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14/16 (88%) patients developed CRS; 11/14 (79%) had grade 1-2 CRS and 3 (19%) had grade 3 or greater CRS. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. 5 (31%) patients had ICANS; 2 (12.5%) had grade 1-2 ICANS, and 3 (19%) had grade 3 or greater ICANS. [Extracted from the article]

B Introduction: b Despite recent successes with CAR T-cell therapy against CD19 in patients with B-celllymphomas, only ~30%-40% of DLBCL and FL patients maintain a durable complete long-term remission, and over half of the patients will ultimately relapse. To investigate CAR T-cell-mediated tumor killing in human cells in combination with EZH2i tazemetostat, we used the GCB-DLBCL cell lines SUDHL4 (EZH2 SP Y641F sp ), OCI-Ly18 and Toledo (WT EZH2). [Extracted from the article]

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) ( p = 0.00004). Older age at diagnosis ( p = 0.001), stage III or IV disease ( p = 0.05), and bone marrow involvement ( p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL ( p = 0.04) and CD5+ ATLL ( p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 elicits remarkable clinical efficacy in B-cell malignancies, but many patients relapse due to failed expansion and/or progressive loss of CAR-T cells. We recently reported a strategy to potently restimulate CAR-T cells in vivo, enhancing their functionality by administration of a vaccine-like stimulus comprised of surrogate peptide ligands for a CAR linked to a lymph node-targeting amphiphilic PEG-lipid (termed CAR-T-vax). Here, we demonstrate a general strategy to generate and optimize peptide mimotopes enabling CAR-T-vax generation for any CAR. Using the clinical CD19 CAR FMC63 as a test case, we employed yeast surface display to identify peptide binders to soluble IgG versions of FMC63, which were subsequently affinity matured by directed evolution. CAR-T vaccines using these optimized mimotopes triggered marked expansion of both murine CD19 CAR-T cells in a syngeneic model and human CAR-T cells in a humanized mouse model of B cell acute lymphoblastic leukemia (B-ALL), and enhanced control of leukemia progression. This approach thus enables vaccine boosting to be applied to any clinically-relevant CAR-T cell product.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1 CreER :Tak1 fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing., Competing Interests: Potential conflicts of interest. E. A. C. receives research support from Genentech/Roche and AbbVie and has served as a consultant for Beigene, AstraZeneca, and TG Therapeutics. J. S. has served as a consultant for ATARA, AstraZeneca, Celgene Corporation, Adaptive, and Genmab, and receives research support from AstraZeneca, Merck, Incyte, Bristol-Myers Squibb, Pharmacyclics, TG Therapeutics, Seattle Genetics, and Adaptive. S. K. B. received honoraria from Acrotech, Seagen, Kyowa Kirin, and Daiichi Sankyo. S. D. N. receives research support from Roche, Rafael, ATARA, Pharmacyclics, and Takeda/Millennium; is a data monitoring committee member for Merck; and has served as a consultant for Epizyme and Morphosys. D. J. L. received research funding from Curis and Triphase; is a data and safety monitoring board member for Karyopharm; and has served as a consultant for Morphosys/Incyte, Epizyme, and ADC Therapeutics. J. N. G. received research funding from Loxo and has served as a consultant for Genentech, AbbVie, and Kite. E. L. P. received funding from Roche Diagnostics Corporation for the evaluation of serologic tests for SARS-CoV-2. E. J. W. is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences; and is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S. J. S. reports research funding from Acerta, Celgene, Genentech/Roche, Merck, Novartis, Pharmacyclics, and TG Therapeutics; received honoraria/consulting fees from Acerta, AstraZeneca, Celgene, Incyte, Janssen, Loxo Oncology, Morphosys, and Nordic Nanovector; is a steering committee member for Celgene, Nordic Nanovector, and Novartis; and has a patent for combination therapies of CAR T cells and PD-1 inhibitors. M. R. holds patents related to CAR T cells; has served as a consultant for nanoString, BMS, GSK, Bayer, Sana Therapeutics, and AbClon; receives research funding from AbClon, nanoString, viTToria biotherapeutics, Oxford Nanoimaging, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD., (Copyright © 2024. Published by Elsevier Inc.)

In this commentary, we discuss the investigation into reports of T-cell malignancies following chimeric antigen receptor T-cell therapy. We argue that although these cases should be thoroughly examined, current data suggest that such risks with autologous chimeric antigen receptor T cells are remarkably low compared with other cancer treatments. We also emphasize the importance of continued research, transparent reporting, and participation in postauthorization safety studies., (©2024 American Association for Cancer Research.)

Despite advancements, acute myeloid leukemia (AML) remains unconquered by current therapies. Evidence of immune evasion during AML progression, such as HLA loss and T-cell exhaustion, suggests that antileukemic immune responses contribute to disease control and could be harnessed by immunotherapy. In this review, we discuss a spectrum of AML immunotherapy targets, encompassing cancer cell-intrinsic and surface antigens as well as targeting in the leukemic milieu, and how they can be tailored for personalized approaches. These targets are overviewed across major immunotherapy modalities applied to AML: immune checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, bispecific/trispecific antibodies, and chimeric antigen receptor (CAR)-T and CAR-NK cells. Significance: Immune therapies in AML treatment show evolving promise. Ongoing research aims to customize approaches for varied patient profiles and clinical scenarios. This review covers immune surveillance mechanisms, therapy options like checkpoint inhibitors, antibodies, CAR-T/NK cells, and vaccines, as well as resistance mechanisms and microenvironment considerations., (©2024 American Association for Cancer Research.)

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: The V3 segment of the vertebral artery (V3-VA) is at risk during diverse approaches to the craniovertebral junction. Our objective is to present a system of anatomic and topographic landmarks to identify the V3-VA during the paramedian suboccipital approach (PMSOA) with the help of minimal or basic tools., Material and Methods: The first was a retrospective analysis of the angiotomography (CTA) of 50 patients over 18-years old, and 9 anatomical dissections. A series of lines were defined between the different bony landmarks. Within this lines the risk area of the vertebral artery (RAsV3-VA) and the risk point of the vertebral artery (RPsV3-VA) were defined. The second stage was a prospective study, where the previously defined measurements were carried out by using neuronavigation in 10 patients (20 sides) operated with the PMSO approach in order to confirm the presence of the V3 segment in the RAsV3-VA and RPsV3-VA., Results: In the first stage, the V3 segment was found in the middle third of the X line in 96,6% of the cases. The distance between the inion and the UCP (percentile 5) was 20 mm and to the LCP (percentile 95) was 40 mm. In the range between the UCP and the LCP, in the middle third of the inion-mastoid line (RAsV3-VA), we found 90% of the V3-VA. The measurements taken during the second stage revealed that the artery was in the middle third of the X line in 97% of the cases. 85% of the patients presented the total of the V3s-VA on the RAsV3-VA and in 85% there was a direct relationship with the V3 segment and the RPV3s-VA., Conclusion: We propose an easy-to-implement system to delimit the risk area of the V3-VA during the PMSOA. We believe that these landmarks provide a practical, reliable, costless and useful tool that could decrease the risk of lesion of the V3-VA during this approach without the need of using., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background Aims: The successful development of CD19-targeted chimeric antigen receptor (CAR) T-cell therapies has led to an exponential increase in the number of patients recieving treatment and the advancement of novel CAR T products. Therefore, there is a strong need to develop streamlined platforms that allow rapid, cost-effective, and accurate measurement of the key characteristics of CAR T cells during manufacturing (i.e., cell number, cell size, viability, and basic phenotype)., Methods: In this study, we compared the novel benchtop cell analyzer Moxi GO II (ORFLO Technologies), which enables simultaneous evaluation of all the aforementioned parameters, with current gold standards in the field: the Multisizer Coulter Counter (cell counter) and the BD LSRFortessa (flow cytometer)., Results: Our results demonstrated that the Moxi GO II can accurately measure cell number and cell size (i.e., cell volume) while simultaneously assessing simple two-color flow cytometry parameters, such as CAR T-cell viability and CD4 or CAR expression., Conclusions: These measurements are comparable with those of gold standard instruments, demonstrating that the Moxi GO II is a promising platform for quickly monitoring CAR T-cell growth and phenotype in research-grade and clinical samples., Competing Interests: Declaration of Competing Interest MR holds patents related to CAR T cells that are licensed to Novartis, Tmunity (Kite) and viTToria biotherapeutics. MR has served as a consultant for nanoString, BMS, GSK, GLG, GuidePoint, Sana, Bayer and AbClon. MR receives research funding from AbClon, Beckman Coulter, Oxford Nano Imaging, Curiox and viTToria biotherapeutics. MR is the scientific founder of viTToria biotherapeutics. The Ruella laboratory was provided a Moxi GO II device and supplies to perform this study. GD is an employee of ORFLO Technologies. All other authors declare no competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).