Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. We anticipate these modifications will further expand CAR T cell therapy in clinical practice.

Pharmacophore multiplets are useful tools for 3D database searching, with the queries used ordinarily being derived from ensembles of random conformations of active ligands. It seems reasonable to expect that their usefulness can be augmented by instead using queries derived from single ligand conformations obtained from aligned ligands. Comparisons of pharmacophore multiplet searching using random conformations with multiplet searching using single conformations derived from GALAHAD (a genetic algorithm with linear assignment for hypermolecular alignment of datasets) models do indeed show that, while query hypotheses based on random conformations are quite effective, hypotheses based on aligned conformations do a better job of discriminating between active and inactive compounds. In particular, the hypothesis created from a neuraminidase inhibitor model was more similar to half of 18 known actives than all but 0.2% of the compounds in a structurally diverse subset of the World Drug Index. Similarly, a model developed from five angiotensin II antagonists yielded hypotheses that placed 65 known antagonists within the top 0.1-1% of decoy databases. The differences in discriminating power ranged from 2 to 20-fold, depending on the protein target and the type of pharmacophore multiplet used.

The current treatment of relapsed or refractory AML is associated with low rates of complete response (CR) and considerable complications. As a result, only a minority of patients (pts) proceed to allogeneic hematopoietic stem cell transplantation (alloHSCT) with curative intent. Furthermore, outcomes for AML pts with disease relapse after alloHSCT are dismal. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and incurable blood cancer with a median survival of <18 months and no standard of care. Thus, there are clear unmet therapeutic needs in both these conditions. CD123 is overexpressed on AML blasts and leukemic stem cell (LSC)-enriched cell subpopulations compared to normal hematopoietic stem cells and myeloid progenitors. High levels of CD123 expression is also one of the diagnostic hallmarks for BPDCN. All these features make CD123 an attractive target for T cell based adoptive immunotherapy. We have previously demonstrated preclinically the anti-AML activity of CD123-chimeric antigen receptor (CAR) T cell therapy (Mardiros, Blood 2013). The CD123CAR contains an anti-CD123 single-chain variable fragment, an optimized IgG4 CH2CH3 linker, a CD28 co-stimulatory domain, and a CD3 zeta signaling domain and is used to engineer T cells for patients enrolled on a single center, first-in-human phase I dose escalation clinical trial open at our Institution (NCT02159495). The primary objective is to test the safety and activity of escalating doses of CD123CAR T cells for patients with relapsed or refractory AML (cohort 1) and BPDCN (cohort 2). Donor-derived or autologous T cells from leukapheresed peripheral blood mononuclear cells were lentivirally transduced with the CD123CAR vector. Prior to T cell infusion, all patients undergo a lymphodepleting regimen including fludarabine 25-30 mg/m2 daily for 3 days and cyclophosphamide 300 mg/m2 daily for 3 days. Pts receive a single dose of CD123CAR T cells with an option for a second infusion if they continue to meet safety and eligibility criteria and still have CD123+ disease. To date, 14 patients have been enrolled and 7 treated (6 AML, 1 BPDCN). All 6 patients in the AML cohort had refractory AML following alloHSCT, and a median of 4 (range: 4-7) prior lines of therapy. Of the 2 pts treated at dose level (DL) 1 (50M CAR+ T), 1 achieved a morphologic leukemic-free state, which lasted 2 months. She received a second infusion 3 months later with subsequent blast reduction from 77.9% to 0.9% (flow cytometry) after 35 days. Of the 4 pts on DL 2 (200M CAR+ T), 1 achieved CR and became transfusion independent. She proceeded to a second alloHSCT on day 70. Restaging on day +161 post-transplant showed she has remained in MRD-negative CR with good engraftment and 100% donor chimerism. Another pt with CR prior to treatment remained in CR at day 28 and has proceeded to a second alloHSCT. The remaining 2 patients had reductions in blast counts, but did not achieve remission. All toxicities were reversible and manageable: cytokine release syndrome (CRS; 4 grade 1, 1 grade 2); 1 adenoviral pneumonia requiring intubation; and 1 grade 3 rash due to drug hypersensitivity. There were no dose limiting toxicities and no treatment-related cytopenias. One pt with prior alloHSCT had mild recurrent cutaneous GVHD, which occurred after the completion of CAR T treatment. Correlative studies including T cell persistence and CD123 expression are underway and will be reported. In the BPDCN cohort, 1 pt has been treated so far, a 74-year-old man with a persistent bulky subcutaneous mass after clinical trial treatment with a CD123 antibody-drug conjugate. Following lymphodepletion, he received a single dose of 100M autologous CD123CAR T cells and continues to be in CR at 60 days post-infusion. Skin biopsies at the tumor site on days 14 and 28 showed no evidence of disease. Restaging work-up at day 28 revealed disease-free bone marrow, no new masses by CT scan, normalized blood counts, and complete resolution of clinical symptoms. The pt tolerated the treatment well with no CRS or neurologic toxicity. In this first-in-human clinical trial of CD123CAR T cell therapy, we have demonstrated the feasibility and safety of targeting CD123. We have also observed promising anti-leukemic activity in both AML and BPDCN. Importantly, no myeloablative effects have been observed, supporting further testing of this immunotherapeutic strategy in both transplant eligible and ineligible patients. Disclosures Stein: Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau.

Since the establishment of the Journal of Medical Case Reports in 2006, the number of journals that publish case reports has increased rapidly, and most of these journals are open access. Open access publishing usually requires authors to pay publication fees while offering the articles online, free of charge, and free of most copyright and licensing restrictions. The movement for open access has gained support in the research community, with the publishers BioMed Central and PLOS ONE becoming leaders in scientific publishing in their number of articles and citations. As the number of open access publishers has exploded, so too has the number of publishers that act in bad faith to profit from the open access model. Simple guidelines have been developed and resources are available to help authors choose a suitable journal for publication of their case reports.