Immunotherapy of malignant brain tumors

Abstract

Despite aggressive multi-modality therapy including surgery, radiation, and chemotherapy, the prognosis for patients with malignant primary brain tumors remains very poor. Moreover, the non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues. Thus, there is an urgent need for the development of therapeutic strategies that precisely target tumor cells while minimizing collateral damage to neighboring eloquent cerebral cortex. The rationale for using the immune system to target brain tumors is based on the premise that the inherent specificity of immunologic reactivity could meet the clear need for more specific and precise therapy. The success of this modality is dependent on our ability to understand the mechanisms of immune regulation within the central nervous system (CNS), as well as counter the broad defects in host cell-mediated immunity that malignant gliomas are known to elicit. Recent advances in our understanding of tumor-induced and host-mediated immunosuppressive mechanisms, the development of effective strategies to combat these suppressive effects, and a better understanding of how to deliver immunologic effector molecules more efficiently to CNS tumors have all facilitated significant progress toward the realization of true clinical benefit from immunotherapeutic treatment of malignant gliomas.

Fig. 1. CD25 and CTLA-4 blockade: complementary strategies to overcome regulatory T-cell immunosuppression

Systemic CTLA-4 blockade in experimental mice enhances CD4⁺CD25⁻ T-cell proliferation and makes them resistant to Treg-mediated suppression but does not alter Treg function (373). Systemic anti-CD25 administration only partially depletes Tregs but renders remaining Tregs incapable of mediating T-cell suppression (142). Thus, CD25 and CTLA-4 blockade represent potentially complementary strategies for overcoming Treg-mediated immunosuppression in patients with malignant glioma. The diagram shows potential synergistic effects of anti-CTLA-4 and anti-CD25 mAb treatment in enhancing activation of tumor-specific lymphocytes. Antigen released by dying tumor cells is taken up and processed by resident or infiltrating APCs and presented as peptides to CD4⁺ and CD8⁺ T cells. Tregs, which are elevated in proportion in patients with malignant glioma, attenuate these responses through interaction with APCs and T cells, and these suppressive effects may be counteracted through anti-CD25 treatment to partially deplete Tregs and functionally inactivate remaining Tregs as well as through CTLA-4 blockade, which renders activated effector cells resistant to Treg-mediated immunosuppression.