Autophagy Predicts Therapy Response in Melanoma
Ma et al., Page 3478
Autophagy allows cancer cells to recycle damaged components and promotes survival in many model systems. Ma and colleagues found that high autophagy levels in the tumors of metastatic melanoma patients predicted poor response to therapy and shorter overall survival rates. Higher levels of autophagy were found in aggressive compared to indolent melanoma cell lines grown as three-dimensional spheroids or xenograft tumors. Autophagy inhibition with RNAi or hydroxychloroquine, alone or in combination with chemotherapy, resulted in cell death in aggressive spheroids. These findings establish autophagy as a potential prognostic or predictive factor in melanoma and a new target for melanoma therapy.
Recommendations on Immunotherapy Biomarkers
Butterfield et al., Page 3064
Immunotherapy of cancer has seen recent clinical successes, but there is a need to define biomarkers that can identify patients who will have clinical benefit or identify appropriate patient groups to enroll. The iSBTc- SITC, FDA, and NCI partnered to address these issues, and Butterfield and colleagues now present the recommendations resulting from meetings that included participation from 10 partner societies and representation of 20 countries. The recommendations focus on assay standardization, blood and tissue banking, high throughput assays, and data reporting to promote improved understanding of clinical responders and nonresponders, mechanisms of action, and development of novel hypotheses.
Enhancement of T-Cell-Mediated Antitumor Response
Dings et al., Page 3134
Temporal changes in the flux of endothelial adhesion molecules (EAM) during tumor progression influence leukocyte extravasation. Whereas angiogenic growth factors like VEGF and bFGF act to downregulate EAM expression in tumors, angiostatic agents can overcome EAM downregulation, thereby enhancing an antitumor immune response. In this issue, Dings and colleagues show that adoptive T-cell transfer in combination with angiogenesis therapy results in improved tumor growth inhibition in mice. These results suggest that the combination of adjuvant therapy with angiogenesis inhibitors (administered within an appropriate time frame) holds promise for cellular immunotherapy in the clinic.
Anti-Trop-2-SN-38 Conjugate for Cancer Therapy
Cardillo et al., Page 3157
Clinical efficacy of irinotecan is limited by a patient's ability to convert this prodrug into its active metabolite, SN-38. Cardillo and coworkers sought to limit this variability and improve bioavailability by conjugating SN-38 to hRS7, a tumor-targeting anti-Trop- 2 humanized antibody (Trop-2 is expressed on a wide range of cancers of epithelial origin). The resulting hRS7-CL2A-SN-38 antibody-drug conjugate showed significant antitumor effects in vivo against non-small cell lung, pancreatic, colorectal, and squamous cell lung carcinomas. In monkeys, doselimiting toxicity was achieved at clinically relevant concentrations of SN-38. Taken together, these data support further clinical testing of hRS7-CL2A-SN-38 against Trop-2-positive solid tumors.