Cell therapy for brain tumors: The first 60 years

Abstract

Primary brain tumors remain among the most lethal cancers, but immunotherapy holds immense potential to overcome limitations of current standard treatment modalities. Since the late 1960s, early-phase clinical trials have iteratively tested cellular immunotherapies for the treatment of brain tumors. Six decades ago, in the earliest studies, brain tumor patients were treated with infusions of nonspecific leukocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells. These earliest studies demonstrated safety and occasional durable antitumor responses, particularly when cell therapies were combined with conventional modalities or administered in the upfront setting. These early cell therapy approaches were chronologically followed by lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), ex vivo nonspecifically expanded and antigen-specific T cells, natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells. In this historical review, we summarize the clinical experience with adoptive cell therapies for brain tumors and review key findings from published clinical studies.

Graphical abstract

Figure 1

The 60-year evolution of cell therapy trials for brain tumors (A) A timeline of key clinical milestones in cellular immunotherapy for brain tumors; year of publication is shown unless the year of infusion was reported in the publication (denoted by ∗). PubMed Identifier, PMID; for the 1972 study with no PMID, see Takakura et al. (B) A timeline representing the progression of clinical implementation of major cell therapy products for brain tumors (Leukos, PBMCs, BM, leukocytes, peripheral blood mononuclear cells, bone marrow; LAKs, lymphokine-activated killer cells; TILs, tumor-infiltrating lymphocytes; NKs, natural killer cells; CARTs, chimeric antigen receptor T cells). (C) Total number of patients infused with the different major cell therapy products in clinical trials for brain tumors.