Highlights of This Issue

One way to potentially improve adoptive T-cell therapy is to combine it with the administration of small molecule inhibitors. Vemurafenib specifically inhibits mutated BRAF^V600E/K molecules and directs cell death of BRAF^V600E/K -expressing tumors. Vemurafenib has been reported to increase tumor infiltration of lymphocytes and increase expression of melanoma/melanocyte T cell antigens. This pilot clinical trial evaluated the combination of vemurafenib with T cell transfer. Objective clinical responses were observed in 7 of 11 patients (64%), including 2 of 11 patients (18%) with complete regressions of metastatic disease. Comparisons of metastases before and after vemurafenib treatment revealed an increased presence of tumor-infiltrating T cells but similar recognition of autologous tumor. This pilot trial showed the safety and feasibility of administering a kinase inhibitor with T cell transfer.

Blockade of the PD-1 axis reinvigorates the antitumor immune response and induces clinical benefit in nearly 20% of patients with advanced lung cancer. The presence of PD-L1 (or B7-H1) in the tumor is associated with increased benefit from these therapies. The association and biological role of additional and potentially actionable immune inhibitory targets in lung cancer are not well understood. By quantitatively measuring PD-L1, B7-H4, IDO-1, and different immune cell subsets, Schalper and colleagues show that lung carcinomas display limited coexpression of these immuno-suppressive markers. The presence of the markers in lung tumors is also differentially associated with immune infiltration and specific tumor features. The data suggest that lung malignancies use preferentially discrete and nonoverlapping routes to evade immunity that could participate in immunotherapy resistance. These results could support the design of clinical studies using biomarker-driven immunotherapies.

Stratification of colorectal cancer transcriptional profiles into subtypes with prognostic and predictive differences has an immediate clinical implication in personalization of therapies. A subsequent challenge, however, is the adaptation of this classification system for diagnostic purposes given the requirement for a rapid scoring system, which uses minimal quantities of tumor material. Trinh and colleagues report an immunohistochemistry-based classifier, which uses pathologist scoring or automated image analysis of tissue microarrays as inputs. This approach improves clinical utility of the current molecular taxonomy and allows retrospective access to large clinical cohorts for which only formalin-fixed paraffin-embedded material is available. This retrospective analysis of four cohorts validates the prognostic value of colorectal cancer subtyping and identifies a subset of patients (∼30%) who benefitted from anti-EGFR therapy, potentially improving the efficacy of this class of drugs.

Resistance to targeted molecular therapy has been a longstanding problem in gastrointestinal stromal tumor (GIST). Tumor cells develop multiple mechanisms to evade immune surveillance. Seifert and colleagues demonstrated the expression of multiple inhibitory receptors on tumor infiltrating T cells in over 100 human GIST specimens, of which PD-1 was the most highly expressed. In a spontaneous mouse model of GIST, the addition of PD-1/PD-L1 blockade enhanced the antitumor efficacy of imatinib. Thus, the combination of tyrosine kinase inhibition and checkpoint blockade is a promising therapeutic strategy in GIST.