Next-generation immunotherapies for brain metastatic cancers

Brain microenvironment plays a key role in the development of brain metastases (BM). Interaction between the different cell populations within the brain and the metastatic tumor cells is crucial for the establishment of the metastatic niche and the progression of BMs. Immune cells promptly infiltrate the tumor microenvironment (TME) and interact with metastatic tumor cells early in the formation of BMs. The ability of BMs to escape immune surveillance hinders the initial efforts of the immune system to mount an effective immune response towards the tumor, resulting in an ultimately immunosuppressive TME that contributes to the growth of the metastases. Recent understandings of the brain immunology and immune/tumor crosstalk have resulted in an increasing number of preclinical and clinical trials for immunotherapies in BM patients. The success of immune-based therapies in other malignancies, together with the encouraging results for cell- and vaccine-based immunotherapies in preclinical models, suggests that immunotherapy could potentially fill the unmet need for treatment of BMs. Patients with extracranial tumors, like lung, breast, and skin cancers, often develop brain metastases (BM) during the course of their diseases and BM commonly represent the terminal stage of cancer progression. Recent insights in the immune biology of BM and the increasing focus of immunotherapy as a therapeutic option for cancer has prompted testing of promising biological immunotherapies, including immune cell-targeting, virotherapy, vaccines, and different cell-based therapies. Here, we review the pathobiology of BM progression and evaluate the potential of next-generation immunotherapies for BM tumors. We also provide future perspectives on the development and implementation of such therapies for brain metastatic cancer patients. Patients with extracranial tumors, like lung, breast, and skin cancers, often develop brain metastases (BM) during the course of their diseases and BM commonly represent the terminal stage of cancer progression. Recent insights in the immune biology of BM and the increasing focus of immunotherapy as a therapeutic option for cancer has prompted testing of promising biological immunotherapies, including immune cell-targeting, virotherapy, vaccines, and different cell-based therapies. Here, we review the pathobiology of BM progression and evaluate the potential of next-generation immunotherapies for BM tumors. We also provide future perspectives on the development and implementation of such therapies for brain metastatic cancer patients. adoptive chimeric receptor (CAR)-T cell therapy consists of generically modifying T cells expressing CARs that can target and bind to antigens expressed on tumor cells. Once these CAR-T cells are transferred back to the patients, an adaptive immune response against the tumor is induced. highly selective barrier that imposes a physical boundary between the CNS and the rest of the body, regulating the entry of ions, molecules, and cells into the brain and spinal cord. secondary brain tumor originated from cancer cells that have spread to the brain from primary tumor sites. mostly composed of tumor-derived peptides or ex vivo maturated cells, mainly DCs. Once implanted in a patient, induces an immune response towards the tumor. enzyme that hydrolyzes the prodrug CPT-11 to an inhibitor of the topoisomerase 1. form of treatment that aims at boosting the immune system of the patient to recognize and attack tumor cells. main regulators of immune pathways. Interaction of immune checkpoint receptors, such as PD-1 or CTLA-4, expressed on T cells and their respective ligands expressed on tumor cells and a number of immune cells within the TME leads to inactivation of TCR signaling and T cell elimination. spreading of cancer cells from primary tumor sites to distal organs. term used to describe the transformation associated with acquired metastatic capability, the journey of tumor cells through blood vessels or lymphatic system, and formation of new colonies that grow into metastatic tumors in a specific organ. virus that is able to selectively replicate inside tumor cells while sparing normal, healthy cells, eventually causing immunogenic cell death and evoking strong immune response locally. undifferentiated cells with the potential to self-renewal and to develop into multiple cell lineages. They are able to migrate to different tissues (‘homing’) as part of normal homeostasis or in response of signals of damage, such as inflammatory cytokines released by the TME. TNF-related apoptosis inducing ligand, a proapoptotic cytokine that induces cell death via the extrinsic apoptosis pathway upon binding to its receptors DR4/5. talimogene laherparepvec, an oncolytic herpes simplex virus engineered to express human GM-CSF and approved for clinical use in melanoma patients.