Efficacy and Safety of PD-1 Immune Checkpoint Inhibitors in Locally Advanced and Advanced NSCLC Patients With Chronic Viral Infection

IntroductionImmune checkpoint inhibitors (ICIs) have become new research hotspots in the treatment of non-small cell lung cancer, but the efficacy and safety of immunotherapy for patients with chronic viral infection are still unclear, because existing clinical trials often exclude those patients. Methods We identified 78 locally advanced or advanced NSCLC patients with chronic viral infection treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. ResultsObjective responses were observed in 19 out of 78(24.36%) patients, and the disease control rate (DCR) was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI:3.71-9.27). PFS was 1.44 months (95%CI:0.00-4.34) for monotherapy versus 7.34 months (95%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, P = 0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 adverse events. The incidence of leukopenia was the highest (57.69%), followed by anemia (25.64%) and elevated hepatic transaminase (24.36%). Hepatic transaminase increased in 26.7% (16/60) of HBV patients, and remained unchanged in 65.0% (39/60) patients.ConclusionsThe PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on locally advanced and advanced NSCLC patients with chronic viral infection, but still has the potential to increase the incidence of hepatitis. We recommend that those patients be monitored closely and treated with antiviral therapy.

Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries

Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.

Efficacy and safety of PD-1 immune checkpoint inhibitors in locally advanced and advanced non-small cell lung cancer patients with chronic viral infection

Immune checkpoint inhibitors (ICIs) have become new research hotspots in the treatment of non-small cell lung cancer, but the efficacy and safety of immunotherapy for patients with chronic viral infection are still unclear, because existing clinical trials often exclude those patients. Materials and Methods We identified 78 locally advanced or advanced NSCLC patients with chronic viral infection treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results Objective responses were observed in 19 out of 78(24.36%) patients, and the disease control rate (DCR) was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI:3.71-9.27). PFS was 1.44 months (95%CI:0.00-4.34) for monotherapy versus 7.34 months (95%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, P = 0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 adverse events. The incidence of leukopenia in any grade of adverse reactions was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%) and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients, and remained unchanged in 63.3% (38/60) patients. Conclusions The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic viral infection, but still has the potential to increase the incidence of hepatitis.

Prevention of CD8 T Cell Deletion during Chronic Viral Infection

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.

Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P <0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age >75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]