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New Mechanisms in Tumor Rejection Highlighted During Presidential Session

Tony Berberabe, MPH
Published Online: 10:14 AM, Thu November 17, 2016
The scientific abstracts chosen for presentation during the Presidential Session of the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting and Associated Programs represent some of the best abstracts submitted to the society, said Howard L. Kaufman, MD, FACS, associate director for clinical science, Rutgers Cancer Institute of New Jersey.

“The work collectively represents a sampling of the best science in the field right now,” said Kaufman, president of SITC, in an interview with Targeted Oncology prior to the session. “I think the presentations cover a range of different topics, reflecting the diverse interests across the field.”

Five presentations were highlighted during the session, which tend to be from individuals who are early in their career path, said Kaufman. “It gives the presenters a chance to showcase their work in front of a large international audience.” In addition, a new feature to the session is that 2 highly regarded experts in the field provided commentary and offered their perspectives on why these abstracts are important.

The first presentation, by Peled et al, addressed the potential influence of gut microbiota on mortality outcomes in patients who have recently received an allogeneic hematopoietic-cell transplantation (allo-HCT).1 In cases of allo-HCT, common causes of mortality include relapse, graft-versus-host disease (GVHD), and infection. In previous studies, the researchers reported that the intestinal flora was associated with the development of GVHD, bacteremia, and reduced overall survival after allo-HCT. In the research that will be presented, the authors hypothesize that specific components of the intestinal flora are associated with relapse after transplantation.

Researchers profiled the intestinal flora of 541 patients who underwent allo-HCT, following them for 2 years posttransplantation. They determined the relationship between the abundance of microbiota species or groups of related species with relapse/progression of disease using the Cox proportional hazards model in this retrospective discovery-validation study. The researchers suggest that the association between the abundance of a group of bacteria in intestinal flora and relapse/progression of disease could serve as a potential biomarker to prevent relapse and improve survival, said Kaufman.

The researchers noted that the presence of Eubacterium limosum in the validation set was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31-0.87; P = .01). They noted that the 2-year cumulative incidence of relapse/progression among patients with and without this group of bacteria was 33.8% and 19.8%, respectively. Less relapse/progression was observed when the bacteria were abundant (HR, 0.82; 95% CI, 0.71-0.95; P = .009).

“Research that involves the microbiome and its role in influencing immune response is somewhat controversial, and theories are evolving,” said Kaufman.

Another presentation focuses on mitochondrial dysfunction within tumor-infiltrating CD8+ T cells. Scharping et al. hypothesized that metabolic mechanisms may have a role in suppressing tumor-infiltrating lymphocyte activity within the tumor microenvironment. Existing evidence, including the robust metabolic demands of T-cell activation and poor metabolite availability within the tumor microenvironment, supports a potential role of mitochondrial dysfunction in this process.2

“Emerging research shows that tumors can release soluble factors that interact at the cell surface causing dysfunction in T cells,” said Kaufman. “But one of the things that is less well known is how the basic metabolism inside the cells can influence the immune responses to cancer.” The researchers note that by understanding these metabolic insufficiencies, metabolic modulation strategies might improve cancer immunotherapy.

Two of the papers in the Presidential Session focus on various biomarkers associated with changes in the function of regulatory T cells (Tregs) in clinical trials—1 presentation focuses on the effect of a glucocorticoid-induced tumor necrosis factor-related gene (GITR) agonist, and the other examines the role of STAT3 signaling.

Zappasodi et al presented results of a pharmacodynamics analysis of the first-in-human phase I trial studying the fully humanized agonist anti-GITR antibody TRX518 as a monotherapy in patients with advanced refractory solid tumors.3 GITR stimulation abrogates Treg suppression and enhances T-cell effector function. This suggests that GITR could be an attractive target for immunotherapy with agonist antibodies.

Patients included in the analysis had received a single dose of TRX518 ≥0.005 mg/kg, including 6 patients with melanoma, 7 patients with nonsmall cell lung cancer (NSCLC), 7 patients with colorectal cancer (CRC), and 17 patients with other solid tumors. Serum samples collected at different time points, up to 12 weeks after treatment, were analyzed for cytokine levels, and, using flow cytometry, for the frequency and phenotype of circulating T cells.

Researchers identified frequent reductions in circulating Tregs after treatment with TRX518 across all cohorts that were maintained throughout the 12-week period. In patients with melanoma and CRC who had received TRX518, researchers identified a dose-dependent reduction in levels of peripheral Tregs. Reductions in levels of peripheral Tregs were not always observed in patients with NSCLC.

In 6 patients who had undergone tumor biopsies before and after treatment, researchers assessed the effect of TRX518 on levels of intratumoral Tregs. In 4 of these patients (2 with melanoma and 2 with CRC), reductions in intratumoral Foxp3+ Tregs were observed, consistent with downregulation of peripheral Tregs observed in these patients. Although reductions in levels of peripheral Tregs were not always observed in patients with NSCLC, reductions in peripheral Tregs among lung cancer patients were consistently associated with stable or increased intratumoral infiltration of Tregs after administration of TRX518.

Researchers concluded that circulating Tregs reduction is a potential pharmacodynamics biomarker of TRX518 activity that may enable for the prediction of stable or increased intratumoral Treg infiltration. Further investigation is warranted.

In Woods et al, the authors identified decreased suppressive function of Tregs and increased STAT3 signaling in Tregs as predictive biomarkers of improved response to PD-1 blockade with nivolumab in patients with metastatic melanoma who received adjuvant immunotherapy before surgical resection.4 Using an allogeneic mixed lymphocyte reaction assay, researchers evaluated the suppressive capacity of Tregs that were isolated for each patient before and after treatment. Researchers also evaluated levels of phosphorylated STAT3 (pSTAT3) in Tregs through flow cytometry, and assessed changes in gene expression through RNA sequencing.

Tregs collected before and after nivolumab therapy from non-relapsing patients showed a significant decrease in suppressive capacity posttreatment (P <.05), as evaluated through the allogeneic mixed lymphocyte reaction. However, the suppressive capacity of Tregs in relapsing patients did not decrease, and, relative to non-relapsers, the Tregs of relapsing patients were significantly more suppressive after treatment (P <.01).

Consistent with these results, significant increases in levels of pSTAT3 were observed in nonrelapsers (P <.05) following treatment, but not in patients who relapsed (P <.40). These relationships between PD-1 blockade, increased STAT3 signaling, and Treg proliferation were confirmed through in vitro studies. Relationships between relapse or non-relapse and genetic expression data were also identified.

The findings highlight pSTAT induction and reduced Tregs suppressive capacity as potential biomarkers of improved clinical outcomes in patients receiving nivolumab for metastatic melanoma. These results also demonstrate distinct differences in the impact of PD-1 blockade in Tregs versus conventional T cells.
 
 
References:
  1. Peled J, Devlin S, Staffas A, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation. Presented at: 2016 SITC Annual Meeting. November 9-13, 2016; National Harbor, MD. Abstract 300.
  2. Scharping N, Menk AV, Moreci R, et al. Mitochondrial biogenesis is repressed in tumor-infiltrating CD8+ T cells resulting in metabolic insufficiency and T cell dysfunction. Presented at: 2016 SITC Annual Meeting. November 9-13, 2016; National Harbor, MD. Abstract 280.
  3. Zappasodi R, Li Y, Qi J, et al. Analysis of pharmacodynamic biomarkers in the first in-human trial of GITR co-stimulation with the agonist antibody TRX-518 in advanced solid cancer patients. Presented at: 2016 SITC Annual Meeting. November 9-13, 2016; National Harbor, MD. Abstract 125.
  4. Woods D, Berglund A, Ramakrishnan R, et al. Increased STAT3 signaling and decreased suppressive function of regulatory T cells are biomarkers of positive patient outcome to nivolumab therapy. Presented at: 2016 SITC Annual Meeting. November 9-13, 2016; National Harbor, MD. Abstract 124.


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