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Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x. [Epub ahead of print]

Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination.

Author information

1
Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Celldex Therapeutics, Inc., Needham, MA, USA.
6
Oncovir, Inc, Washington, DC, USA.
7
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, York, NY, USA.
8
Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joshua.brody@mssm.edu.
9
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joshua.brody@mssm.edu.

Abstract

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.

PMID:
30962585
DOI:
10.1038/s41591-019-0410-x

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