Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy.

CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.

Complementary therapies in addition to medication for patients with nonchronic, nonradicular low back pain: a systematic review.

BACKGROUND: A total of 2.7 million patients present to US emergency departments annually for management of low back pain (LBP). Despite optimal medical therapy, more than 50% remain functionally impaired 3 months later. We performed a systematic review to address the following question: Among patients with nonchronic LBP, does spinal manipulation, massage, exercise, or yoga, when combined with standard medical therapy, improve pain and functional outcomes more than standard medical therapy alone? METHODS: We used published searches to identify relevant studies, supplemented with our own updated search. Studies were culled from the Cochrane Register of Controlled Trials, Medline, EMBASE, CINAHL, and the Index to Chiropractic Literature. Our goal was to identify randomized studies that included patients with nonradicular LBP of <12 weeks' duration that compared the complementary therapy to usual care, sham therapy, or interventions known not to be efficacious, while providing all patients with standard analgesics. The outcomes of interest were improvement in pain scores or measures of functionality. RESULTS: We identified 2 randomized controlled trials in which chiropractic manipulation + medical therapy failed to show benefit vs medical therapy alone. We identified 4 randomized controlled trials in which exercise therapy + medical therapy failed to show benefit vs medical therapy alone. We did not identify any eligible studies of yoga or massage therapy. CONCLUSIONS: In conclusion, for patients with nonchronic, nonradicular LBP, available evidence does not support the use of spinal manipulation or exercise therapy in addition to standard medical therapy. There is insufficient evidence to determine if yoga or massage is beneficial.