Masters of Immunology | Free Article
Ellis L. Reinherz
Cancer Immunol Res April 1 2015 3 (4) 305-312; DOI:10.1158/2326-6066.CIR-15-0042
Mitchell and colleagues report the induction of a grade 3 immunologic reaction in a patient with glioblastoma receiving autologous RNA-pulsed dendritic-cell vaccines admixed with GM-CSF and coordinated cycles of temozolomide, highlighting the capacity for potent immunologic induction with this regimen.
Wimberly and colleagues analyzed pretreatment biopsies and outcomes from 105 breast cancer patients; they report the association of PD-L1 expression with hormone receptor–negative and triple-negative status and pathologic complete responseand suggest that PD-L1 expression is a biomarker in this treatment cohort.
Chu and colleagues show that K562-mbIL15-41BBL–expanded peripheral blood NK cells, modified with mRNA nucleofection of an anti-CD20 CAR, significantly enhanced cytotoxicity against CD20+B-cell non-Hodgkin lymphoma, extended survival time, and reduced tumor size in xenografted NSG mice.
Sharabi and colleagues show in two mouse tumor models that radiotherapy combined with PD-1 blockade or Treg depletion improves local tumor control by increasing antigen-experienced and effector-memory T cells, antigen-MHC complexes, and T-cell infiltration into tumors via antigen cross-presentation in the tumor-draining lymph node.
Frigault, Lee, and colleagues compared chimeric antigen receptors (CAR) encoding signaling domains comprising CD28, ICOS, and 4-1BB and found that some CD28 CAR-T cells have antigen-independent constitutive proliferation and cytokine secretion when highly expressed, leading to inferior antitumor effects.
Künkele and colleagues demonstrate in a solid tumor model that CARs with the highest in vitro activity exhibit attenuated antitumor potency in vivo as CTLs expressing hyperactive CARs are susceptible to activation-induced cell death; CARs tuned for moderate signaling outputs mediate effective tumor eradication.
Maker and colleagues analyzed liver tumor specimens and outcomes from 96 patients with colorectal cancer liver metastases and report that genetic evidence of T-cell activation/proliferationin liver tumors, specifically the increased expression of TNFSF14/LIGHT, is associated with longer overall and disease-free survival.
Makkouk and colleagues show that intratumoral delivery of doxorubicin in polylactide-co-glycolide micro-particles combined with antibodies against OX40 and CTLA-4 induced T cell–dependent systemic responses that enhanced T-cell infiltration into and eradication of distant tumors and improved survival in mouse models of lymphoma.
Winograd and colleagues used an engineered KPC mouse model of pancreatic ductal adenocarcinoma (PDA) reflecting that of human PDA to show that baseline refractoriness to checkpoint inhibitors can be rescued by priming a T-cell response with αCD40 plus chemotherapy with gemcitabine and nab-paclitaxel.
Kouo and colleagues report the development of neutralizing Abs to galectin-3 in PDA patients who showed improved survival in response to a GM-CSF–secreting allogeneic tumor vaccine, and they propose that carbohydrate signaling be considered as "signal 4" of immune-cell programming and differentiation.