Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank

Abstract

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.

Keywords: clinical trial; conference report; glioblastoma; immunosuppression; immunotherapy.

Fig. 1

Bystander T cells in the tumor microenvironment. Schematic representation of the source and nature of T cells present in tumors. Tumors contain neoantigen-specific, tumor-specific, and viral-specific T cells that may be distinguished by CD39 expression. Concepts based on results are presented in Simoni et al.

Fig. 2

Potential types of T-cell dysfunction relevant for neuro-oncology. Summary of the major factors contributing to T-cell dysfunction.

Fig. 3

Interaction of cells and molecules as potential targets for immunotherapy. A large number of immunoregulatory cells, cell-surface molecules, and secreted cytokines and chemokines regulate the immune response to tumors and help define the tumor microenvironment. Effective immunotherapy with vaccines or adoptively transferred T cells will likely require overcoming many of these immunosuppressive agents. To block each one individually is a Herculean task, so we need to identify nodes at which these suppressive pathways intersect, to allow simultaneous inhibition of many of them. Transforming growth factor (TGF)-β may be one such node, as it plays a critical role in immune escape as it is able to suppress CD8⁺ T cells and activate regulatory T cells. TGF-β is made by many cells, including tumor cells, as well as myeloid-derived suppressor cells (MDSCs) when stimulated by interleukin (IL)-13 from type II natural killer T (NKT) cells. Type II NKT cells also inhibit protective type I NKT cells and make IL-13 that can induce M2 macrophages. All of these and the Tregs induced by TGF-β can inhibit CD8 anti-tumor T cells. Thus, TGF-β and the cells it acts upon are central to a complex circuity involving several different cell types and cytokines, positioning TGF-β at the intersection of multiple immunosuppressive mechanisms that could be targeted simultaneously by blocking this one cytokine.

Fig. 4

Replication-competent viruses infect tumor cells and activate immune responses. As they lead to tumor cell cytotoxicity and spread an infection to surrounding tumor cells, innate immune cells, such as macrophages, are activated and release cytokines, inflaming the tumor microenvironment. Lysis of tumor cells is thought to improve antigen presentation and infiltration of activated effector T cells against tumor and viral antigens. This leads to durable antitumor responses (adapted from Chiocca et al.).

Fig. 5

Neoadjuvant trial design schema. A factorial approach facilitates the simultaneous evaluation of several combinations of agents (Drug X + placebo, Drug Y + placebo, placebo + placebo, Drug X + Drug Y). By applying a therapy and then undergoing resection to obtain tissue, neoadjuvant studies provide a systematic method of isolation of pharmacodynamics, immune, and clinical effects of treatment.

Fig. 6

The roadmap.