Modulation of tumor immunity: a patent evaluation of WO2015026684A1

ABSTRACT

A high percentage of regulatory T cells (Tregs) among tumor-infiltrating lymphocytes weakens the immune response against tumors. The anergy of effector T cells (Teff) can be reversed by immune checkpoint treatment, which inhibits Tregs and boosts the activation of Teff. Both effects can be obtained by triggering the glucocorticoid-induced TNF receptor-related (GITR), a costimulatory molecule expressed by Teff and Tregs, and by inhibiting the programmed cell death (PD)-1 receptor, an inhibitory molecule expressed by Teff. Patent W02015026684A1 provides a method of treating human tumors using a combination of a molecule triggering GITR and another inhibiting PD-1. The treatment approach was tested on three murine models of cancer, and the synergic effect of antihuman antibodies (Abs) in combination was tested in mixed lymphocyte reactions. Immune checkpoint treatment can break tolerance toward tumors and promote tumor rejection. The patented approach is very interesting and might be successful. The combined use of PD-1 antagonists and GITR agonists is synergic and tumor-centered, and adverse events might be less problematic than expected. A crucial point in translating the murine studies to humans is the differences between murine and human GITR and the evidence that some antihuman GITR Abs are not agonists.

KEYWORDS:

• Immune checkpoint treatment
• co-accessory molecules
• GITR (glucocorticoid-induced TNF receptor-related molecule)
• PD-1 (programmed cell death 1)
• combination treatment
• Tregs (regulatory T cells)
• TILs (tumor-infiltrating lymphocytes)
• solid tumors

Declaration of interest

G Nocentini was an Amgen Consultant in 2014, providing information relating to GITR as a therapeutic target in cancer; his studies were supported by the Ministero dell’Istruzione dell’Università e della Ricerca (MIUR) under grant number 2008SKTMME_003 for a project titled “Modulation of T lymphocyte activity in autoimmune diseases.” C Riccardi was supported by the MIUR, under grant number 2006052432_001, for two projects titled “GITR-derived signals in T lymphocyte regulation” and “Identification of new pharmacological targets for treating allodynia and peripheral and central immune-inflammation.” C Riccardi was also supported by Associazione Italiana per la Ricerca contro il Cancro (AIRC) under grant numbers IG-10677 and IG-14291. Authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. All this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Writing assistance was utilized in the production of this manuscript, in the form of English editing by BioScience Writers, LLC, funded by the above disclosed AIRC grant number IG-14291 to C Riccardi.