Journal Article

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

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

2019

Overview

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.In situ vaccine recruits and activates cross-presenting dendritic cells and augments PD1 blockade efficacy in patients with indolent non-Hodgkin’s lymphoma.

• Publisher: Nature Publishing Group
• Subject: Antigen presentation / CD8 antigen / Dendritic cells / FLT3L protein / Immune checkpoint / Immunity / Lymphocytes / Lymphocytes T / Lymphoma / Non-Hodgkin's lymphoma / PD-1 protein / Priming / Radiation therapy / Remission / TLR3 protein / Toll-like receptors / Tumors / Vaccination / Vaccines