In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study

Abstract

AbstractAbstract 286 Background:In a murine model, our in situ vaccination therapy combining tumor antigens with TLR9 agonist cured mice of lymphoma. Our phase I/II study in indolent B-cell lymphoma demonstrated that this in situ vaccination maneuver utilizing local radiation to expose tumor antigens combined with CpG ODN was well-tolerated without treatment limiting toxicities. It induced meaningful systemic clinical responses and tumor-reactive memory CD8 T-cells. In parallel, we explored this in situ vaccination strategy in cutaneous T-cell lymphoma (CTCL), specifically mycosis fungoides (MF). Our objectives were to determine the feasibility and safety and to assess the local and systemic antitumor effects in MF. Methods:Patients with MF stages IA-IVA who failed ≥1 standard therapy were eligible. Immunization site was treated with low-dose radiation (2 Gy × 2 d), bracketed by intratumoral injection of CpG followed by weekly intratumoral CpG × 8. Local (immunized site) and systemic antitumor responses were assessed at wk 0, 2, 4, 8, 12, then monthly until PD/off-study. Clinical response was evaluated by assessing skin disease burden at sites not treated with immunization procedure. Results:Study enrollment was completed with total of 15 patients. Median age was 57 yrs (range 18–71 yrs), 12 of 15 were male. Six patients had stage IB and 9 with stage IIB (3 with large-cell transformation). Median number of prior therapies was 5 with range of 2–9. After the initial 6 patients, a second immunization site was added at wk 4 to enhance systemic response. Total of 5 partial responses were observed (30% OR); 2 of 6 treated with single immunization and 3 of 9 with dual immunization. Median time to response was 8 wks (range 4–12 wks), duration of response 7 wks (range 4–44 wks), and time to progression 20+ wks (range 3–44+ wks). Patients with large-cell transformed MF did not respond. Common toxicities were injection site and flu-like symptoms; mostly grade 1–2 and all transient. No clinical or laboratory findings of any autoimmune disorder were observed. Local tissue tumor/immune responses were assessed by immunostaining. CpG + local radiation treated immunization site showed a significant reduction of CD25+, Foxp3+ T-cells (p<0.01) consisting of MF cells and tumor-infiltrating lymphocytes. Similar reduction in S100+, CD1a+ dendritic cells (DCs) was observed post immunization (p < 0.025). A qualitative analysis suggested more remarkable reduction of CD25+ T-cells and skin DCs in clinical responders vs. non-responders (p= 0.058, 0.121). CpG dose-responsive activation of peripheral blood pDCs was observed in vitro. Conclusions:Our novel in situ vaccination strategy using a combination of intratumoral CpG ODN and low-dose radiation is feasible in CTCL/MF with acceptable toxicities. Depletion of tissue T-regs may be observed at immunized sites. Reduction of skin DCs may suggest cross-priming and migration of DCs to regional lymph nodes. Clinical responses in subset of patients and CpG responsiveness of pDCs may warrant further study with modifications to augment therapeutic effects. [Display omitted] Disclosures:No relevant conflicts of interest to declare.