Preliminary Report on a Phase I/II Study of Intratumoral Injection of PF-3512676 (CpG 7909), a TLR9 Agonist, Combined with Radiation in Recurrent Low-Grade Lymphomas.

Background: Low-grade lymphomas are considered incurable, but they are among the most immune-responsive of all human cancers. CpG belongs to a new class of immunomodulators, which activates B cells and plasmacytoid dendritic cells through Toll-like Receptor 9 (TLR 9). We have developed a novel immunotherapy approach that combines low-dose radiation with intra-tumoral injection of CpG for recurrent low-grade lymphomas. We hypothesized that CpG would stimulate tumor-antigen uptake and presentation by dendritic cells in vivo. Tumor cells induced to die by irradiation release tumor antigens and recruit dendritic cells. In this setting, CpG injected into the irradiated tumor stimulates dendritic cell uptake and presentation of tumor antigens. Having demonstrated the validity of this hypothesis in animal models, we developed a clinical trial based on this combination regimen for patients with recurrent low-grade lymphoma. Our primary objective was to test the safety of this combination CpG-radiation regimen. The secondary objective was to assess systemic anti-tumor effect by monitoring tumor regression at sites other than the irradiated/injected site.

Patients and Methods: Patients with biopsy confirmed low-grade follicular B-cell lymphoma (FL) of any initial stage or mycosis fungoides (MF) with stage IB-IVA were eligible for the study. B-cell lymphoma patients failed at least one prior treatment. Mycosis fungoides patients failed or were intolerant of at least 2 topical or one systemic treatment. Patients had at least one site of disease accessible for intratumoral injection of CpG and had a Karnofsky Performance Status (KPS) of ≥ 70 with adequate organ and bone marrow functions. Patients received low-dose radiotherapy to a single tumor site on days 1 and 2 (2 Gy each day). PF-3512676 (CpG 7909) injections were administered at a dose of 6mg into the same tumor site within the 24 hours before and the 24 hours after the radiation, and on days 8 and 15. Weekly injections of PF-3512676 were then administered at the same dose subcutaneously in the region of previous injections for 6 additional doses.

Results: Of seven patients treated to date (5 with FL and 2 with MF), 7/7 experienced grade 1 and 2 injection site reactions, including erythema, swelling and tenderness; 3/7 had grade 1 fevers after the injection; 4/7 experienced myalgia or arthralgia, 6/7 reported fatigue. All adverse reactions were transient. No hematological adverse reactions or SAEs occurred. One patient experienced transient swelling of the lymph nodes draining the CpG injection site. One of 4 FL and 1 of 2 MF patients who have completed treatment achieved a partial response with tumor regression observed at all un-irradiated sites and the remaining patients had stable disease.

Conclusion: Intra-tumoral injection of PF-3512676 (CpG 7909), at a fixed dose of 6mg, combined with low-dose radiation (2Gy x 2) is a safe and well tolerated regimen in patients with recurrent low-grade lymphomas. In addition, an anti-tumor effect has been observed. The study is ongoing.