Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage?

Abstract

Immunotherapy of cancer is living through a revolutionary period prompted by the extraordinary efficacy results of antibodies blocking CTLA-4 or PD-1/PD-L1 against a variety of solid cancers [1,2]. In parallel, durable clinical responses are achieved by adoptive T cell therapy against B cell lineage leukemias and lymphomas, using genetransduced T lymphocytes to express chimeric antigen receptors recognizing the B cell marker CD19 [3][4][5]. Very likely, significant additional benefit of innovative immunotherapy will result from combinatorial approaches [1,2], as recently reported by combining anti-PD1-and anti-CTLA-4-targeted therapy in a phase III clinical trial for metastatic melanoma patients [6] that was conducive to FDA approval. As yet clinically unexplored avenue, combining adoptive T cell therapy with immune-augmenting strategies could additionally increase the efficacy of immune control in solid tumors and improve outcome.CD137 (4-1BB, tnfrsf9) is a surface receptor of the TNF receptor family that is expressed by activated but not resting T lymphocytes and NK cells [7]. Expression on T cells requires antigen recognition since it requires intense signaling through the antigen receptor complex. Therefore, only T cells that have been antigen-primed acquire the expression of CD137, the downstream signaling of which promotes T cell proliferation, memory differentiation, and effector functions and further prevents T cell apoptosis [8]. Under physiological circumstances, this receptor is ligated by CD137 ligand (4-1BB ligand), an agonist membrane molecule expressed by professional antigen-presenting cells, but also by some tumor cells. In order to exploit this pathway therapeutically, monoclonal antibodies which achieve much stronger, supraphysiological stimulation of CD137 signaling were designed to enhance costimulation of CD8 T lymphocytes and strongly improve the defense against syngeneic Abstract CD137(4-1BB) costimulation and adoptive T cell therapy strongly synergize in terms of achieving maximal efficacy against experimental cancers. These costimulatory biological functions of CD137 have been exploited by means of introducing the CD137 signaling domain in clinically successful chimeric antigen receptors and to more efficiently expand T cells in culture. In addition, immunomagnetic sorting of CD137-positive T cells among tumor-infiltrating lymphocytes selects for the fittest antitumor T lymphocytes for subsequent cultures. In mouse models, co-infusion of both agonist antibodies and T cells attains marked synergistic effects that result from more focused and intense cytolytic activity visualized under in vivo microscopy and from more efficient entrance of T cells into the tumor through the vasculature. These several levels of dynamic interaction between adoptive T cell therapy and CD137 offer much opportunity to raise the efficacy of current cancer immunotherapies.

Allergen‐specific immunotherapy enhances CD8+ CD25+ CD137+ regulatory T cells and decreases nasal nitric oxide

“…However, the significance of such mechanisms being proposed in CD137‐based immunotherapy remains to be completely elucidated. Immunomagnetic sorting of CD137‐positive T cells among tumor‐infiltrating lymphocytes offers a great opportunity to raise the efficacy of current cancer immunotherapies . In summary, functional control of CD8 + Tregs by TLR2 signaling via CD137 stimulation may offer new avenues toward developing a valuable potential target during AIT.…”

Cancer immunotherapy: broadening the scope of targetable tumours

“…Additional research will be important to address resistance to first-generation immune checkpoint blockers as, for instance, LAG-3 and TIM-3 upregulation is observed following anti-PD-1 treatment [ 86 ]. Likewise, CD137 co-stimulation is studied for its synergistic effects with ACT [ 91 , 92 ]. Finally, checkpoint blockade therapies may also be used in combination with standard chemo- and radiotherapy interventions which are known to enhance tumour immunogenicity [ 93 , 94 ].…”

Review of Approaches to Immunotherapy in Oncology

“…Одна из наиболее изученных молекул данного семейства -4-1BB (CD137, tumor necrosis factor receptor superfamily, member 9), экспрессируемая на поверхности Т-лимфоцитов, NK-клеток и моноцитов [49]. Стимуляция Т-клеток с помощью специфичного лиганда, 4-1BBL, синтезируемого антигенпрезентирующими клетками, через каскад реакций и регуляторов приводит к уменьшению частоты апоптоза лимфоцитов [52,53]. Доклинические исследования показали противоопухолевый эффект антител -агонистов 4-1BB как в условиях монотерапии, так и в комбинации с различными видами иммунотерапии [54,55].…”

“…При проведении клинического исследования урелумаба применение человеческого антителаагониста к 4-1 ВВ продемонстрировало хороший клинический эффект у пациентов с меланомой, сочетавшийся, однако, с жизнеугрожающими нежелательными явлениями, что привело к отмене последующего клинического исследования 2-й фазы [56]. В настоящий момент изучается возможность применения урелумаба в комбинациях с другими терапиями, чтобы минимизировать дозозависимые побочные эффекты [53].…”