PD-1 blockade does not enhance alloimmunization after allogeneic dendritic cell vaccination in cancer patients

Severine Planel¹Guillaume Vayssière¹Gianni Maggipinto²Estelle Leplus¹Karine Laulagnier¹Florence Renard³Francoise Myster³Marie Gerard⁴Ingel Demedts⁵Kristof Cuppens⁶Elvire Pons-Tostivint⁷Els Wauters⁸Frank Borm⁹Anne Sibille¹⁰Benoît Colinet¹¹Maurice Pérol¹²Willemijn Theelen¹³Bonne Biemsa¹⁴Charlotte Van De Kerkhove¹⁵Eva Buchmeier¹⁶Friederike Althoff¹⁷Sofie Derijcke¹⁸Denis Moro-Sibilot¹⁹Frederique Cantero¹Laurence Chaperot⁴Philippe Saas⁴Marcin Skrzypski²⁰Johan Vansteenkiste⁸Joel Plumas^1*

• ¹PDC*line Pharma, Grenoble, France
• ²G.M. consultant company, Liege, Belgium
• ³PDC*line Pharma SA, Liege, Belgium
• ⁴Etablissement Francais du Sang Auvergne-Rhone-Alpes, Décines-Charpieu, France
• ⁵AZ Delta vzw, Roeselare, Belgium
• ⁶Jessa Ziekenhuis vwz, Hasselt, Belgium
• ⁷Centre Hospitalier Universitaire de Nantes, Nantes, France
• ⁸UZ Leuven, Leuven, Belgium
• ⁹Leids Universitair Medisch Centrum, Leiden, Netherlands
• ¹⁰CHU de Liege, Liège, Belgium
• ¹¹Grand Hopital de Charleroi, Charleroi, Belgium
• ¹²Centre Leon Berard, Lyon, France
• ¹³Netherlands Cancer Institute, Amsterdam, Netherlands
• ¹⁴Jeroen Bosch Ziekenhuis, 's Hertogenbosch, Netherlands
• ¹⁵VITAZ vzw, Sint-Niklaas, Belgium
• ¹⁶Kliniken der Stadt Koln gGmbH, Cologne, Germany
• ¹⁷Goethe-Universitat Frankfurt am Main, Frankfurt, Germany
• ¹⁸AZ Groeninge, Kortrijk, Belgium
• ¹⁹Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
• ²⁰Gdanski Uniwersytet Medyczny, Gdańsk, Poland

ABSTRACT Blocking programmed cell death protein 1 (PD-1) has become a standard cancer immunotherapy, increasingly used in kidney, liver, or heart transplant recipients who develop skin cancer or hepatocellular carcinoma, despite the increased risk of graft failure or rejection. The mechanism of action of PD-1 blockade relies on stimulating CD8+ T cell activity, but its impact on humoral immunity in general and on alloimmunization in particular remains uncertain. The aim of this study was to investigate the impact on anti-PD-1 treatment on alloimmunization. The effect of anti-PD-1 treatment on the generation of anti-HLA (Human Leucocyte Antigen) antibodies was investigated in 72 patients with non-small cell lung cancer vaccinated with an allogeneic plasmacytoid dendritic cell line (PDC*line; six weekly injections), with or without pembrolizumab administered every three weeks. The kinetics and functionality of the anti-HLA generated were analyzed. The results show that 51.4% of the patients developed anti-HLA antibodies, primarily dependent on the vaccine dose. In 60% of cases, the antibody response appeared after the sixth injection, peaked after one month, and then gradually declined over two years. Anti-HLA class II antibodies appeared earlier than class I antibodies. Functional assays demonstrated complement-dependent cytotoxicity against allogeneic B lymphocytes and PDC*line cells in the serum of some patients, with no difference related to treatment. PD-1 blockade did not alter the magnitude, kinetics, or cytotoxic potential of the vaccine-induced humoral response. These results indicate that, during allogeneic human vaccination, PD-1 signaling exerts a limited effect on antibody production and effector function, suggesting a more complex regulatory role in humoral immunity than previously thought.