Switching to burosumab from conventional therapy in siblings with relatively well-controlled X-linked hypophosphatemia.

Burosumab, a fully human monoclonal antibody against fibroblast growth factor 23, is mainly administered to patients with severe X-linked hypophosphatemia (XLH). However, there have been few reports on its use in relatively mild cases. In this report, we administered burosumab to two siblings with XLH who had been effectively treated with oral phosphate and active vitamin D. Both patients showed further improvement in radiographic and laboratory findings with burosumab compared with conventional treatment. Upon switching treatment, popliteal pain was reported in case 1 until her phosphorus levels normalized. This emphasizes the importance of monitoring not only rickets and calcium/phosphate metabolism but all symptoms of XLH after initiating burosumab. Notably, in cases 1 and 2, burosumab sustained catch-up growth, especially in case 1, who had not yet reached puberty. Further clinical studies are needed to determine whether burosumab improves growth and proportional abnormalities in patients with mild XLH.

Internet search analysis on the treatment of rheumatoid arthritis: What do people ask and read online?

OBJECTIVES: This study aimed to characterize the content of frequently asked questions about the treatment of rheumatoid arthritis (RA) on the internet in Japan and to evaluate the quality of websites related to the questions. METHODS: We searched terms on the treatment of RA on Google and extracted frequently asked questions generated by the Google "people also ask" function. The website that answered each question was also obtained. We categorized the questions based on the content. The quality of the websites was evaluated using the brief DISCERN, Journal of American Medical Association benchmark criteria, and Clear Communication Index. RESULTS: Our search yielded 83 questions and the corresponding websites. The most frequently asked questions were regarding the timeline of treatment (n = 17, 23%) and those on the timeline of the clinical course (n = 13, 16%). The median score of brief DISCERN was 11 points, with only 7 (8%) websites having sufficient quality. Websites having sufficient quality based on the Journal of American Medical Association benchmark criteria and Clear Communication Index were absent. CONCLUSIONS: The questions were most frequently related to the timeline of treatment and clinical course. Physicians should provide such information to patients with RA in the counseling and education materials.

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.

Exome-wide variation in a diverse barley panel reveals genetic associations with ten agronomic traits in Eastern landraces.

Barley (Hordeum vulgare ssp. vulgare) is one of the first crops to be domesticated and is adapted to a wide range of environments. Worldwide barley germplasm collections possess valuable allelic variations that could further improve barley productivity. Although barley genomics has offered a global picture of allelic variation among varieties and its association with various agronomic traits, polymorphisms from East Asian varieties remain scarce. In this study, we analyze exome polymorphisms in a panel of 274 barley varieties collected worldwide, including 137 varieties from East Asian countries and Ethiopia. We reveal the underlying population structure and conduct genome-wide association studies for 10 agronomic traits. Moreover, we examin genome-wide associations for traits related to grain size such as awn length and glume length. Our results demonstrate the value of diverse barley germplasm panels containing Eastern varieties, highlighting their distinct genomic signatures relative to Western subpopulations.

PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages.

BACKGROUND: The immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163+ M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear. METHODS: To model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14+ peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings. RESULTS: We observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163+ M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells. CONCLUSION: This study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.

Lowering the setting value of the esophageal endoscopic submucosal dissection device enabled tissue damage control in vitro porcine model.

One of the complications of esophageal endoscopic submucosal dissection (ESD) is postoperative stricture formation. Stenosis formation is associated with inflammation and fibrosis in the healing process. We hypothesized that the degree of thermal damage caused by the device is related to stricture formation. We aimed to reveal the relationship between thermal damage and setting value of the device. We energized a resected porcine esophagus using the ESD device (Flush Knife 1.5). We performed 10 energization points for 1 s, 3 s, and 5 s at four setting values of the device. We measured the amount of current flowing to the conducted points and the temperature and evaluated the effects of thermal damage pathologically. As results, the mean highest temperatures for 1 s were I (SWIFT Effect3 Wat20): 61.19 °C, II (SWIFT Effect3 Wat30): 77.28 °C, III (SWIFT Effect4 Wat20): 94.50 °C, and IV (SWIFT Effect4 Wat30): 94.29 °C. The mean heat denaturation areas were I: 0.84 mm2, II: 1.00 mm2, III: 1.91 mm2, and IV: 1.54 mm2. The mean highest temperature and mean heat denaturation area were significantly correlated (P < 0.001). In conclusion, Low-current ESD can suppress the actual temperature and thermal damage in the ESD wound.

A double-scope technique enabled a patient with an esophageal plastic fork foreign body to avoid surgery: a case report and review of the literature.

Foreign body ingestion is a common problem, and endoscopic removal is often performed with ancillary equipment. However, long, sharp foreign bodies are much more difficult to remove endoscopically than other objects and require emergent surgery. A 68-year-old man with a history of distal gastrectomy accidentally swallowed a plastic fork. He complained of chest pain at the visit. The plastic fork was located between the thoracic esophagus and remnant stomach. Endoscopic removal of the plastic fork was considered difficult, and surgery was deemed necessary. However, we were able to avoid surgery to remove the object using two endoscopes with hoods and a polypectomy snare. The first endoscope covered the sharp edge with a hood, and the snare grasped the neck of the plastic fork. The second endoscope covered the remaining sharp tip. A single operator held the two endoscopes and the snare and pulled them out together. This new double-scope technique is simple and useful for removing long, sharp foreign bodies, such as forks, from the esophagus.

Cellular and transcriptomic analyses reveal two-staged chloroplast biogenesis underpinning photosynthesis build-up in the wheat leaf.

BACKGROUND: The developmental gradient in monocot leaves has been exploited to uncover leaf developmental gene expression programs and chloroplast biogenesis processes. However, the relationship between the two is barely understood, which limits the value of transcriptome data to understand the process of chloroplast development. RESULTS: Taking advantage of the developmental gradient in the bread wheat leaf, we provide a simultaneous quantitative analysis for the development of mesophyll cells and of chloroplasts as a cellular compartment. This allows us to generate the first biologically-informed gene expression map of this leaf, with the entire developmental gradient from meristematic to fully differentiated cells captured. We show that the first phase of plastid development begins with organelle proliferation, which extends well beyond cell proliferation, and continues with the establishment and then the build-up of the plastid genetic machinery. The second phase is marked by the development of photosynthetic chloroplasts which occupy the available cellular space. Using a network reconstruction algorithm, we predict that known chloroplast gene expression regulators are differentially involved across those developmental stages. CONCLUSIONS: Our analysis generates both the first wheat leaf transcriptional map and one of the most comprehensive descriptions to date of the developmental history of chloroplasts in higher plants. It reveals functionally distinct plastid and chloroplast development stages, identifies processes occurring in each of them, and highlights our very limited knowledge of the earliest drivers of plastid biogenesis, while providing a basis for their future identification.

Introduction of precordial Doppler ultrasound to confirm correct peripheral venous access during general anesthesia in children: A preliminary study.

BACKGROUND: Delayed identification of infiltration and dysfunction of peripheral intravenous (PIV) access can lead to serious consequences during general anesthesia in children. This preliminary study aimed to describe the application of precordial Doppler ultrasound during general anesthesia in children to detect and confirm the correct PIV access and to evaluate the accuracy of this method. METHODS: This was a single-center, preliminary study that was conducted in children (<18 years) who were scheduled for elective surgeries between October 2019 and March 2020. Rater anesthesiologists judged the change in precordial Doppler sound (S test) before and after injection of 0.5 mL/kg of normal saline (NS) via PIV. Blood flow velocity before and after NS injection was recorded, and multiple cutoff points were set to analyze the accuracy of detecting the infiltration and dysfunction of PIV catheter (V test). RESULTS: The total incidence of peripheral infiltration and dysfunction of PIV catheter was 7/512 (1.4%). In the S test, the sensitivity, specificity, positive and negative likelihood ratios, and area under the receiver-operating characteristic curves (AUCs) were 5/7 (71.4%; 95% confidence interval [CI], 29.0%-96.3%), 490/505 (97.0%; 95% CI, 95.1%-98.3%), 24.0, 0.29, and 0.84, respectively. The V test showed that the reasonable threshold of blood flow velocity change was 1.0 m/s, with sensitivity, specificity, positive and negative likelihood ratios, and AUC of 4/7 (57.1%; 95% CI, 18.4%-90.1%), 489/505 (96.8%; 95% CI, 94.9%-98.2%), 18.0 and 0.44, and 0.84, respectively. CONCLUSIONS: This preliminary study demonstrated that precordial Doppler ultrasound is a feasible, easy-to-use, and noninvasive technique with good accuracy to confirm the correct PIV access during general anesthesia in children. However, its accuracy requires further evaluation.

Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity.

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.

Genetic Elucidation for Response of Flowering Time to Ambient Temperatures in Asian Rice Cultivars.

Climate resilience of crops is critical for global food security. Understanding the genetic basis of plant responses to ambient environmental changes is key to developing resilient crops. To detect genetic factors that set flowering time according to seasonal temperature conditions, we evaluated differences of flowering time over years by using chromosome segment substitution lines (CSSLs) derived from japonica rice cultivars "Koshihikari" × "Khao Nam Jen", each with different robustness of flowering time to environmental fluctuations. The difference of flowering times in 9 years' field tests was large in "Khao Nam Jen" (36.7 days) but small in "Koshihikari" (9.9 days). Part of this difference was explained by two QTLs. A CSSL with a "Khao Nam Jen" segment on chromosome 11 showed 28.0 days' difference; this QTL would encode a novel flowering-time gene. Another CSSL with a segment from "Khao Nam Jen" in the region around Hd16 on chromosome 3 showed 23.4 days" difference. A near-isogenic line (NIL) for Hd16 showed 21.6 days' difference, suggesting Hd16 as a candidate for this QTL. RNA-seq analysis showed differential expression of several flowering-time genes between early and late flowering seasons. Low-temperature treatment at panicle initiation stage significantly delayed flowering in the CSSL and NIL compared with "Koshihikari". Our results unravel the molecular control of flowering time under ambient temperature fluctuations.

BdWRKY38 is required for the incompatible interaction of Brachypodium distachyon with the necrotrophic fungus Rhizoctonia solani.

Rhizoctonia solani is a soil-borne necrotrophic fungus that causes sheath blight in grasses. The basal resistance of compatible interactions between R. solani and rice is known to be modulated by some WRKY transcription factors (TFs). However, genes and defense responses involved in incompatible interaction with R. solani remain unexplored, because no such interactions are known in any host plants. Recently, we demonstrated that Bd3-1, an accession of the model grass Brachypodium distachyon, is resistant to R. solani and, upon inoculation with the fungus, undergoes rapid induction of genes responsive to the phytohormone salicylic acid (SA) that encode the WRKY TFs BdWRKY38 and BdWRKY44. Here, we show that endogenous SA and these WRKY TFs positively regulate this accession-specific R. solani resistance. In contrast to a susceptible accession (Bd21), the infection process in the resistant accessions Bd3-1 and Tek-3 was suppressed at early stages before the development of fungal biomass and infection machinery. A comparative transcriptome analysis during pathogen infection revealed that putative WRKY-dependent defense genes were induced faster in the resistant accessions than in Bd21. A gene regulatory network (GRN) analysis based on the transcriptome dataset demonstrated that BdWRKY38 was a GRN hub connected to many target genes specifically in resistant accessions, whereas BdWRKY44 was shared in the GRNs of all three accessions. Moreover, overexpression of BdWRKY38 increased R. solani resistance in Bd21. Our findings demonstrate that these resistant accessions can activate an incompatible host response to R. solani, and BdWRKY38 regulates this response by mediating SA signaling.

Genetic Factors Associated with Heading Responses Revealed by Field Evaluation of 274 Barley Accessions for 20 Seasons.

Heading time is a key trait in cereals affecting the maturation period for optimal grain filling before harvest. Here, we aimed to understand the factors controlling heading time in barley (Hordeum vulgare). We characterized a set of 274 barley accessions collected worldwide by planting them for 20 seasons under different environmental conditions at the same location in Kurashiki, Japan. We examined interactions among accessions, known genetic factors, and an environmental factor to determine the factors controlling heading response. Locally adapted accessions have been selected for genetic factors that stabilize heading responses appropriate for barley cultivation, and these accessions show stable heading responses even under varying environmental conditions. We identified vernalization requirement and PPD-H1 haplotype as major stabilizing mechanisms of the heading response for regional adaptation in Kurashiki.

Parental legacy and regulatory novelty in Brachypodium diurnal transcriptomes accompanying their polyploidy.

Polyploidy is a widespread phenomenon in eukaryotes that can lead to phenotypic novelty and has important implications for evolution and diversification. The modification of phenotypes in polyploids relative to their diploid progenitors may be associated with altered gene expression. However, it is largely unknown how interactions between duplicated genes affect their diurnal expression in allopolyploid species. In this study, we explored parental legacy and hybrid novelty in the transcriptomes of an allopolyploid species and its diploid progenitors. We compared the diurnal transcriptomes of representative Brachypodium cytotypes, including the allotetraploid Brachypodium hybridum and its diploid progenitors Brachypodium distachyon and Brachypodium stacei. We also artificially induced an autotetraploid B. distachyon. We identified patterns of homoeolog expression bias (HEB) across Brachypodium cytotypes and time-dependent gain and loss of HEB in B. hybridum. Furthermore, we established that many genes with diurnal expression experienced HEB, while their expression patterns and peak times were correlated between homoeologs in B. hybridum relative to B. distachyon and B. stacei, suggesting diurnal synchronization of homoeolog expression in B. hybridum. Our findings provide insight into the parental legacy and hybrid novelty associated with polyploidy in Brachypodium, and highlight the evolutionary consequences of diurnal transcriptional regulation that accompanied allopolyploidy.

Genetic Variation for Seed Metabolite Levels in Brachypodium distachyon.

Metabolite composition and concentrations in seed grains are important traits of cereals. To identify the variation in the seed metabolotypes of a model grass, namely Brachypodium distachyon, we applied a widely targeted metabolome analysis to forty inbred lines of B. distachyon and examined the accumulation patterns of 183 compounds in the seeds. By comparing the metabolotypes with the population structure of these lines, we found signature metabolites that represent different accumulation patterns for each of the three B. distachyon subpopulations. Moreover, we found that thirty-seven metabolites exhibited significant differences in their accumulation between the lines Bd21 and Bd3-1. Using a recombinant inbred line (RIL) population from a cross between Bd3-1 and Bd21, we identified the quantitative trait loci (QTLs) linked with this variation in the accumulation of thirteen metabolites. Our metabolite QTL analysis illustrated that different genetic factors may presumably regulate the accumulation of 4-pyridoxate and pyridoxamine in vitamin B6 metabolism. Moreover, we found two QTLs on chromosomes 1 and 4 that affect the accumulation of an anthocyanin, chrysanthemin. These QTLs genetically interacted to regulate the accumulation of this compound. This study demonstrates the potential for metabolite QTL mapping in B. distachyon and provides new insights into the genetic dissection of metabolomic traits in temperate grasses.

Polysomnographic assessment of respiratory disturbance during deep propofol sedation for endoscopic submucosal dissection of gastric tumors.

AIM: To investigate that polysomnographic monitoring can accurately evaluate respiratory disturbance incidence during sedation for gastrointestinal endoscopy compare to pulse oximetry alone. METHODS: This prospective observational study included 10 elderly patients with early gastric cancer undergoing endoscopic submucosal dissection (ESD) under propofol sedation. Apart from routine cardiorespiratory monitoring, polysomnography measurements were acquired. The primary hypothesis was tested by comparing the apnea hypopnea index (AHI), defined as the number of apnea and hypopnea instances per hour during sedation, with and without hypoxemia; hypoxemia was defined as the reduction in oxygen saturation by ≥ 3% from baseline. RESULTS: Polysomnography (PSG) detected 207 respiratory disturbances in the 10 patients. PSG yielded a significantly greater AHI (10.44 ± 5.68/h) compared with pulse oximetry (1.54 ± 1.81/h, P < 0.001), thus supporting our hypothesis. Obstructive AHI (9.26 ± 5.44/h) was significantly greater than central AHI (1.19 ± 0.90/h, P < 0.001). Compared with pulse oximetry, PSG detected the 25 instances of respiratory disturbances with hypoxemia 107.4 s earlier on average. CONCLUSION: Compared with pulse oximetry, PSG can better detect respiratory irregularities and thus provide superior AHI values, leading to avoidance of fatal respiratory complications during ESD under propofol-induced sedation.

Transcriptional alterations during proliferation and lignification in Phyllostachys nigra cells.

Highly-lignified culms of bamboo show distinctive anatomical and mechanical properties compared with the culms of other grass species. A cell culture system for Phyllostachys nigra has enabled investigating the alterations in cellular states associated with secondary cell wall formation during its proliferation and lignification in woody bamboos. To reveal transcriptional changes related to lignification in bamboo, we analyzed transcriptome in P. nigra cells treated with the synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) and the synthetic cytokinin benzylaminopurine (BA) by RNA-seq analysis. We found that some genes putatively involved in cell wall biogenesis and cell division were up-regulated in response to the 2,4-D treatment, and the induction of lignification by the BA treatment was correlated with up-regulation of genes involved in the shikimate pathway. We also found that genes encoding MYB transcription factors (TFs) show correlated expression patterns with those encoding cinnamyl alcohol dehydrogenase (CAD), suggesting that MYB TFs presumably regulate secondary cell wall formation in the bamboo cells. These findings suggest that cytokinin signaling may regulate lignification in P. nigra cells through coordinated transcriptional regulation and metabolic alterations. Our results have also produced a useful resource for better understanding of secondary cell wall formation in bamboo plants.

Homoeolog-specific activation of genes for heat acclimation in the allopolyploid grass Brachypodium hybridum.

Background: Allopolyploid plants often show wider environmental tolerances than their ancestors; this is expected to be due to the merger of multiple distinct genomes with a fixed heterozygosity. The complex homoeologous gene expression could have been evolutionarily advantageous for the adaptation of allopolyploid plants. Despite multiple previous studies reporting homoeolog-specific gene expression in allopolyploid species, there are no clear examples of homoeolog-specific function in acclimation to a long-term stress condition. Results: We found that the allopolyploid grass Brachypodium hybridum and its ancestor Brachypodium stacei show long-term heat stress tolerance, unlike its other ancestor, Brachypodium distachyon. To understand the physiological traits of B. hybridum, we compared the transcriptome of the 3 Brachypodium species grown under normal and heat stress conditions. We found that the expression patterns of approximately 26% and approximately 38% of the homoeolog groups in B. hybridum changed toward nonadditive expression and nonancestral expression, respectively, under normal condition. Moreover, we found that B. distachyon showed similar expression patterns between normal and heat stress conditions, whereas B. hybridum and B. stacei significantly altered their transcriptome in response to heat after 3 days of stress exposure, and homoeologs that were inherited from B. stacei may have contributed to the transcriptional stress response to heat in B. hybridum. After 15 days of heat exposure, B. hybridum and B. stacei maintained transcriptional states similar to those under normal conditions. These results suggest that an earlier response to heat that was specific to homoeologs originating from B. stacei contributed to cellular homeostasis under long-term heat stress in B. hybridum. Conclusions: Our results provide insights into different regulatory events of the homoeo-transcriptome that are associated with stress acclimation in allopolyploid plants.

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.