Checkpoint Blockade in Combination With Doxorubicin Augments Tumor Cell Apoptosis in Osteosarcoma The aim of this study was to provide a basis for the theory that the combination of conventional chemotherapy and immunotherapy would be an effective treatment for osteosarcoma. Here, the expression of programmed death ligand 1 (PD-L1) in 26 clinical osteosarcoma tissue samples collected before and after chemotherapy was analyzed. The effects of osteosarcoma cells treated with doxorubicin, a conventional chemotherapeutic agent, on the proliferation and apoptosis of CD8+ T lymphocytes were investigated in vitro. Thereafter, the effectiveness of doxorubicin combined with an anti-PD-L1 antibody as an osteosarcoma therapy was tested in 24 subcutaneous tumor mouse models. The results showed that the expression of PD-L1 was upregulated by chemotherapy in both the clinical osteosarcoma tissue samples and the osteosarcoma cell lines. The proliferation of CD8+ T lymphocytes was inhibited, and apoptosis in CD8+ T lymphocytes was enhanced by the doxorubicin-pretreated osteosarcoma cells, whereas this effect was reversed by the anti-PD-L1 antibody. A more effective result was observed when doxorubicin was combined with the anti-PD-L1 antibody in vivo. In short, the combination of conventional chemotherapy and an anti-PD-L1 antibody might be an effective option for osteosarcoma treatment, as anti-PD-L1 antibody can reverse the immunosuppression induced by chemotherapy.

Improving Immunotherapy Against B-Cell Malignancies Using γδ T-Cell–specific Stimulation and Therapeutic Monoclonal Antibodies Tumor antigen–targeting monoclonal antibodies (mAbs) are an important element of current cancer therapies. Some of these therapeutic mAbs enable antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells. However, cancer-related functional impairment of immune effector cells may limit the clinical efficacy of antibody treatments. We reckoned that combining mAbs with cell-based immunotherapies would provide a clinically relevant synergism and benefit for cancer patients. Here, we focus on γδ T cells, as earlier studies demonstrated that γδ T-cell–based therapies are safe and promising for several types of malignancies. Similar to natural killer cells, their antitumor effects can be enhanced using antibodies, and they could, therefore, become a versatile effector cell platform for use with a variety of licensed therapeutic mAbs against cancer. In this study, we explore the potential of a combination therapy of activated γδ T cells with rituximab and the more recently developed mAbs (obinutuzumab and daratumumab) in different B-cell malignancies in vitro. Obinutuzumab outperformed the other mAbs with regard to direct target cell lysis and ADCC by γδ T cells in several CD20+ cell lines and primary lymphoma specimens. We demonstrate that comparatively few CD16low γδ T cells are sufficient to mediate a strong ADCC. Using Fc-receptor-positive B-cell lymphomas as target cells, ADCC cannot be blocked by high concentrations of immunoglobulins or anti-CD16 antibodies, but both substances can promote cell mediated target cell lysis. This study expands on earlier reports on the therapeutic potential of distinctive tumor antigen–targeting mAbs and facilitates the understanding of the mechanism and potential of ADCC by γδ T-cell subsets.

Linear IgA Disease of the Gingiva Following Nivolumab Therapy Immunotherapy has advanced the treatment of solid organ malignancies. Although generally well tolerated, treatment with immune checkpoint inhibitors can be complicated by immune-related adverse events, some of which are relatively uncommon. We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody. A 73-year-old male with advanced non–small cell lung cancer achieved a durable response to nivolumab monotherapy. After 1 year of treatment, he developed gingival swelling and pain. Biopsy revealed linear immunoglobulin A disease of the gingiva which was effectively treated with systemic steroids. Ongoing vigilance for immune-mediated toxicity is paramount during and after treatment with immune checkpoint inhibitors.

Nivolumab and Ipilimumab-induced Acute Inflammatory Demyelinating Polyradiculoneuropathy: A Case Report Immunotherapies such as the cytotoxic T-lymphocyte–associated protein 4 inhibitor ipilimumab and the programmed cell death protein 1 inhibitor nivolumab have become ubiquitous in cancer treatment. Recently, the FDA approved nivolumab with or without ipilimumab for the treatment of refractory small cell lung cancer. Immunotherapies increase the immune response to cancer cells by interfering with inhibitory molecular pathways that prevent tumor cell killing, thus augmenting tumor cell death without many of the cytotoxic side effects associated with chemotherapy. However, this augmented immune response may result in unwanted immune-mediated inflammation of different organs and are therefore associated with immune-related adverse events, unlike traditional chemotherapies or targeted therapies. Here, we describe 1 patient with advanced small cell lung cancer who developed grade III–IV acute inflammatory demyelinating polyradiculoneuropathy after treatment with ipilimumab and nivolumab. The patient was treated with intravenous immunoglobulin alone and showed symptomatic improvement.

Superimposed Clostridium difficile Infection During Checkpoint Inhibitor Immunotherapy-induced Colitis Immunotherapy with checkpoint inhibitors (ICI) is widely used to treat a variety of neoplasms. ICI can induce an immune response against cancer; however, ICI can also induce autoimmunity, an undesirable side effect. Autoimmune colitis is one of the most well-known and troubling side effects of ICI. In this report, we described a series of 5 patients who developed ICI-induced colitis. During the course of this complication, all developed Clostridium difficile infection (CDI). This report described the course of the 2 medical conditions in these patients. On the basis of our experiences, CDI may occur as a superimposed infection during ICI-induced colitis. Although ICI-induced colitis may be a risk factor for CDI, the observed association may be fortuitous. Future study will be needed to characterize the association between CDI and ICI-induced colitis. Clinicians should be mindful of possible co-occurrence of both conditions to promptly and adequately institute effective interventions.

Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature The clinical validity and utility of complex biomarkers have not been extensively studied in bladder cancer. Three patients with nonmuscle invasive bladder cancer [1 patient with an exceptional response; complete response (CR) for 30 months] who failed intravesical BCG were evaluated using an NYS CLEP approved assay, Immune Report Card, which measures programmed death-ligand 1 expression, CD8+ T-cell infiltration pattern, mutational burden, and gene expression of 51 immune-related transcripts using RNA-Seq. Patients were tested before being treated under our expanded access protocol for intravesical BCG with ALT-803. Subject 1 had failed his fourth line of therapy, subject 2 had failed only his first line of therapy, and subject 3 had failed his seventh line of therapy. Surprisingly, subject 1 had an unusually prolonged CR which lasted 30 months; subject 2 had the persistent and recurrent disease until 12 months when he then developed a CR; subject 3 had disease recurrence at 3 months, along with progression noted at 6 months. Immunomutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for subject 1, who had an exceptional response. Compared with subject 3, tumor in subject 1 demonstrated a high level of expression for CTLA4 (immunosuppression) and CD39 (immunosuppressive). Together, an immunosuppressive tumor environment in nonmuscle invasive bladder cancer that have failed prior BCG may respond better to interleukin-15 immunotherapy compared with tumors without an immunosuppressive environment.

A Severe, Refractory Case of Mucous Membrane Pemphigoid After Treatment With Pembrolizumab: Brief Communication Pembrolizumab is a humanized antibody that targets the programmed death-1 receptor expressed in T cells with high selectivity. This therapeutic is of great importance in cancer immunotherapy yet managing the potential immune-related adverse events remains a concern. Here, we report a rare case of mucous membrane pemphigoid in the oral mucosa, upper respiratory tract, and conjunctiva of a patient with ovarian adenocarcinoma without cutaneous manifestation, which persisted even after pembrolizumab discontinuation. A brief review of pembrolizumab-related bullous pemphigoid cases is presented and possible mechanisms underlying these lesions are discussed.