With the recent approval of sipuleucel-T for metastatic castration-resistant prostate cancer and ipilimumab for metastatic melanoma, there is increasing excitement in the field of cancer immunotherapy. A large number of clinical trials are currently testing various vaccine vectors in a diverse array of cancer types. Which of these strategies will ultimately prove successful has yet to be determined. However, a better understanding of the complex interplay of tumor-specific T cells and the challenges faced at the tumor microenvironment, advances in biotechnology, and lessons learned from prior successes and failures will likely lead to approvals of other therapeutic cancer vaccines.
Dung T. Le and Elizabeth M. Jaffee
Katherine M. Bever and Dung T. Le
Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the United States. Response rates to second- and third-line therapy for metastatic CRC (mCRC) remain low, and immunotherapy is an attractive strategy for treatment in these patients given generally better tolerability than conventional chemotherapy and the potential for long-lasting durable responses. In particular, the novel checkpoint inhibitors (CPIs) have demonstrated unprecedented clinical activity in a wide range of cancers. The observation of clinical activity in microsatellite instability–high (MSI-H) mCRC was the first indication of a potential for CRC to respond to these agents, and has led to a breakthrough designation by the FDA for CPI use in this subset. Despite this, a proportion of MSI-H and nearly all microsatellite stable disease will not respond to single-agent checkpoint inhibition, and clinical trials are ongoing to increase responses to immunotherapy in mCRC through both better patient selection and novel combinations of immunotherapeutic agents. This review will provide a focused update on the most compelling clinical results of immunotherapy in CRC to date, as well as a summary of current strategies being tested in clinical trials in increase responses to immunotherapy in CRC.
Katherine Y. Fan, Avani S. Dholakia, Aaron T. Wild, Zheng Su, Amy Hacker-Prietz, Rachit Kumar, Mary Hodgin, Charles C. Hsu, Dung T. Le, Ana De Jesus-Acosta, Luis A. Diaz Jr, Daniel A. Laheru, Ralph H. Hruban, Elliot K. Fishman, Todd D. Brown, Timothy M. Pawlik, Christopher L. Wolfgang, Phuoc T. Tran, and Joseph M. Herman
An association between diabetes mellitus and pancreatic ductal adenocarcinoma (PDA) has long been recognized. This article assesses the effect of the baseline hemoglobin-A1c (HbA1c) value on the clinical outcomes of patients with PDA. HbA1c values were prospectively collected on 656 consecutive patients presenting to a pancreas multidisciplinary cancer clinic from 2009 to 2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Excluded were those with prior treatment for PDA or a history of chronic diabetes mellitus (>1-year or unknown duration), resulting in a final cohort of 284 patients. Of 284 patients, 44 had benign disease, 62 had R-PDA, 115 had BL-PDA, and 63 had M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had a higher average HbA1c value than patients with BPD (6.1% vs 5.6%; P<.001). Among patients with PDA (n=240), HbA1c values of 6.5% or greater were significantly associated with inferior overall survival (OS) compared with patients with HbA1c values less than 6.5% (hazard ratio [HR], 1.74; OS, 10.2 vs 13.0 months; P=.007), along with other known prognostic factors, such as age of 65 years or older, ECOG performance status of 1 or greater, carbohydrate antigen 19-9 level greater than 90, tumor size larger than 3 cm, and disease stage. HbA1c values of 6.5% or greater remained in the final predictive model using backward elimination (HR, 1.46; P=.097), indicating that HbA1c values of 6.5% or greater influence OS of patients with PDA even when accounting for other known prognostic factors. HbA1c level at presentation is significantly higher in patients with PDA than patients with BPD and seems to affect survival.