title: Immunotherapy for neuro-oncology: the critical rationale for combinatorial therapy.
abstract: A successful therapeutic paradigm established historically in oncology involves combining agents with potentially complementary mechanisms of antitumor activity into rationally designed regimens. For example, cocktails of cytotoxic agents, which were carefully designed based on mechanisms of action, dose, and scheduling considerations, have led to dramatic improvements in survival including cures for childhood leukemia, Hodgkin's lymphoma, and several other complex cancers. Outcome for glioblastoma, the most common primary malignant CNS cancer, has been more modest, but nonetheless our current standard of care derives from confirmation that combination therapy surpasses single modality therapy. Immunotherapy has recently come of age for medical oncology with exciting therapeutic benefits achieved by several types of agents including vaccines, adoptive T cells, and immune checkpoint inhibitors against several types of cancers. Nonetheless, most benefits are relatively short, while others are durable but are limited to a minority of treated patients. Critical factors limiting efficacy of immunotherapeutics include insufficient immunogenicity and/or inadequate ability to overcome immunosuppressive factors exploited by tumors. The paradigm of rationally designed combinatorial regimens, originally established by cytotoxic therapy for oncology, may also prove relevant for immunotherapy. Realization of the true therapeutic potential of immunotherapy for medical oncology and neuro-oncology patients may require development of combinatorial regimens that optimize immunogenicity and target tumor adaptive immunosuppressive factors.
authors.affiliation: Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Neurology Clinic and National Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (M.R.G.); Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W); Brain Tumor Program, Department of Neurosurgery, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, California (L.L.).
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Neurology Clinic and National Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (M.R.G.); Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W); Brain Tumor Program, Department of Neurosurgery, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, California (L.L.).
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Neurology Clinic and National Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (M.R.G.); Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W); Brain Tumor Program, Department of Neurosurgery, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, California (L.L.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (D.A.R.); Neurology Clinic and National Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (M.R.G.); Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W); Brain Tumor Program, Department of Neurosurgery, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, California (L.L.).
authors.forename: Linda
authors.initials: L
authors.lastname: Liau
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009423:Nervous System Neoplasms / Q000628:therapy*
keywords: glioblastoma; immune checkpoint; immunotherapy; programmed-death 1; vaccine