Background: Lymphomas are the 5^th most incident cancer in the U.S. and indolent non-Hodgkin's lymphoma (iNHL) are incurable with standard therapy. We previously completed three trials of ‘in situ vaccination’ - combining low-dose radiotherapy (XRT) with intratumoral administration of a TLR9 agonist (CpG). We demonstrated induction of tumor-specific CD8 T cell responses and clinical remissions of patients’ untreated sites of disease, lasting up to > 4 years. One limitation may have been the scarcity of intratumoral dendritic cells (DC). DC are uniquely able to endocytose dying (e.g. irradiated) tumor cells for cross-presentation to anti-tumor CD8 T cells. Methods: Flt3L– the predominant DC differentiation factor– induces tumor leukocyte infiltration and regression of lymphoma tumors pre-clinically and a new formulation of this cytokine -CDX-301- was shown to mobilize BDCA-1 and BDCA-3 DC subsets in an early phase trial. These DC subsets respond to several TLR agonists and cross-present antigens more effectively than plasmacytoid DC (the CpG-responsive DC subset). We initiated a phase I/II study of a new iteration of the in situ vaccine, adding Flt3L-priming and replacing the prior TLR9 agonist with the TLR3 agonist poly-ICLC (Fig 1A). The vaccine consists of: -intratumoral Flt3L administration to increase DC within the tumor -low-dose XRT to induce immunogenic tumor cell death and release tumor-associated antigens, and -intratumoral poly-ICLC administration to activate tumor antigen-loaded DC. The current study will assess two cohorts of patients (n = 15, each) with either previously untreated or relapsed/refractory iNHL to test the hypothesis that in situ vaccination will induce clinical remissions at distant (untreated) tumor sites. Eligibility: iNHL, either previously untreated or relapsed/refractory. Treatment: Intratumoral CDX-301 25ug/kg x 9 days. Local radiotherapy 2Gy x 2. Intratumoral poly-ICLC 2mg weekly x 8 weeks. Patients will have tumor (FNA) and blood collected for immune monitoring at weeks 0, 2, 4, 6, 8, 12 as well as pre treatment biopsy. Restaging CT scans will be done pretreatment and at week 12. Clinical trial information: NCT01976585. Clinical trial information: NCT01976585