The combination of a FLT3L-primed in situ vaccine, low-dose radiotherapy, and a TLR 3 agonist has been shown to be feasible, safe, and immunologically and clinically effective in a phase I/II study for patients with low-grade lymphoma.
Joshua Brody, MD
The combination of a FLT3L-primed in situ vaccine, low-dose radiotherapy, and a toll-like receptor 3 (TLR) 3 agonist has been shown to be feasible, safe, and immunologically and clinically effective in a phase I/II study for patients with low-grade lymphoma, according to a presentation by Joshua Brody, MD, during the 2014 Chemotherapy Foundation Symposium.
Although conventional chemotherapy for lymphoma has advanced greatly, most cases of lymphoma are incurable, demonstrating the need for novel therapies with less toxicity and more specific targeting of tumor cells. TLR agonists work as immune cell stimulants to activate dendritic cells. An earlier version of the treatment utilized a TLR9 agonist; however, further research suggested that a TLR3 inhibitor would induce higher rates of dendritic cell activation, specifically those impacted by FLT3L. TLRs are involved in tumorigenesis and have potential in immunotherapeutics or vaccine adjuvants.
“TLR9 would not be the right agonist to use because the dendritic cells express more TLR3. That’s the rationale for using a TLR3 agonist,” said Joshua Brody, MD, an assistant professor of Medicine, Hematology, and Medical Oncology at Mount Sinai Hospital.
In the phase I/II study, patients were treated with an intratumoral injection of the FLT3L-primed vaccine therapy followed by low-dose radiotherapy along with an intratumoral injection of the TLR agonist poly-ICLC. At the time of the presentation, 6 patients had been enrolled into the study, with 2 completing the treatment. Treated patients had 2- to 200-fold increases in BDCA1 and BDCA3 intratumoral dendritic cells after FLT3L administration and marked immune cell activation after radiation therapy and poly-ICLC, suggesting an antitumor response.
Both treated patients have had partial remissions of untreated sites per Cheson criteria, persisting or improving for >6 months after vaccination. Patients who responded experienced regressions of bulky lymph nodes, as well as peripheral blood and bone marrow disease. Brody said that 1 patient with significant peripheral blood tumor burden experienced >10-fold decrease in malignant B cells with concurrent increase in nontumor B cells, suggesting a degree of cell specificity in the tumor-killing mechanism. Adverse effects have been mild said Brody.
“These new results are way too preliminary to say if this will lead to an FDA-approved therapy,” said Brody. “But it’s fair to say that some more targeted immune therapies will have an effect on community oncologiststhose somewhat less specific, but promising immune therapies like PD-1 blockade or PD-L1 blockade will affect community oncologists today.”
Research into the combination regimen using the TLR9 agonists also demonstrated early success. In this study, 60 patients were treated with the in situ vaccine in trials for low-grade B-cell and T-cell lymphoma and it induced partial and complete remissions, some lasting for years. Brody said that this previous therapy regimen became more powerful with repeated use, as is expected with vaccines.
This approach and the long last remissions are a contrast to chemotherapy; however, the treatment can still be made even more effective, said Brody. One likely limitation is that there are very few dendritic cells at the tumor site constraining the ability to prime the antitumor T-cell response.
In preclinical studies, FLT3L induced tumor leukocyte infiltration and regression of lymphoma. A new formulation of this cytokine, CDX-301, has been shown to mobilize dendritic cell subsets BDCA-1 and BDCA-3. These dendritic cell subsets respond to TLR agonists more effectively than plasmacytoid dendritic cells (the CpG-responsive dendritic cell subset).
“We now have a way to bring more dendritic cells to the tumor with a clinical-grade recombinant FLT3L,” said Brody. “It’s known that dendritic cells are better at presenting antigens than other types of antigen-presenting cells.”