Activation of Peroxisome Proliferator-Activated Receptors α and δ Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy.

Memory CD8+ T cells (Tmem) are superior mediators of adoptive cell therapy (ACT) compared with effector CD8+ T cells (Teff) due to increased persistence in vivo. Underpinning Tmem survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). Here we investigated the impact of the peroxisome proliferator-activated receptor (PPAR) agonist GW501516 (GW), an agent known to boost FAO in other tissues, on CD8+ T-cell metabolism, function, and efficacy in a murine ACT model. Via activation of both PPARα and PPARδ/ß, GW treatment increased expression of carnitine palmitoyl transferase 1a, the rate-limiting enzyme of FAO, in activated CD8+ T cells. Using a metabolomics approach, we demonstrated that GW increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. T cells activated in the presence of GW and inflammatory signals, either mature dendritic cells or IL12, also demonstrated enhanced production of IFNγ and expression of T-bet. Despite high expression of T-bet, a characteristic of short-lived effector cells, GW-treated cells demonstrated enhanced persistence in vivo and superior efficacy in a model of ACT. Collectively, these data identify combined PPARα and PPARδ/ß agonists as attractive candidates for further studies and rapid translation into clinical trials of ACT. SIGNIFICANCE: Dual activation of peroxisome proliferator-activated receptors α and δ improves the efficacy of adoptive cell therapy by reprogramming T-cell metabolism and cytokine expression.

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia.

High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs.

Evaluation of 2009 pandemic H1N1 influenza vaccination in adults with lymphoid malignancies receiving chemotherapy or following autologous stem cell transplant.

This is a randomized trial evaluating the safety and immunogenicity of one or two doses of 2009 pandemic H1N1 influenza vaccination in adults with lymphoid malignancies. Adults with a lymphoid malignancy receiving active systemic therapy, or within a year after autologous stem cell transplant, received one dose of AS03-adjuvanted A/California/7/2009 (H1N1) vaccine, and were randomized 21 days later to a second dose or no further vaccination. The primary outcomes were seroprotection and seroconversion rates by hemagglutination inhibition 21 and 42 days after initial vaccination. Twenty-two patients received one dose, and 20 patients received a second dose. Seroconversion rates at day 21 were 30% (one dose) and 5% (two doses), and subsequently 30% for both groups at day 42. Seroprotection rates at day 21 were 40% (one dose) and 15% (two doses), and subsequently 35% (one dose) and 40% (two doses) at day 42. Differences in serologic endpoints were not statistically significant between both study arms at day 42. Patients with low levels of B-cells (CD19-positive) had low seroconversion rates on days 21 (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.59-0.93, p = 0.043) and 42 (OR 0.12, 95% CI 0.01-1.07, p = 0.058). Only three of the 14 patients who received rituximab achieved seroprotective titers by day 42. Patients with lymphoid malignancies did not achieve rates of seroconversion or seroprotection seen in healthy subjects despite a second dose and the use of an adjuvant. Notwithstanding suboptimal immunogenicity, seasonal and pandemic influenza vaccination should continue to be recommended.