Formulation with nanoparticles and adjuvant can induce stronger immune responses of vaccines than adjuvant alone, due to enhanced permeability and retention (EPR) effect of nanoparticles in the tumor [102], the depot effect (retention of liposomes and antigens at the injection site as mentioned for the DPX-Survivac vaccine), and selective targeting of tumor-associated but not normal macrophages [42]. on immunologic mechanisms underlying the therapeutic effectiveness and resistance. with a fusion protein of recombinant PAP and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), and then re-infuses mature APC (the major Sipuleucel-t product) and other antitumor immune cells into patients [12]. Currently, no other therapeutic cancer vaccine SERPINF1 has been approved by the FDA. Various vaccine strategies are being developed in B-cell lymphoma, most in indolent or low-grade types, however. In this article, we focus on the review of clinical and preclinical studies on autologous and allogeneic therapeutic vaccines against DLBCL. Autologous therapeutic vaccines for DLBCL Autologous lymphoma vaccines use autologous lymphoma cells and/or autologous tumor-pulsed dendritic cells along with immunological adjuvants, some of which have advanced to clinical trials. Vaccination with tumor cells alone is not sufficient to elicit antitumor T-cell responses [13], and vaccine adjuvants are necessary to enhance the phagocytosis, activation, and antigen presentation ability of APC (dendritic cells and macrophages, also B/lymphoma cells in Li et al. [14]) for optimal therapeutic effects. Combining with T-cell-modulation using antibodies can further enhance the therapeutic effects [15]. Vaccine adjuvants include synthetic CpG oligodeoxynucleotides, which contains unmethylated C-G motif as a ligand for the Toll-like receptor (TLR) 9 to stimulate both APC and lymphoma B cells [14,16] (which can be inhibited by hydroxychloroquine/HCQ [17,18]), Poly-ICLC, a ligand for TLR3 [13], Flt3L (Flt3 ligand, mobilizing dendritic cells), GM-CSF (cytokine), and heat-shock proteins (HSPs, in trials mainly gp96, also HSP70 and HSP90. Chaperone for tumor peptides, binding to CD91 on dendritic cells) in clinical trials, as well as -galactosylceramide (GC or -GalCer, an NKT cell agonist), -mannosylceramide (-ManCer) [19,20], Freunds adjuvant [21], and an inducible engineered MYD88/CD40 fusion protein in lymphoma mouse models [22]. The MYD88 protein is a critical adaptor in the Toll/interleukin receptor pathway whereas CD40 is a costimulatory molecule for APC. Vaccination with inactivated autologous tumor cells and adjuvant A number of pre-clinical studies have shown that autologous or syngeneic tumor vaccines can generate potent tumor-specific immunity in lymphoma-bearing mouse models that mimic human DLBCL (A20 or E-myc 299). These vaccines include irradiated CpG-loaded whole lymphoma cells through intratumoral injection into syngeneic mice [16], vaccine by direct CpG injection into CADD522 a site of dying tumor cells [14], -GalCer or -ManCer-loaded irradiated whole syngeneic/autologous tumor cells through intravenous injection [19,20], lysed lymphoma cells (soluble lysate by a freeze-thaw method but not tumor lysate loaded onto polymer microparticles) followed by intra-peritoneal injection of -GalCer (but not CpG or Poly-ICLC adjuvant) [23], and A20-derived exosomes through intravenous injection without adjuvant (no long-term therapeutic data in this study) [24]. In these pre-clinical studies, immune cells critical for CADD522 the therapeutic efficacy varied in different studies, including CD4+ T cells [16,19]; NKT, NK, and CD8+ T cells [20]; and CD8+ T cells [14,23]. IFN- cytokine was consistently critical and predictive for therapeutic efficacy in CADD522 these studies, but the source of IFN- production was different, including CD8+ T cells in one study [16], CD8+ and CD4+ T cells in one study [14], CD4+ T or Th1 cells in two studies [19,23], and NKT and NK cells dependent on the IL-12 cytokine in one study [20]. The strength of germinal center reaction was also a predictor for durable anti-lymphoma response induced by a soluble lymphoma cell lysate-based vaccine [23]. The preclinical results have been translated into a phase I/II clinical trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT00490529″,”term_id”:”NCT00490529″NCT00490529) in mantle cell lymphoma (a rare type of NHL) evaluating vaccination with irradiated CpG-activated whole autologous lymphoma cells followed by autologous stem cell transplantation and adoptive transfer of vaccine-primed T cells and booster vaccination. Promising results have been reported recently. PD-L1 expression on tumor cells was found to correlate with poorer clinical outcome [25]. In addition, in a clinical trial in a pet dog model of DLBCL, vaccination with purified autologous HSPs and the chaperoned peptides in tumor (a mixed HSPs version of the HSPPC-96 vaccine used in human solid CADD522 cancers and indolent lymphoma) loaded on hydroxyapatite particles significantly prolonged time-to-progression and lymphoma-specific survival in dogs with naturally occurring DLBCL [26]. In situ vaccination In other clinical trials in NHL, vaccination.