Preclinical Optimization of a CD20-specific Chimeric Antigen Receptor Vector and Culture Conditions
We describe here several improvements, including replacement of the immunogenic murine antigen-binding moiety with a fully human domain, streamlining the transgene insert to enhance lentiviral titers, modifications to the extracellular IgG spacer that abrogate nonspecific activation resulting from binding to Fc receptors, and evaluation of CD28, 4-1BB, or CD28 and 4-1BB costimulatory domains. We also found that restimulation of CAR T cells with an irradiated CD20+ cell line boosted cell growth, increased the fraction of CAR-expressing cells, and preserved in vivo function despite leading to a reduced capacity for cytokine ...
Source: Journal of Immunotherapy - December 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
CD11c-targeted Delivery of DNA to Dendritic Cells Leads to cGAS- and STING-dependent Maturation
Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti–PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor ce...
Source: Journal of Immunotherapy - December 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
A Bispecific Antibody Based on Pertuzumab Fab Has Potent Antitumor Activity
In this study, we have generated a bispecific antibody, Her2(Per)-S-Fab, by linking the pertuzumab Fab to an anti-CD16 single domain antibody. The Her2(Per)-S-Fab can be expressed and purified efficiently from Escherichia coli. In vitro and in vivo experiments showed Her2(Per)-S-Fab had potent cytotoxicity against Her2-positive tumor cells. Thus, Her2(Per)-S-Fab may provide an alternative to treat Her2-positive cancer patients. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - December 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report
Conclusions: The time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - October 14, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature
We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as thes...
Source: Journal of Immunotherapy - October 14, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program
KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAFV600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology ...
Source: Journal of Immunotherapy - October 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Relationship Between PD-L1 Expression and CD8+ T-cell Immune Responses in Hepatocellular Carcinoma
In conclusion, our findings reveal an interaction between PD-L1 expression and CD8+ T-cell immunity in HCC, although PD-L1 is not a prognostic factor for the patients. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - October 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
DCOne as an Allogeneic Cell-based Vaccine for Multiple Myeloma
We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted...
Source: Journal of Immunotherapy - October 14, 2017 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Two Cases of Sinusitis Induced by Immune Checkpoint Inhibition
We report the acute onset of aseptic sinusitis in 2 patients receiving the immune checkpoint inhibitors, ipilimumab and nivolumab, for treatment of metastatic melanoma. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4, and nivolumab, targeting programmed cell death-1, have been associated with numerous immune-related adverse events. To the authors’ knowledge, this is the first report of aseptic sinusitis as a consequence of immune checkpoint inhibition therapy. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - September 12, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma
We present 2 cases of pulmonary and cutaneous sarcoidosis developing in patients with stage IV melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and both experienced good oncologic responses to treatment; neither had evidence of preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis developed after initiation of anti-PD-1 therapy, 3 months after the last dose of anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of both checkpoint inhibitors. Ultimately, both patients’ s...
Source: Journal of Immunotherapy - September 12, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
First-in-Human Treatment With a Dendritic Cell-targeting Lentiviral Vector-expressing NY-ESO-1, LV305, Induces Deep, Durable Response in Refractory Metastatic Synovial Sarcoma Patient
Effective induction of antitumor T cells is a pivotal goal of cancer immunotherapy. To this end, lentiviral vectors (LV) are uniquely poised to directly prime CD8 T-cell responses via transduction of dendritic cells in vivo and have shown promise as active cancer therapeutics in preclinical tumor models. However, until now, significant barriers related to production and regulation have prevented their widespread use in the clinic. We developed LV305, a dendritic cell-targeting, integration-deficient, replication incompetent LV from the ZVex platform, encoding the full-length cancer-testis antigen NY-ESO-1. LV305 is current...
Source: Journal of Immunotherapy - September 12, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Immunologic Response Elicited in Breast Cancer Patients Receiving a NeuGcGM3-based Vaccine as Adjuvant Therapy
This study aimed to investigate the immunogenicity of a cancer vaccine consisting of the NeuGcGM3 ganglioside combined with the outer membrane protein complex of Neisseria meningitides to form very small size particles. The vaccine is administered together with Montanide ISA51, as adjuvant treatment for breast cancer patients. After surgical resection and standard first-line chemo/radiotherapy, breast cancer patients in stage II–III were enrolled in a phase III clinical trial and allocated into 2 strata, according to the number of positive lymph nodes [stratum I (0–3); stratum II (≥4)]. Subsequently, patients were ra...
Source: Journal of Immunotherapy - September 12, 2017 Category: Allergy & Immunology Tags: Basic Study Source Type: research
Immune-related Neurological Symptoms in an Adolescent Patient Receiving the Checkpoint Inhibitor Nivolumab
We present the case of an adolescent with refractory Hodgkin lymphoma treated with nivolumab, a PD1 inhibitor, who developed Hashimoto thyroiditis, posterior reversible encephalopathy syndrome causing seizures, as well as urinary retention, truncal/appendicular spasticity, dysphagia, and a progressive encephalopathy that was clinically consistent with a diagnosis of progressive encephalopathy with rigidity and myoclonus, a stiff-person-syndrome spectrum disorder. He showed response and ultimately full recovery to a combination of intravenous steroids, intravenous immunoglobulin, and plasma exchange. To our knowledge, this ...
Source: Journal of Immunotherapy - August 23, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases
Ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I–III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimu...
Source: Journal of Immunotherapy - August 23, 2017 Category: Allergy & Immunology Tags: Case Reports Source Type: research
Immune Checkpoint Inhibitors in Organ Transplant Patients
Modulation of T-cell activity through blockade of coinhibitory molecules has revolutionized the treatment of various malignancies. Several immune checkpoint inhibitors are currently Food and Drug Administration approved which target various coinhibitory pathways including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 receptor (PD-1), and programmed cell death ligand-1. Clinical trials that lead to the Food and Drug Administration approval of these agents often excluded patients with an organ transplant. Excluding these patients was deliberate due to concern that immune checkpoint inhibitor therap...
Source: Journal of Immunotherapy - August 23, 2017 Category: Allergy & Immunology Tags: Review Article Source Type: research
