w.l.r . has received commercial research grants , consulting fees , and/or royalties from bristol - myers squibb , merck , galectin therapeutics , and nektar therapeutics .
abstractnumerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy . 
 furthermore , dual ctla-4/pd-1 checkpoint blockade recently received fda - approval for patients with metastatic melanoma , becoming the first combination immunotherapy to garner this designation in a rapidly evolving field . despite this progress 
 , the majority of patients do not respond to treatment , underscoring the critical need for more effective therapies . 
 we have been investigating the mechanisms by which combination immunotherapy with an ox40 agonist plus ctla-4 checkpoint blockade augments effector t cell responses to elicit anti - tumor immunity . 
 surprisingly , this approach failed to eradicate well - established tumors , in part due to the induction of anergy in cytotoxic cd8 + t cells . 
 further work revealed that anergic cd8 + t cells could be rescued by combining a dendritic cell - targeted vaccine with combination immunotherapy . 
 taken together , these data suggest that novel combinatorial immunotherapeutic strategies incorporating a vaccination strategy may be needed to generate effective anti - tumor responses in the majority of patients with metastatic disease .