Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor–transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma
A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generatio...
Source: Journal of Immunotherapy - April 11, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Generation of a Transgenic BALB/c Mouse Line With Selective Expression of Human Mesothelin in Thyroid Gland: Application in Mesothelin-targeted Immunotherapy
Despite encouraging clinical results with immune checkpoint inhibitors and other types of immunotherapies, the rate of failure is still very high. The development of proper animal models which could be applied to the screening of effective preclinical antitumor drugs targeting human tumor antigens, such as mesothelin (MSLN), is a great need. MSLN is a 40 kDa cell-surface glycoprotein which is highly expressed in a variety of human cancers, and has great value as a target for antibody-based therapies. The present study reports the establishment of an immunocompetent transgenic mouse expressing human MSLN (hMSLN) only in t...
Source: Journal of Immunotherapy - April 11, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Suppressive Characteristics of Umbilical Cord Blood–derived Regulatory T Cells After Ex Vivo Expansion on Autologous and Allogeneic T Effectors and Various Lymphoblastic Cells
The third-party umbilical cord blood (UCB)-derived regulatory T cells (Treg) are an alternative to donor-derived Treg as cellular therapy of graft-versus-host disease following hematopoietic stem cell transplantation. However, their suppressive characteristics against autologous and allogeneic T effector cells (Teff) have rarely been documented. The exact role of UCB-Treg in hematologic malignancies is also uncertain. Here, we investigated the direct effects of UCB-Treg on the proliferation of autologous Teff, as compared with allogeneic Teff, and also determined cellular fates of lymphoblasts after UCB-Treg co-culture. UC...
Source: Journal of Immunotherapy - April 11, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
An Ig Transmembrane Domain Motif Improves the Function of TCRs Transduced in Human T Cells: Implications for Immunotherapy
Adoptive transfer of T lymphocytes (ACT) engineered with T-cell receptors (TCRs) of known antitumor specificity is an effective therapeutic strategy. However, a major constraint of ACT is the unpredictable interference of the endogenous TCR α and β chains in pairing of the transduced TCR. This effect reduces the efficacy of the genetically modified primary T cells and carries the risk of generating novel TCR reactivities with unintended functional consequences. Here, we show a powerful approach to overcome these limitations. We engineered TCR α and β chains with mutations encompassing a conserved motif (FXXXFXXS) requi...
Source: Journal of Immunotherapy - April 11, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Facial Palsy Induced by Checkpoint Blockade: A Single Center Retrospective Study
The augmented immune response caused by immune checkpoint inhibitors leads to the emergence of a class of side effects called immune-related adverse events (irAEs). Facial palsy (FP) is rarely reported as an irAE. In this retrospective study, we reviewed the records of 353 patients treated with immunotherapy in our center from 2015–2018. We identified 4 male patients and 1 female patient with FP. Four had metastatic melanoma and were treated with ipilimumab either as monotherapy or in combination with nivolumab or pembrolizumab. The remaining patient had metastatic bladder cancer, treated with atezolizumab. FP was unilat...
Source: Journal of Immunotherapy - March 9, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Immunoglobulin G and Subclasses as Potential Biomarkers in Metastatic Melanoma Patients Starting Checkpoint Inhibitor Treatment
Checkpoint inhibitors have improved survival of metastatic melanoma. However, reliable biomarkers to predict response are still needed. Immunoglobulin G (IgG) antibody subclasses reflect immunocompetence in individuals and are known to be involved in essential functions in our immune system. This prospective study evaluated the association between serum IgG with its subclasses IgG1, IgG2, IgG3, and IgG4 and antitumor response according to RECIST 1.1. Serum samples from 49 patients were prospectively collected before the start of treatment with a checkpoint inhibitor. We observed a statistically significant association of b...
Source: Journal of Immunotherapy - March 9, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Chimeric Antigen Receptor-modified Donor Lymphocyte Infusion Improves the Survival of Acute Lymphoblastic Leukemia Patients With Relapsed Diseases After Allogeneic Hematopoietic Stem Cell Transplantation
In this study, 5 B-ALL patients who relapsed after allo-HSCT received CAR-DLI (CAR-DLI group), and the outcome was compared with 27 relapsed B-ALL patients who received DLI therapy (DLI group). The median complete remission duration of CAR-DLI group was significantly (P=0.020) longer when compared with DLI group: 9 months (range, 2–29) versus 3.2 months (range, 0–17.4). Furthermore, patients receiving CAR-DLI showed significant (P=0.049) survival advantage over DLI group, with median overall survival of 12 months (range, 3–29) and 3.7 months (range, 0–65), respectively. Of note, no patient developed acute graft ver...
Source: Journal of Immunotherapy - March 9, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Activated Allogeneic Donor-derived Marrow-infiltrating Lymphocytes Display Measurable In Vitro Antitumor Activity
A major limitation in current allogeneic hematopoietic stem cell transplantation (alloHSCT) is disease relapse after transplant, indicating that donor-derived T cells are inadequate in imparting an effective antitumor response. The current standard treatment approach to relapse utilizes donor lymphocyte infusions that have limited documented efficacy and are also associated with significant morbidity mainly related to graft-versus-host disease. We have previously shown that marrow-infiltrating lymphocytes (MILs) have a broader antigenic specificity compared with their peripheral blood counterpart in an autologous adoptive ...
Source: Journal of Immunotherapy - March 9, 2019 Category: Allergy & Immunology Tags: Basic Study Source Type: research
Treatment With Tumor-infiltrating Lymphocytes in Advanced Melanoma: Evaluation of Early Clinical Implementation of an Advanced Therapy Medicinal Product
Tumor-infiltrating lymphocytes (TIL)-therapy in advanced melanoma is an advanced therapy medicinal product (ATMP) which, despite promising results, has not been implemented widely. In a European setting, TIL-therapy has been in use since 2011 and is currently being evaluated in a randomized controlled trial. As clinical implementation of ATMPs is challenging, this study aims to evaluate early application of TIL-therapy, through the application of a constructive technology assessment (CTA). First the literature on ATMP barriers and facilitators in clinical translation was summarized. Subsequently, application of TIL-therapy...
Source: Journal of Immunotherapy - October 16, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Ipilimumab/Nivolumab-related Opsoclonus-Myoclonus-Ataxia Syndrome Variant in a Patient with Malignant Pleural Mesothelioma
Conclusions:
A variant of opsoclonus-myoclonus-ataxia syndrome may occur following treatment with ipilimumab and nivolumab. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - October 16, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Hemofiltration Successfully Eliminates Severe Cytokine Release Syndrome Following CD19 CAR-T-Cell Therapy
Cytokine release syndrome (CRS) remains to be a major adverse effect of chimeric antigen receptor T (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL) and lymphoma. It was urgent to explore novel strategy for managing severe CRS. We conducted a clinical trial to assess the safety and efficacy of CD19-targeting CAR-T-cells in the treatment of relapsed and chemotherapy-refractory B-ALL and lymphoma. A 10-year-old boy with B-ALL who never achieved minimal residual disease (MRD) negative status after 5 courses of chemotherapy was enrolled into our study and received a total of 3.19×106/kg autologous CD19 CAR-...
Source: Journal of Immunotherapy - October 16, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma
In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy—the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8+ TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8+CD3+ TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in (Source: Jou...
Source: Journal of Immunotherapy - October 16, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
The Hexavalent CD40 Agonist HERA-CD40L Induces T-Cell–mediated Antitumor Immune Response Through Activation of Antigen-presenting Cells
CD40 ligand (TNFSF5/CD154/CD40L), a member of the tumor necrosis factor (TNF) superfamily is a key regulator of the immune system. The cognate receptor CD40 (TNFRSF5) is expressed broadly on antigen-presenting cells and many tumor types, and has emerged as an attractive target for immunologic cancer treatment. Most of the CD40 targeting drugs in clinical development are antibodies which display some disadvantages: their activity typically depends on Fcγ receptor–mediated crosslinking, and depletion of CD40-expressing immune cells by antibody-dependent cellular cytotoxicity compromises an efficient antitumor response. To...
Source: Journal of Immunotherapy - October 16, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Nivolumab Treatment for Cancers in the HIV-infected Population
We describe a case series of people living with HIV (PLWH) receiving nivolumab in the Veterans Health Administration (VA) and report responses and toxicities. We identified all PLWH who received nivolumab at any VA facility since 2000 in the Corporate Data Warehouse (CDW), which provides nationwide research access to VA electronic medical records. We identified 16 HIV-infected nivolumab recipients. The median number of nivolumab doses received was 6 (range, 1–32). Changes in CD4 count during therapy were variable, with 70% (7/10) of patients experiencing increases. Half of PLWH were treated for non–small-cell lung canc...
Source: Journal of Immunotherapy - September 19, 2018 Category: Allergy & Immunology Tags: Clinical Study Source Type: research
Tumor Regression and Cure Depends on Sustained Th1 Responses
While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th...
Source: Journal of Immunotherapy - September 19, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
