Journal of Clinical and Cellular Immunology
Open Access
ISSN: 2155-9899
ISSN: 2155-9899
Joshua Brody, Seunghee Kim-Schulze, Nina Bhardwaj and Miriam Merad
Accepted Abstracts: J Clin Cell Immunol
Objectives: Though low-grade lymphoma is generally incurable, T-cell based therapy such as allogeneic transplant can induce prolonged remissions, possibly cures, even for chemo-resistant disease. If anti-tumor T cell immunity could be mobilized without the morbidity of transplant, it could change the paradigm of lymphoma therapy. Previously, we completed three trials of an 'in situ vaccine' combining low-dose XRT with intratumoral administration of a TLR agonist demonstrating partial and complete remissions of patients? non-irradiated sites of disease, lasting as long as 4+ years. One obstacle to the induction of potent anti-tumor immunity with the in situ vaccine approach is the paucity of professional antigen presenting cells, e.g. dendritic cells (DC) at the tumor site. Methods: To address this problem, we have adopted the approach by adding a priming step of intratumoral administration of the predominant DC differentiation factor - Flt3L. The aim of the adopted approach is to use: ? intratumoral Flt3L administration to recruit DC to the tumor, ? low-dose XRT to induce immunogenic cell death and release tumor-associated antigens, and ? intratumoral poly-ICLC administration to activate tumor antigen-loaded DC, inducing anti-tumor T cells and anti-tumor immunity. Results: Preliminary immune correlative data for the first two patients receiving the in situ vaccine demonstrate a significant (up to 200-fold) increase in the proportion of intratumoral DC subsets (BDCA-1 and BDCA-3) at the treated tumor site. We also observe a marked increase in the intratumoral proportion of CD80 (high) PD-L1 (low) activated DCs after XRT and poly- ICLC administration. This latter finding is in contrast to the activation status of DC in the peripheral blood. Conclusions: Flt3L-primed in situ vaccination demonstrates immunologic and clinical proof-of-principle and warrants continued investigation. We will present additional immunologic and clinical results as well as ongoing studies to quantify anti-tumor T cells and to determine potential tumor-associated antigens