In an ongoing in situ vaccine (ISV) phase I trial, 11 patients with indolent non-Hodgkin’s B cell lymphoma had a single lesion treated with Flt3L, radiation, and poly-ICLC (TLR3 agonist). In mice, Flt3L recruited TLR3+IRF8+ DCs to the tumor, and radiation synergized with poly-ICLC to induce their maturation into cross-presenting CD103+ DCs, mediating the influx and activation of tumor-reactive TILs; similar results were observed in patients. ISV induced regression of treated and untreated distant tumors in patients. In non-responders, ISV greatly increased PD-1 expression on CD8+ T cells, prompting a follow-up trial of combination ISV and anti-PD-1.
Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8(+) T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1(+)CD8(+) T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
Author Info: (1) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
Author Info: (1) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Celldex Therapeutics, Inc., Needham, MA, USA. (10) Celldex Therapeutics, Inc., Needham, MA, USA. (11) Oncovir, Inc, Washington, DC, USA. (12) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, York, NY, USA. (15) Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joshua.brody@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joshua.brody@mssm.edu.
