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

Linda Hammerich; Thomas U Marron; Ranjan Upadhyay; Judit Svensson-Arvelund; Maxime Dhainaut; Shafinaz Hussein; Yougen Zhan; Dana Ostrowski; Michael Yellin; Henry Marsh; Andres M Salazar; Adeeb H Rahman; Brian D Brown; Miriam Merad; Joshua D Brody

doi:10.1038/s41591-019-0410-x

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

Nat Med. 2019 May;25(5):814-824. doi: 10.1038/s41591-019-0410-x. Epub 2019 Apr 8.

Authors

Linda Hammerich^{1

2}, Thomas U Marron^{1

2}, Ranjan Upadhyay^{1

2}, Judit Svensson-Arvelund^{1

2}, Maxime Dhainaut^{2

3}, Shafinaz Hussein⁴, Yougen Zhan⁴, Dana Ostrowski¹, Michael Yellin⁵, Henry Marsh⁵, Andres M Salazar⁶, Adeeb H Rahman², Brian D Brown^{2

3}, Miriam Merad^{2

7}, Joshua D Brody^{8

9}

Affiliations

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.

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

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.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Antigen Presentation
CD8-Positive T-Lymphocytes / immunology
Cancer Vaccines*
Carboxymethylcellulose Sodium / analogs & derivatives
Carboxymethylcellulose Sodium / therapeutic use
Cell Line, Tumor
Combined Modality Therapy
Dendritic Cells / immunology
Female
Humans
Immunotherapy, Adoptive
Lymphoma, B-Cell / immunology
Lymphoma, B-Cell / pathology
Lymphoma, B-Cell / therapy*
Male
Membrane Proteins / immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Poly I-C / therapeutic use
Polylysine / analogs & derivatives
Polylysine / therapeutic use
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / immunology
Toll-Like Receptor 3 / agonists
Vaccination

Substances

Cancer Vaccines
Membrane Proteins
PDCD1 protein, human
Programmed Cell Death 1 Receptor
TLR3 protein, human
Toll-Like Receptor 3
flt3 ligand protein
Polylysine
poly ICLC
Carboxymethylcellulose Sodium
Poly I-C