Chimeric antigen receptor (CAR) T cells are a form of autologous immunotherapy that has changed the therapeutic landscape of hematologic malignancies. CAR T cell therapy involves collection of a ...patient’s T cells by apheresis, ex vivo genetic modification of the T cells to encode a synthetic receptor that binds a specific tumor antigen, and infusion of the T cells back into the patient. With the unprecedented success of CAR T cells in leukemia and lymphoma, a growing number of preclinical studies and clinical trials have focused on translating this treatment to solid tumors. In non-hematologic malignancies, however, response rates have been much less favorable. Some of the most significant challenges for CAR T cell immunotherapy in solid cancers include a paucity of unique tumor target antigens, limited CAR T cell trafficking to tumor sites, tumor heterogeneity and antigen loss, and the severely immunosuppressive tumor microenvironment. This review article provides an update on completed and ongoing clinical trials of CAR T cells for solid tumors, as well as an overview of strategies to improve CAR T cell efficacy in non-hematologic malignancies.
In this CCR Translations, we discuss pharmacologic ascorbate as a novel therapeutic for glioblastoma (GBM). Aberrant iron metabolism in GBM can be assessed noninvasively by MRI and exploited to ...potentially improve the efficacy of chemoradiotherapy. We contextualize the study's results and discuss the next steps to further develop this paradigm. See related article by Petronek et al., p. 283.
BACKGROUND
Disparities in healthcare access and delivery, caused by transportation and health workforce difficulties, negatively impact individuals living in rural areas. These challenges are ...especially prominent in older adults.
DESIGN
We systematically evaluated the feasibility, acceptability, and effectiveness in providing telemedicine (TMed), searching the English‐language literature for studies (January 2012 to July 2018) in the following databases: Medline (PubMed); Cochrane Library (Wiley); Web of Science; CINAHL; EMBASE (Ovid); and PsycINFO (EBSCO).
PARTICIPANTS
Older adults (mean age = 65 years or older, and none were younger than 60 years).
INTERVENTIONS
Interventions consisted of live, synchronous, two‐way videoconferencing communication in nonhospital settings. All medical interventions were included.
MEASUREMENTS
Quality assessment, using the Cochrane Collaboration's Risk‐of‐Bias Tool, was applied on all included articles, including a qualitative summary of all articles.
RESULTS
Of 6616 citations, we reviewed the full text of 1173 articles, excluding 1047 that did not meet criteria. Of the 17 randomized controlled trials, the United States was the country with the most trials (6 35%), with cohort sizes ranging from 3 to 844 (median = 35) participants. Risk of bias among included studies varied from low to high. Our qualitative analysis suggests that TMed can improve health outcomes in older adults and that it could be used in this population.
CONCLUSIONS
TMed is feasible and acceptable in delivering care to older adults. Research should focus on well‐designed randomized trials to overcome the high degree of bias observed in our synthesis. Clinicians should consider using TMed in routine practice to overcome barriers of distance and access to care. J Am Geriatr Soc 67:1737–1749, 2019
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a ...pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients ...revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.
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•EGFRA289D/T/V-mutated GBM tumors have distinct in vivo imaging characteristics•EGFRA289D/T/V-associated decrease in OS is driven by tumor proliferation and invasion•EGFRA289V leads to phosphorylation of Erk followed by increased MMP1 secretion•Targeting of EGFRA289V via mAb806 can reduce tumor growth and increase survival
Binder et al. show that glioblastoma (GBM) expressing EGFR A289 mutants exhibit invasive features and are associated with shorter survival in patients and mice. GBM cells expressing EGFRA289V increase ERK-dependent MMP1 expression but are sensitive to an EGFR monoclonal antibody being clinically developed.
In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. ...Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.
Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of ...intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×10
cells; n = 3) and dose level 2 (2.5 × 10
cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .
Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when ...dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA
or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.
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