Milestones in Cancer Immunology
Cancer Immunol Res December 1 2015 3 (12) 1291-1291; DOI:10.1158/2326-6066.CIR-15-0278
Checkpoint blockade carries risks of immune-related adverse effects, but frequency and severity are unknown. A patient is described who received anti–CTLA-4 (ipilimumab), and then anti–PD-1 (nivolumab). The patient developed lethal subacute and progressive CNS demyelination.
Sarcomatoid renal cell cancer (RCC) is an aggressive form of RCC that responds poorly to IL2 immunotherapy. Both PD-1 and PD-L1 were found expressed in sarcomatoid RCC samples, suggesting that blockade of the PD-L1/PD-1 pathway may have immunotherapeutic potential.
Unambiguous assessment of the presence of PD-L1 in the membrane of tumor cells could increase its utility as a prognostic marker for PD-1 blockade treatment. Three monoclonal antibodies to PD-L1's cytoplasmic domain clearly demarcated membrane from cytoplasmic staining.
The efficacy of anticancer monoclonal antibodies (mAbs) is limited by the exhaustion of cellular effector mechanisms. The combination of IgG and IgA to two different tumor targets leads to enhanced cytotoxicity, providing a basis for therapeutic mAb improvements.
Select early-stage lung cancer patients never develop metastasis. Some of these patients have antibodies that inactivate a protein that protects tumor cells from complement lysis, thus making tumor cells more susceptible to being killed.
Lung cancers harboring ALK translocations are treated with protein kinase inhibitors, which can extend survival. A cancer vaccine against ALK induced strong immune responses and enhanced survival when used alone, or in combination with kinase inhibitors or checkpoint inhibitors.
T cells within non–small cell lung cancer tumors acquire greater numbers, and more diversity, of inhibitory receptors as tumors progress, correlating with a loss in function as well as in their ability to be reactivated after anti-checkpoint treatment.
Prognostic indicators are needed for malignant melanoma. The presence of high densities of CD169+ macrophages in the draining lymph nodes of patients significantly correlates with CTL infiltration and longer overall survival, providing a potentially useful biomarker.
Adoptive cellular immunotherapy requires donor cells to survive and accumulate, which this study shows requires an IL12/IL7 axis in activated CD8+ T cells. IL12 leads to enhanced IL7Ra expression and IL7 responsiveness, which maximizes antitumor efficacy.
Combining other agents with immune-based approaches can enhance treatment for melanoma. PDL-1 gene expression was increased after inhibition of histone deacetylases. Combining PD-1–blockade immunotherapy with histone deacetylase inhibition increased responses in a mouse model of melanoma.