on 47 patients (Table 1). All patients received cells in the FDA approved range (0.6 to 6 x 108 CAR+ viable T cells) with a median of 1.7 x 108 (range 0.6-3.5 x 108). The median follow-up time for survivors was 5.8 months (0.9-8.9 months). The overall response rate (ORR) was 59.6% (28 of 47 patients) including 38.3% (18 patients) achieving a CR. The rate of grade 3 or higher CRS and ICANS was 4.3% and 4.3%, respectively. Tocilizumab and corticosteroids were administered in 40.9% and 9.1% among patients who had CRS. The median time to onset of CRS was 4.5 days and lasted for an average of 5 days. A total of 14 (29.8%) patients died after treatment, all due to disease progression and no deaths were attributed to toxicities from tisagenlecleucel. A secondary malignancy was reported in 1 patient (basal cell carcinoma) that was present prior to CAR-T cell infusion. Out of the products manufactured for these 47 patients, 21 were out-of-commercial specification (OOS) because of low cell viability (< 80%), however, efficacy and safety outcomes were similar to those with batches meeting viability specifications. None of the manufacturing characteristics analyzed (such as cell viability, potency or transduction efficiency) correlated with either efficacy (ORR) or safety (CRS or ICANS). Importantly, analysis of cell viability showed no association with best overall response (Table 2). Conclusions The CIBMTR CT registry represents real-world data for the treatment of adults with DLBCL and allows capture of long-term follow up (15 years). The efficacy and safety in the real world setting demonstrate similar efficacy and safety as compared with the pivotal JULIET trial. Cell product characteristics analyzed, including percentage of viable cells, do not correlate with response rates, CRS or ICANS. Updated results, including tisagenlecleucel cell product characterization, will be presented at the meeting. Disclosures Kamdar: Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; University of Colorado: Employment. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Merck: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Jeschke:Novartis: Employment. Chawla:Novartis Pharma AG: Employment. Horowitz:Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Chimerix: Other: Unrestricted educational and research grant; Janssen: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Daiichi Sankyo: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Regeneron: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Actinium: Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; Oncoimmune: Other: Unrestricted educational and research grant. Bleickardt:Novartis: Employment. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Kit Pharma: Research Funding; Novartis: Research Funding.
Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes. Thus, to minimize GVHD and maximize GVL we selectively activated and expanded stem-cell donor-derived T cells that were reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, NY-ESO-1). Products were successfully generated from 29 HCT donors, and they demonstrated multi-leukemia antigen specificity (mLSTs). In contrast to DLIs, mLSTs selectively recognized and killed leukemia-antigen-pulsed cells with no activity against recipient-derived normal cells in vitro. We have now administered escalating doses of these mLSTs (0.5-10x107 cells/m2) to 25 trial enrollees with AML/MDS after HCT, 17 of whom were at high risk for relapse and 8 of whom had relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD up to a dose of 10x107 cells/m2. We observed anti-leukemia effects in vivo that translated into not yet reached median LFS and OS at 1.9 years of follow-up among survivors, evidence of sustained immune pressure and objective responses in the active disease cohort (1 CR and 1 PR). In conclusion, mLSTs are safe and promising for the prevention or treatment of AML/MDS following HCT.
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 × 107 cells/m2) 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 × 107 cells/m2) 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 × 107 cells/m2 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.