Autoimmune Bell’s Palsy Following Immunotherapy For Metastatic Melanoma: A Report of 2 Cases
We describe 2 cases of autoimmune Bell’s palsy following the administration of combination ICT using ipilimumab and nivolumab in 2 patients with metastatic melanoma. The use of a steroid taper in addition to the cessation of combination immunotherapy resulted in resolution of symptoms for both patients. In the first case, the patient was subsequently started on nivolumab monotherapy but developed autoimmune polyneuropathy, and immunotherapy was discontinued indefinitely. In the second case, the initiation of nivolumab monotherapy following resolution of symptoms resulted in an inadequate antitumoral response. Subsequ...
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

Combination Nivolumab/Ipilimumab Immunotherapy For Melanoma With Subsequent Unexpected Cardiac Arrest: A Case Report and Review of Literature
We present a case of extensively metastatic oral mucosal melanoma that responded successfully to combined immune checkpoint blockade with ipilimumab and nivolumab but developed multiple immune-related adverse events, including myocarditis, a rare event associated with immunotherapy of elderly melanoma patients. Though the acute myocarditis was managed successfully, the patient succumbed to sudden cardiac death. This case highlights the fact, that autoimmune carditis must be considered when working up the sudden onset of shortness of breath in patients on immune checkpoint blockade. After controlling the acute myocarditis w...
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

Myasthenia Gravis Induced by Immune Checkpoint Inhibitors
We report a case of our experience and review the current literature of MG exacerbated or occurring during immunotherapy to describe characteristics of this AE, warn the oncologist about this toxicity, and summarize the treatments conducted. Thirty-four cases of MG were reported, mostly with anti-programmed cell death protein 1 checkpoint inhibitor, and with melanoma. Onset was quick after the first or second infusion. Treatment comprised corticosteroids, prostigmine, and more or less plasmapheresis or immunoglobulins. Prognosis is poor, as 13 patients died after MG. MG is a rare immune-related AE that must be rapidly evok...
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

PD-1 Expression and Function of T-Cell Subsets in TILs From Human Lung Cancer
On the basis of the autologous tumor-infiltrating lymphocytes (TILs) or genetically modified TILs for adoptive cell therapy have received more attention. Programmed cell death protein 1 (PD-1) expression on the T cells exert complex response during the tumor immune response. But the composition and function of PD-1+T-cell subsets in TILs from human lung cancer still limited. In blood and TILs from human lung cancer patients, we confirmed that PD-1 is expressed in higher levels in CD4+T-cell subsets than in CD8+T-cell subsets. To further analyze the function of PD-1+T cells in TILs, we observed the cytokine production in di...
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Anti-αFR CAR-engineered NK-92 Cells Display Potent Cytotoxicity Against αFR-positive Ovarian Cancer
Folate receptor alpha (αFR) is overexpressed in 90% of ovarian cancers, one of the most lethal gynecologic cancers. Recent studies have suggested that natural killer (NK) cells may be better chimeric antigen receptor (CAR) drivers because of their favorable innate characteristics, such as directly recognizing and killing tumor cells. However, the therapeutic effects of CAR-engineered NK cells targeting αFR in ovarian cancer have not been reported. In this research, 3 generations of anti-αFR CAR were constructed, namely αFR-ζ (first generation), αFR-28ζ (second generation), and &alpha...
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target
We performed a prospective immunohistochemical analysis of lymphocyte activation gene 3 (LAG3) for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic cancer (33.3%, 2/6), gastric cancer (24.7%, 21/85), colorectal cancer (23.6%, 48/203), melanoma (12.5%, 1/8), genitourinary cancer (9.5%, 4/46), biliary tract cancer (6.3%, 1/16), and sarcoma (5.4%, 2/37), but not miscellaneous (0....
Source: Journal of Immunotherapy - September 7, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Metastatic Mixed Adenoneuroendocrine Carcinoma of the Colon with Response to Immunotherapy with Pembrolizumab: A Case Report
We present the case of a 51-year-old female patient with histopathologically confirmed diagnosis of a MANEC of the descending colon. At presentation, the tumor had already spread to the liver causing extensive hepatic metastases. Immunohistochemical examination showed 5%–10% of tumor cells to express the programmed cell death receptor ligand 1 and FoundationOne testing revealed a high mutational tumor burden with 149 Muts/Mb. The patient responded very well clinically and radiologically to anti-programmed death 1 receptor monoclonal antibody pembrolizumab therapy after having undergone 3 previous systemic treatment r...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

PD-L1 Expression in De Novo Metastatic Castration-sensitive Prostate Cancer
De novo metastatic castration-sensitive prostate cancer (mCSPC) is small subgroup of prostate cancer associated with poor prognosis. The aim of our study was to assess the expression of programmed death-ligand 1 (PD-L1) in tumor cells of de novo mCSPC patients. Patients referred to our institution from January 2007 to October 2017 with de novo mCSPC and available diagnostic tissue were included. We tested the PD-L1 pharmaDx qualitative immunohistochemical assay, a monoclonal rabbit anti-PD-L1, clone 28-8 intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded. Kaplan-Meier method was used to ...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab
Upregulation of T-regulatory lymphocytes (Tregs) is one of numerous immune escape mechanisms of malignancies. In the present pilot study we aimed to study the effect of adjuvant nivolumab during the initiation of treatment on circulating Tregs subpopulations in patients with stage III melanoma. We subsequently recruited patients with stage III melanoma who had the indication for adjuvant anti-programmed death 1 (PD-1) treatment with nivolumab. Blood collections were performed before the initiation of nivolumab and before every 2-week therapy cycle. Flow cytometry was performed for the determination of circulating CD4+CD25h...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

Prognostic Significance of Hematological Indices in Malignant Melanoma Treated With Immune Checkpoint Inhibitors
Local and systemic inflammation significantly effects tumor progression and its response to therapy. We aim to evaluate the prognostic significance of inflammatory cells, their ratios, and a change in these indices while patients are receiving immune checkpoint inhibitors (ICIs). We retrospectively reviewed 120 malignant melanoma patients who had received any ICIs from 2011 until December 2017 and evaluated the effect of hematological indices on survival and radiographic responses. We followed the trends of these indices at 0, 6, and 12 weeks while on ICIs. Univariate and multivariate survival analyses were performed. The ...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Clincal Studies Source Type: research

Identification of a Promiscuous Epitope Peptide Derived From HSP70
We previously found that heat-shock protein 70 (HSP70) is expressed on hepatocellular carcinoma cells and developed an HSP70 mRNA-transfected dendritic cell therapy for treating unresectable or recurrent hepatocellular carcinoma. The phase I trial was completed successfully. The purpose of this study is to identify a promiscuous epitope peptide derived from HSP70 for the purpose of developing a novel cancer peptide vaccine. Using a computational algorithm to analyze the specificity of previously reported major histocompatibility complex class I–binding peptides, we selected candidates that bound to>2 of the 3 HLA ...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

The VE-PTP Inhibitor AKB-9778 Improves Antitumor Activity and Diminishes the Toxicity of Interleukin 2 (IL-2) Administration
Administration of interleukin (IL)-2 has led to a durable response in patients with advanced renal cancer and melanoma but is restricted for clinical application because of adverse effects, including the vascular leak syndrome (VLS). VLS is associated with increased circulating levels of the Tie2 antagonist ligand, angiopoietin 2, and decreased Tie2 receptor phosphorylation and downstream signaling in endothelial cells (ECs). Given that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a specific membrane phosphatase in ECs that dephosphorylates Tie2, the effects of targeting VE-PTP by a selective inhibitor AKB...
Source: Journal of Immunotherapy - August 9, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Racial and Socioeconomic Disparities in the Delivery of Immunotherapy for Metastatic Melanoma in the United States
This study addressed a crucial public health priority by evaluating disparities in administration of immunotherapy for metastatic melanoma. The National Cancer Database was queried for newly diagnosed metastatic melanoma. Patients were dichotomized based on receipt of immunotherapy based on National Cancer Database coding. Multivariable logistic regression ascertained factors associated with immunotherapy delivery. Subgroup analysis evaluated the interaction between race, insurance status, and income. Secondarily, Cox multivariate and propensity-matched Kaplan-Meier analyses assessed overall survival based on immunotherapy...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Clinical Correlates of Response to Anti-PD-1–based Therapy in Patients With Metastatic Melanoma
Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor ≤2 cm had a 53% RR, whereas those with largest tumor>2 cm had a ...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Variation of Programmed Death Ligand 1 Expression After Platinum-based Neoadjuvant Chemotherapy in Lung Cancer
The effect of chemotherapy on programmed cell death-ligand 1 (PD-L1) expression has been previously studied in lung cancer, while the results remain controversial. The aim of this study was to investigate the variation of PD-L1 expression after neoadjuvant chemotherapy and explore the association between chemotherapy response, prognosis and the variation of PD-L1 expression in lung cancer patients. A total of 63 lung cancer patients who received platinum-based neoadjuvant chemotherapy and subsequently underwent surgical resection were selected. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) w...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Association Between Pembrolizumab-related Adverse Events and Treatment Outcome in Advanced Melanoma: Results From the Dutch Expanded Access Program
In this study, we aim to evaluate this association for pembrolizumab. To this end, data of 147 patients included in the Dutch cohort of the Pembrolizumab Expanded Access Program were collected. All data were collected prospectively. Patients with adverse events (AEs) at any time during therapy showed a higher chance of achieving disease control compared with patients without AEs (low-grade AEs vs. no AEs: odds ratio=12.8, P=0.0002, high-grade AEs vs. no AEs: odds ratio=38.5, P=0.0001) according to a multivariate logistic regression analysis. In addition, Cox regression analysis showed a lower risk of death (hazard ratio: 0...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Preferential Homing of Tumor-specific and Functional CD8+ Stem Cell-like Memory T Cells to the Bone Marrow
The bone marrow (BM) harbors not only hematopoietic stem cells but also conventional memory T and B cells. Studies of BM-resident memory T cells have revealed the complex relationship between BM and immunologic memory. In the present study, we identified CD122high stem cells antigen-1 (Sca-1)high, B-cell lymphoma protein-2 (Bcl-2)high, CD8+ stem cell-like memory T cells (TSCMs) as a distinct memory T-cell subset preferentially residing in the BM, where these cells respond vigorously to blood-borne antigens. We found that the most TSCMs favorably relocate to the BM by adhesion molecules such as vascular cell adhesion protei...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

“Acquired” NKG2D Ligand Stimulates NK Cell–mediated Tumor Immunosurveillance
Engagement of activating receptor NKG2D to its ligand mediates natural killer (NK) cell activation and enhances cytotoxicity. NKG2D ligands (NKG2DLs) are frequently expressed on the tumor cell surface. However, the expression patterns of different NKG2DLs vary between tumor cells. Downregulation of certain ligand enables the tumor cells to escape NK cell–mediated immunosurveillance. By generating tumor cell lines with high expression of NKG2D ligand MULT1, we aimed to explore the function of NKG2DLs diversity on the activation and regulation of NKG2D signaling pathway. NK cells were potently activated by the “a...
Source: Journal of Immunotherapy - June 13, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Functionally Defective T Cells After Chemotherapy of B-Cell Malignancies Can Be Activated by the Tetravalent Bispecific CD19/CD3 Antibody AFM11
In conclusion, T cells from lymphoma patients are reduced in number and have functional defects following treatment with certain chemotherapy regimens, also reducing AFM11 efficacy. Importantly, AFM11 was still able to trigger B-cell-directed T-cell immunity in all treatment groups. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - May 16, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey
Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participatin...
Source: Journal of Immunotherapy - May 16, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

UV Light–inactivated HSV-1 Stimulates Natural Killer Cell–induced Killing of Prostate Cancer Cells
Herein we demonstrate that ultraviolet light–inactivated Herpes Simplex Virus-1 (UV-HSV-1) stimulates peripheral blood mononuclear cells (PBMCs) to lyse both androgen-sensitive and androgen-independent prostate cancer (PrCA) cell lines, but not the benign prostatic hyperplastic epithelial cell line, BPH-1, and is 1000–10,000-fold more potent at stimulating this killing than ultraviolet light-inactivated Vesicular Stomatitis Virus, adenovirus, reovirus or cytomegalovirus. Among PBMCs, natural killer (NK) cells appear to be a major cell type involved in this killing and UV-HSV-1 appears to directly and potently s...
Source: Journal of Immunotherapy - May 16, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Role of Interferon (IFN)α in “Cocktails” for the Generation of (Leukemia-derived) Dendritic Cells (DCleu) From Blasts in Blood From Patients (pts) With Acute Myeloid Leukemia (AML) and the Induction of Antileukemic Reactions
Strategies to stabilize remissions by specific elimination of residual acute myeloid leukemia (AML) blasts are needed. Leukemia-derived dendritic cell (DCleu/DC) generated from myeloid blasts improve antileukemic T-cell reactivity and install T-cell memory. Interferon (IFN)α-DC methods produce DCleu from chronic myeloid leukemia-patients (pts’) blood. Various INFα-containing versus other DC methods were studied to produce DCleu (evaluated by flowcytometry) from AML-pts’ blast-containing mononuclear (MNC) or whole blood (WB). After DCleu/DC stimulation in mixed lymphocyte cultures, T cells’ pot...
Source: Journal of Immunotherapy - May 16, 2019 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Response to the Rechallenge With Talimogene Laherparepvec (T-VEC) After Ipilimumab/Nivolumab Treatment in Patient With Cutaneous Malignant Melanoma Who Initially Had a Progression on T-VEC With Pembrolizumab
Talimogene laherparepvec (T-VEC) is approved for unresected stage III–IV malignant melanoma. T-VEC has a direct cytotoxic effect and enhances the antitumor immunity of host cells. Immune checkpoints inhibitors also enhance the immunity of host cells by increasing the recruitment of antigen-presenting cells or activation and restoration of T-cell functions. Both type of therapies can potentiate the effect of the other therapy. We are reporting a case of T-VEC rechallenge who initially progressed on T-VEC with pembrolizumab but then responded to T-VEC rechallenge after intervening ipilimumab/nivolumab. An 83-year-old m...
Source: Journal of Immunotherapy - April 11, 2019 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

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...
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 moti...
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 un...
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...
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 17, 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 17, 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...
Source: Journal of Immunotherapy - October 17, 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:...
Source: Journal of Immunotherapy - October 17, 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 res...
Source: Journal of Immunotherapy - October 17, 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 l...
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

Cancer Stem Cell Vaccination With PD-L1 and CTLA-4 Blockades Enhances the Eradication of Melanoma Stem Cells in a Mouse Tumor Model
In this study, we investigated the CSC targeting effect of the CSC-DC vaccine combined with a dual blockade of programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein (CTLA-4) in B16-F10 murine melanoma tumor model. Our data showed that animals treated with the dual blockade of programmed death-ligand 1 and CTLA-4 and CSC-DC vaccine conferred significantly more tumor regression than the CSC-DC vaccine alone. Importantly, the triple combination treatment dramatically eliminated ALDHhigh CSCs in vivo. We observed that CSC-DC vaccine in combination with anti-PD-L1 and anti-CTLA-4 administration resulted in &si...
Source: Journal of Immunotherapy - September 19, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Understanding Microbiome Effect on Immune Checkpoint Inhibition in Lung Cancer: Placing the Puzzle Pieces Together
Over the past couple of years, human microbiome has received increasing attention as a regulator and predictor of response to the therapies of various diseases. It is speculated that manipulating gut microbiome can modify response to cancer immunotherapies as well. Through this review, we have critically analyzed our current understanding of gut microbiome as a modulator of immunotherapies in lung cancer, explained conflicting data, evaluated current gaps and extrapolated our present knowledge to generate directions for future investigations. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - September 19, 2018 Category: Allergy & Immunology Tags: Review Article Source Type: research

Donor-derived CAR-T Cells Serve as a Reduced-intensity Conditioning Regimen for Haploidentical Stem Cell Transplantation in Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: Case Report and Review of the Literature
Conclusions: Treatment of r/r ALL with RIC including CD19-CAR-T cells followed by allo-HSCT was safe and effective, which suggest that CAR-T cells can be used as a part of RIC regimens in the treatment of r/r ALL in haploidentical HSCT. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Evidence for Efficacy of Treatment With the Anti-PD-1 Mab Nivolumab in Radiation and Multichemorefractory Advanced Penile Squamous Cell Carcinoma
In conclusion, in patients with metastatic PeSCC active immunotherapy combinations with an anti-programmed death-1/programmed death ligand-1 agent may be beneficial and further relative clinical studies are required. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Characteristics and Predictive Value of PD-L1 Status in Real-World Non–Small Cell Lung Cancer Patients
In conclusion, our results suggest that PD-L1 status remains an important predictor of immunotherapy efficacy. The concordance between 22C3 and SP263 assays was greater at a higher cutoff level of positivity. Patients without known actionable driver mutation, along with smokers, particularly those having high smoking pack-years, were more likely to have strong PD-L1 expression. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Evaluating for Pseudoprogression in Colorectal and Pancreatic Tumors Treated With Immunotherapy
Pseudoprogression has been observed in patients with various tumor types treated with immunotherapy. However, the frequency of pseudoprogression is unknown in gastrointestinal malignancies. Metastatic colorectal cancer (mCRC) and advanced pancreatic ductal adenocarcinoma (PDAC) patients who progressed on treatment with immunotherapy beyond RECIST version 1.1 criteria were analyzed. Degree of progression, tumor markers, time to progression, overall survival, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and costs were analyzed for patients treated beyond progression (TBP) and not treated beyond progressio...
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Adoptive Transfer of Interleukin-21-stimulated Human CD8+ T Memory Stem Cells Efficiently Inhibits Tumor Growth
Memory stem T (TSCM) cells, a new subset of memory T cells with self-renewal and multipotent capacities, are considered as a promising candidates for adoptive cellular therapy. However, the low proportion of human TSCM cells in total CD8+ T cells limits their utility. Here, we aimed to induce human CD8+ TSCM cells by stimulating naive precursors with interleukin-21 (IL-21). We found that IL-21 promoted the generation of TSCM cells, described as CD45RA+CD45RO−CD62L+CCR7+CD122+CD95+ cells, with a higher efficiency than that observed with other common γ-chain cytokines. Upon adoptive transfer into an A375 melanoma...
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Implication of Highly Cytotoxic Natural Killer Cells for Esophageal Squamous Cell Carcinoma Treatment
In conclusion, expanded NK cells were highly cytotoxic against NKG2DLs-expressing ESCC cells, particularly the EMT phenotype. These results provide a strong rationale for clinical use of these NK cells in ESCC patients. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - June 26, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Characterization of Postinfusion Phenotypic Differences in Fresh Versus Cryopreserved TCR Engineered Adoptive Cell Therapy Products
Adoptive cell therapy (ACT) consisting of genetically engineered T cells expressing tumor antigen-specific T-cell receptors displays robust initial antitumor activity, followed by loss of T-cell activity/persistence and frequent disease relapse. We characterized baseline and longitudinal T-cell phenotype variations resulting from different manufacturing and administration protocols in patients who received ACT. Patients with melanoma who enrolled in the F5-MART-1 clinical trial (NCT00910650) received infusions of MART-1 T-cell receptors transgenic T cells with MART-1 peptide-pulsed dendritic cell vaccination. Patients were...
Source: Journal of Immunotherapy - May 22, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Outcomes of Adoptive Cell Transfer With Tumor-infiltrating Lymphocytes for Metastatic Melanoma Patients With and Without Brain Metastases
Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall s...
Source: Journal of Immunotherapy - May 22, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Diabetes and Blood Glucose Disorders Under Anti-PD1
Acute type 1 diabetes (AD1) is a rare but definitive immune-related adverse event associated with anti-PD1. Most of the reported cases are close to what has been described as “fulminant type 1 diabetes.” We sought to determine whether anti-PD1 could impair glycoregulation and whether occurrence of AD1 could be anticipated by prior glycemic changes. Fasting glycemia collected before, under, and after treatment in melanoma patients treated with anti-PD1 over a period of 36 months were retrospectively analyzed. Glycemic trend analyses were performed using linear regression analysis. In total, 1470 glucose values w...
Source: Journal of Immunotherapy - May 22, 2018 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

IL-21 Increases the Reactivity of Allogeneic Human Vγ9Vδ2 T Cells Against Primary Glioblastoma Tumors
Glioblastoma multiforme (GBM) remains the most frequent and deadliest primary brain tumor in adults despite aggressive treatments, because of the persistence of infiltrative and resistant tumor cells. Nonalloreactive human Vγ9Vδ2 T lymphocytes, the major peripheral γδ T-cell subset in adults, represent attractive effectors for designing immunotherapeutic strategies to track and eliminate brain tumor cells, with limited side effects. We analyzed the effects of ex vivo sensitizations of Vγ9Vδ2 T cells by IL-21, a modulating cytokine, on their cytolytic reactivity. We first showed that prim...
Source: Journal of Immunotherapy - May 22, 2018 Category: Allergy & Immunology Tags: Basic Studies Source Type: research