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

Authors: 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

Summary:

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.

Source: Nature Medicine, 2019