Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8⁺ T cells

Abstract

Numerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy. Furthermore, dual CTLA-4/PD-1 checkpoint blockade recently received FDA-approval for patients with metastatic melanoma, becoming the first combination immunotherapy to garner this designation in a rapidly evolving field. Despite this progress, the majority of patients do not respond to treatment, underscoring the critical need for more effective therapies. We have been investigating the mechanisms by which combination immunotherapy with an OX40 agonist plus CTLA-4 checkpoint blockade augments effector T cell responses to elicit anti-tumor immunity. Surprisingly, this approach failed to eradicate well-established tumors, in part due to the induction of anergy in cytotoxic CD8+ T cells. Further work revealed that anergic CD8+ T cells could be rescued by combining a dendritic cell-targeted vaccine with combination immunotherapy. Taken together, these data suggest that novel combinatorial immunotherapeutic strategies incorporating a vaccination strategy may be needed to generate effective anti-tumor responses in the majority of patients with metastatic disease.

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

“…Our demonstration that an OX40 agonist can tilt the immune response toward HBV clearance in young mice and in adult chronic mice that encountered antigen when they were young opens new avenues for treating CHB in humans. Preclinical studies using tumor models demonstrate that tumorassociated, antigenspecific CD8 + T cells increase in quantity after OX40 agonist immunotherapy, and OX40 agonists, plus and minus checkpoint blockade, lead to reduced tumor growth and improved overall sur vival (25)(26)(27)(28). Our data suggest that the OX40/OX40L pathway is crucial for effective HBV immunity and that OX40 agonists have po tential in definitively treating CHB by augmenting the virusspecific T cell response.…”

Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

“…Tumor evasive properties are probably fine-tuned to be activated in the wake of a profound T E response which may limit cytolytic functions. Possibly evasive mechanisms include down-regulation of MHC Class I that prevents T E cells from engaging their tumor target [42], the recruitment of regulatory T cells that can directly and indirectly (modulation of cytokine environment) impairs T E function [43] and the up-regulation of checkpoint ligands such as PD-L1 that are known to engage PD-1 on T E cells and interfere with TCR signaling, impairing cytolytic function [44]. Overall, the results of this study highlights the complexity of a two-way cross-regulation between host immunity and a rapidly growing tumor.…”

In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters

“…Highly immunogenic tumor-derived neo-epitopes must be present to be recognized by cytotoxic T cells. Antigen (Ag)-loaded dendritic cells (DCs) are the most commonly used cell-based vaccines with proven safety and, notably, the capability of providing long-lasting protective immunity [ 2 – 4 ]. As such, vaccines hold promise to delay or prevent cancer recurrence, particularly in early-stage disease patients, when immune-suppressive mechanisms are not firmly established.…”