Immunotherapy for Brain Cancer: Recent Progress and Future Promise

Abstract

Immunotherapy is emerging as the newest pillar of cancer treatment, with the potential to assume a place alongside surgical debulking, radiotherapy, and chemotherapy. Early experiences with antitumor vaccines demonstrated the feasibility and potential efficacy of this approach, and newer agents, such as immune checkpoint blocking antibodies and modern vaccine platforms, have ushered in a new era. These efforts are headlined by work in melanoma, prostate cancer, and renal cell carcinoma; however, substantial progress has been achieved in a variety of other cancers, including high-grade gliomas. A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiotherapy and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also use an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas, and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology.

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…5,6 Robust and durable clinical benefits of immunotherapeutic strategies in tumors such as melanoma, prostate cancer, and leukemia have been achieved, and this has driven research efforts into developing a variety of immunotherapeutic strategies for GBMs. 2,[7][8][9][10][11][12] While, traditionally, it was accepted that the CNS was an immuneprivileged organ, recent research has challenged that dogma. 4 The evidence for permeability of the blood-brain barrier (BBB) under conditions of inflammation and tumor growth, such as in GBMs, the presence of lymphatic drainage, and the antigen-presenting ability of microglial cells reveals a more dynamic interaction of the central nervous system (CNS) with the systemic immune system.…”

Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma

“…Moreover, tumor cells have been killed following direct immunization experiments using vaccines in mice, indicating its role in specific protective immunity and tumor destruction mediated by immune cells, such as microglia/macrophages (3). These immunotherapies exert a highly specific, long-term fatal effect on tumor cells by stimulating and supplementing the body's antitumor immunity (4,5), with only minimal adverse reactions (6). However, in the past decade, the main debate has focused on whether immunity exhibits an antitumor role in the CNS or functions as a tumor growth promoter (7).…”

Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma

“…ACHN, 786-0 and RuCa cells (5x10 5 /ml) were cultured in 96well plates for 24 h at 5% CO 2 and 37˚C and incubated with lenvatinib (0.1 mg/ml; Sunbio Inc.) and/or sensitized lymphocytes (1x10 5 /ml; Sunbio Inc.) for 48, 72 and 96 h at 37˚C in triplicate for each condition. Phosphate buffered saline (PBS) was added instead of the lenvatinib or sensitized lymphocytes to act as a control.…”

“…Cellular immunotherapy has the potential to be a highly targeted alternative to these therapies, with a high capacity to eradicate tumors and low toxicity to normal tissues (2)(3)(4). Cellular immunotherapy often employs active immunization with cells, peptides, proteins or nucleic acids, as well as utilizing adoptive transfer of effector cells that directly target antigens on malignant cells (5). A variety of these approaches have been demonstrated to be successful in treating ovarian and lung cancer (6,7).…”