Anti-IL2 monoclonal antibody, clone J3-D8

Tumor-draining lymph nodes (TDLNs) are the primary sites of tumor antigen presentation, as well as the origin of metastasis in most cases. Hence, the type and function of immune cells in TDLNs are critical to the micro environment and potentially affect the clinical outcome of the malignancy. CD8(+)CXCR5(+) T cells are recently described to present high effector functions in infectious diseases, but their role in colorectal cancer (CRC) remains unclear. In forty-four Stage III CRC patients, we examined the CD8(+)CXCR5(+) T cells in blood, tumor, and TDLN. CD8(+)CXCR5(+) T cells represented lass than 2% of CD3(+) T cells in blood, but a much larger population in tumor. In TDLN, the CD8(+)CXCR5(+) T cells represented the vast majority of CD8(+) T cells and between 9.3% and 32.9% of CD3(+) T cells. The prevalence of CD8(+)CXCR5(+) T cells in tumor was not associated with their frequency in peripheral blood, but was positively correlated with their frequency in TDLN. The transcription of effector genes, including IFNG, TNF, IL2, PRF1, and GZMB, and exhaustion markers, including PD1, TIM3, 2B4, and LAG3, were examined in CD8(+)CXCR5(+) T cells and CD8(+)CXCR5(+) T cells. With a few exceptions, CD8(+)CXCR5(+) T cell presented significantly higher effector gene expression, and significantly lower exhaustion marker expression than their CXCR5(-) counterparts. In addition, the prognosis of CRC patients was positively associated with the frequency of TDLN CD8(+)CXCR5(+) T cells, and with the expression of IFNG, PRF1, and GZMB expression by tumor and TDLN CD8(+)CXCR5(+) T cells. Together, these results demonstrated that CD8(+)CXCR5(+) T cells were significant participants of CRC-associated immunity and could potentially serve as therapeutic options.

BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA >= 2000 IU/ mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1: 2: 2: 2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. RESULTS: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. CONCLUSIONS: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response.