Despite initial remission after successful treatments, B lymphoma patients often encounter relapses and resistance causing high mortality. Thus, there is a need to develop therapies that prevent relapse by providing long-term protection and, ultimately, lead to functional cure. In this study, our goal was to develop a simple, clinically relevant, and easily translatable therapeutic vaccine that provides durable immune protection against aggressive B cell lymphoma and identify critical immune biomarkers that are predictive of long-term survival. In a delayed-treatment, aggressive, murine model of A20 B lymphoma that mimics human diffuse large B cell lymphoma, we show that therapeutic A20 lysate vaccine adjuvanted with an NKT cell agonist, alpha-galactosylceramide (alpha-GalCer), provides long-term immune protection against lethal tumor challenges and the antitumor immunity is primarily CD8 T cell dependent. Using experimental and computational methods, we demonstrate that the initial strength of germinal center reaction and the magnitude of class-switching into a Th1 type humoral response are the best predictors for the long-term immunity of B lymphoma lysate vaccine. Our results not only provide fundamentally insights for successful immunotherapy and long-term protection against B lymphomas, but also present a simple, therapeutic vaccine that can be translated easily due to the facile and inexpensive method of preparation.