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 (0.0%, 0/14) or hepatocellular (0.0%, 0/15) cancer. Among 149 metastatic colorectal cancer patients, there was no statistically significant difference in sex, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. nonexpressed). Among 53 metastatic gastric cancer patients, LAG3 was only significantly associated with Epstein Barr virus status (P=0.042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy.

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 αFR-28BBζ (third generation), and were highly expressed on the surface of NK-92 cells by lentivirus gene transfection. Three anti-αFR CAR-engineered NK-92 cells can specifically kill αFR-positive tumor cells in vitro, especially ovarian cancer cells with high αFR expression. Compared with NK-92 cells expressing αFR-ζ or αFR-28ζ, NK-92 cells expressing αFR-28BBζ showed not only higher antigen-specific cytotoxicity and proliferation but also lower antigen-induced apoptosis. Moreover, stronger degranulation and cytokine secretion were detected in NK-92 cells expressing αFR-28BBζ cocultured with αFR-positive tumor cells. Real-time cell analysis and live cell imaging recorded the process of NK-92 cells expressing αFR-28BBζ killing ovarian cancer cells in vitro. Furthermore, NK-92 cells expressing αFR-28BBζ can effectively eliminate cancer cells in a mouse xenograft model of ovarian cancer and significantly prolong the survival of tumor-bearing mice. These results demonstrate that the anti-αFR CARs redirect NK-92 cells with specific antitumor activity, and the third-generation anti-αFR CAR-engineered NK-92 cells display more potent cytotoxicity against αFR-positive ovarian cancer, laying the foundation for future clinical 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 different T-cell subsets. We found that higher interferon-γ and granzyme B production in CD4+/CD8+PD-1+T-cell subsets in TILs than in peripheral blood mononuclear cells (PBMCs); except for PD-1+Tscm, higher tumor necrosis factor-α production was observed in PD-1+T-cell subsets in TILs than in PBMCs; the expression level of interleukin-17 were lower in PD-1++T cells in TILs than in PBMCs; and perforin expression was significantly reduced in CD4+PD-1+T cells subsets in TILs compared with peripheral blood. Clarify elucidating the composition and function of PD-1+T-cell subsets in TILs will have great value in clinical application for evaluating the sensitivity to PD-1 blockade and selecting the promising candidate T-cell subsets in TILs for combination immunotherapy in human lung cancer.

Myasthenia Gravis Induced by Immune Checkpoint Inhibitors Immune checkpoint inhibitors deeply improved the prognosis of metastatic melanoma or other types of cancer, but their related adverse effects (AEs) can be very severe, especially when the neurological system is touched, as in myasthenia gravis (MG). It is a rare immune AE that can be life-threatening and can be revealed by several symptoms. 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 evoked and treated in case of neurological symptoms emerging after immunotherapy.

Combination Nivolumab/Ipilimumab Immunotherapy For Melanoma With Subsequent Unexpected Cardiac Arrest: A Case Report and Review of Literature The success of immunotherapy in the treatment of patients with advanced melanoma has paved the way for unprecedented successes in the treatment of many other malignancies. 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 with high-dose steroids, which should be tapered over 6 weeks, further cardiology care is needed, and a defibrillator might have to be implanted. Understanding the pathophysiology of immune-related adverse events could make cancer immunotherapy both more effective and safer.

Autoimmune Bell’s Palsy Following Immunotherapy For Metastatic Melanoma: A Report of 2 Cases By targeting receptors that serve to downregulate the cellular immune system, monoclonal antibodies such as ipilimumab and nivolumab have transformed the management of metastatic melanoma, and their use is referred to as immune checkpoint therapy (ICT). However, because the antitumoral activity of these agents is achieved through the reversal of mechanisms that naturally serve to temper the immune response, the potential for adverse reactions secondary to autoimmunity is of clinical significance. Neurological immune-related adverse events (irAEs) may occur consequent to ICT, and the development of autoimmune Bell’s palsy is a specific, uncommon manifestation of the body’s immune response against the seventh cranial nerve, resulting in acute paresis of facial muscles. 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. Subsequent transition to treatment with encorafenib/binimetinib initially provided a positive response but also required discontinuation secondary to irAEs. Both of these cases demonstrate the potential for autoimmune Bell’s palsy as a consequence of combination ICT and provide evidence of successful treatment of this irAE through temporary discontinuation of immunotherapy and administration of steroids.