APLA Health

Abstract Introduction CART19/20 was developed by engineering autologous naïve/memory T (TN/MEM) cells with a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR) with the goal of overcoming resistance to single-target CD19-directed CAR-T cells. We report an update of a first-in-human phase 1 clinical trial of CART19/20 for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) (NCT04007029) with a median follow-up of over 4 years. Methods Eligible patients were ≥18 years old with R/R NHL and SLL/CLL, with ECOG 0 or 1. Patients were included if they had 2 or more prior lines of therapy with diffuse large B cell lymphoma (DLBCL) and primary mediastinal B cell lymphoma (PMBCL) and 3 or more prior lines for CLL/SLL, follicular lymphoma (FL), and mantle cell lymphoma (MCL). Autologous leukocytes were obtained by leukapheresis and sorted for CD62L+ TN/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR, and subsequent expansion of gene-modified T-cells. The primary end point was safety, and secondary endpoints were clinical response, progression free survival (PFS), overall survival (OS), and CART19/20 persistence. Results As of the data cutoff of November 25, 2025, 15 patients had received CAR-T 19/20 cells (6 DLBCL, 4 FL, 4 MCL, 1 HGBCL). Patients were treated at two dose levels, either 50x106 +/- 30% CAR+ cells (12 patients) or 200 x106 +/- 30% CAR+ cells (3 patients). The median age was 60 (range 29 to 70). Patients had received a median of 4 prior lines of therapy (range 2 to 8). All patients except one had stage IV disease, and 11 of 15 received bridging therapy. The CART19/20 cells were enriched with central-memory T cells (TCM: CD45RA–/CD45RO+/CD62L+). Maximum CRS was grade 2 which occurred in one patient. There were 9 patients that experienced max grade 1 CRS and no ICANS or neurotoxicity. There were 12 serious adverse events and two dose limiting toxicities. Fourteen of fifteen patients achieved an objective response (93% ORR), with 12 patients (80%) achieving a complete response (CR). With a median follow up of 51 months (range: 6.4 – 73.1), the median PFS was 37.5 months (95% CI 4.8 – not estimable) and the median OS was not yet reached. The median peak CAR-T19/20 cell expansion was 592,500 cells/mL whole blood, with mean persistence of CART 19/20 from date of infusion to last date of measurable CART19/20 cells of 526 days. Conclusion Overall, this phase 1 trial demonstrates that CART19/20 is a safe and effective therapy with the potential to overcome common resistance mechanisms of CAR-T cell therapy. Citation Format: Sophie Carlson, Benjamin Puliafito, Christopher M. Walthers, Brenda Ji, Jacob Naparstek, Jia Chen, Mobina Roshandell, Caitlin Harris, Mobina Khericha Gandhi, Melanie Ayala Ceja, Christy Sidhu, Karla Nawaly, Martin Allen-Auerbach, Sven De Vos, Patricia Young, Caspian Oliai, Gary Schiller, John Timmerman, Antoni Ribas, Yvonne Chen, Sarah Larson. Phase 1 Trial of Bispecific CART19/20 Cells for Relapsed or Refractory Non-Hodgkin Lymphoma: Updated Results with Over Four Years Median Follow Up [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C001.

The glass industry is striving to achieve climate neutrality by 2045 and, like many other industries, is facing profound transformation processes. Different challenges arise along the value chain of glass and façade products: while environmental aspects can be integrated more easily in some areas, others require far‐reaching changes. As part of the CircuClarity initiative, stakeholders from industry and academia are working together on innovations for climate neutrality and circularity. This evaluation study provides an overview of current trends and uses the initiative's structure to assess the state of development using a six‐stage model. The results indicate a varied range: while only limited progress has been made to date in terms of energy sources for glass production and there is still a need for further innovation, the multiple uses of glass are undergoing dynamic development, with further differentiation in terms of products and practical, resource‐saving solutions that have the potential for widespread application.

Across the United Sates, Latino men who have sex with men (LMSM) face disproportionately high HIV risk. Although pre-exposure prophylaxis (PrEP) effectively reduces HIV risk, numerous barriers limit PrEP access among LMSM. Culturally tailored public health campaigns provide one potential strategy for increasing access, awareness, and use of PrEP, including the newest long-acting injectable PrEP (LAI PrEP) formulations. The purpose of the study was to develop community-informed recommendations for a culturally responsive LAI PrEP awareness campaign designed for LMSM. Between June 2023 to March 2024, thirty LMSM participated in four virtual focus groups conducted in Los Angeles, CA. LMSM were recruited through a larger LMSM-centered HIV prevention intervention. In the focus groups, participants shared their perspectives on campaign messaging, imagery, tone, and accessibility. Coding reliability thematic analysis was used to analyze the data. Findings suggest that a LAI PrEP campaign for LMSM should: provide basic information about the strategy; highlight its benefits; incorporate humorous and sex-positive messaging or imagery; communicate the seriousness of HIV without stigmatizing, blaming, or scaring LMSM; incorporate important Latine cultural values; and include Latine celebrities, public figures, and everyday individuals as messengers. In addition, there were mixed opinions regarding the use of a syringe in the imagery, with some participants advocating against its use to avoid fear- and pain-based associations with injections. Finally, participants believed that a LAI PrEP campaign should be made accessible to LMSM by providing materials in both English and Spanish and placing physical advertisements in neighborhoods predominately occupied by Latine people. Our findings offer several practical recommendations for developing a LAI PrEP awareness campaign for LMSM that can be used by health departments, community-based organizations, and others. Incorporating community insights is crucial to ensure that a campaign resonates with and meets the needs of the LMSM community.

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at <50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for chromatin-driven mechanisms in this disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. Importantly, NESC-derived tumors clustered with human G3MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. These gene signatures were associated with the Polycomb Repressive Complex (PRC) and demarcated with H3K27me3; the histone mark directly regulated by PRC. Further interrogation identified JARID1B, a MYC binding partner and H3K4me3 demethylase, as a regulator of these repressed neural genes. This is further reinforced by the observation of higher H3K27me3 levels concurrent with increased JARID1B expression in human G3MB patient samples, compared to other subtypes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. These studies support a critical role of MYC in repressing target genes to drive tumor formation and JARID1B as a new target for therapy. Collectively, we present a critical framework for understanding mechanisms of resistance and the chromatin landscape of MYC- and TGFβ-driven G3MB.

<bold>Rationale:</bold> The Obstructive Spirometric Index (OSI) integrates the forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FEV₁/FVC) to better capture the risk associated with airflow limitation compared to FEV1 and FEV₁/FVC alone. However, its theragnostic value is unclear. <bold>Aim:</bold> To assess OSI’s predictive value for response to the long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC). <bold>Methods:</bold> We conducted a post-hoc analysis of CAPTAIN, a double-blind, 24–52-week randomized controlled trial in uncontrolled moderate-to-severe asthma. Participants were factorially randomised to ICS/LABA inhalers with/without UMEC. The interaction between baseline lung function (FEV₁% or OSI) and UMEC (yes/no) was assessed using multivariable models: negative binomial for asthma attacks and linear for ΔFEV₁ at 52 weeks. <bold>Results:</bold> Among 2,436 patients, neither FEV₁ nor OSI interacted with UMEC for asthma attack risk. In 543 patients with available FEV₁ at 52 weeks, OSI significantly interacted with UMEC for lung function improvement (p=0.01), while FEV₁ did not. Higher OSI was associated with greater lung function improvement following UMEC (Figure). <bold>Conclusions:</bold> The OSI, which integrates FEV1 and FEV1/FVC, predicts lung function improvement with UMEC, whereas FEV₁ alone does not. OSI may identify treatment opportunities. <bold>Funding:</bold> GSK/APQ/FRQS/NIHR (<ext-link>NCT02924688</ext-link>). <fig><object-id>erj;66/suppl_69/PA5764/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

Abstract Background: Older adults with early breast cancer can have very different risks of chemotoxicity despite similar chronological age. This heterogeneity may be due to differences in biological age. However, few studies have evaluated whether epigenetic indicators of biological age can stratify the risk of chemotoxicity in older adults with early breast cancer. Methods: In a prospective multicenter study of 394 adults age &amp;gt;65 with stage I-III breast cancer treated with neo/adjuvant chemo, we analyzed DNA methylation patterns from peripheral blood to estimate epigenetic age acceleration (EAA) prior to chemo. We tested three generations of epigenetic age algorithms (1st gen: Horvath and Hannum; 2nd gen: PhenoAge and GrimAge; 3rd gen: DunedinPACE). We calculated EAA as the residual that results from regressing epigenetic age on chronological age. The primary endpoint was grade 2+ chemotoxicity (yes/no, yes defined as any grade 2+ toxicity attributed to chemo). Using multivariable logistic regression, we examined the association between EAA (analyzed as continuous and categorical [quartiles] variables) and grade 2+ chemotoxicity, adjusting for demographic, geriatric, and clinical covariates. Results: The median (range) pre-treatment chronological age was 70 (65-85), 65% had stage II/III disease, 38% had anthracycline, and 75% received G-CSF prophylaxis. A total of 334 (84.8%) participants experienced a grade 2+ toxicity. After adjusting for age, cell composition, stage, race/ethnicity, education, regimen, organ function, and geriatric assessment variables, there was no significant association between the measures of EAA and grade 2+ chemotoxicity (Table). Conclusions: In this cohort of older adults with early breast cancer, there was no significant association between pre-treatment EAA and grade 2+ chemotoxicity. Further research is needed to examine how measures of biological age can be translated to the clinical care of older patients with breast cancer. Citation Format: Jingran Ji, Canlan Sun, Marla Lipsyc-Sharf, Nikita V. Baclig, Yulia A. Zektser, Ali Al Saleem, Joseph D. Olivera, Kelly S. Synold, Lauren R. Zelman, Alexandra M. Binder, Mina S. Sedrak. Epigenetic age acceleration measures and chemotoxicity in older adults with early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 623.

Abstract Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death. Citation Format: Elizabeth G Fernandez, Wilson X Mai, Kai Song, Nicholas A Bayley, Andrew J. Souers, Jingyi Jessica Li, Thomas G. Graeber, Timothy F Cloughesy, David A. Nathanson. Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A007.

Abstract Pediatric High Grade Glioma (HGG) is an aggressive cancer with a 5-year survival rate of just 10-20% (Fangusaro, 2012). While previous studies using chimeric antigen receptor (CAR) T-cells for brain malignancies demonstrated tolerability (Majzner et al., 2022; Vitanza et al., 2021; Vitanza et al., 2023), the low survival rates demand more efficacious therapies (Majzner et al., 2022). In this study, we perform in vitro modeling of spatiotemporally regulated high-affinity CARs targeting the GD2 antigen to enable use of highly potent CAR variants while mitigating on-target, off-tumor toxicity. By placing CAR affinity variants under control of a heat shock promoter, thermal energy delivered to the tumor tissue by focused ultrasound (FUS) induces CAR expression (Wu et al., 2021) at an optimal temperature of 43oC. We first determine FUS-controlled CAR induction and decay kinetics in vitro for selected signaling domain architectures as well as affinity variants. Following codon optimization, differences in basal expression at 37oC from the heat shock promoter were noted for the three signaling domain architectures, with 28z and BBz displaying the highest and lowest levels of aberrant expression, respectively. Next, we compare expression of CAR constructs with and without 3 cycles of heat shock at 43oC in CAR-T cells. Then, using live cell imaging, we analyze the kinetics of expression and decay of the CAR following heat shock. Finally, we perform effector function assays of the CAR-T cells to compare the cytotoxicity and persistence for each construct. We identify the CAR architecture harboring the CD28 transmembrane domain and the 4-1BB cytoplasmic domain as the optimal balance between basal and induced expression. We plan to move this architecture forward to in vivo studies to assess the ability to maintain robust tumor lysis and minimal on-target, off-tumor toxicity. Citation Format: Edward Trope, Yun-Yun Su, Rie Nakata, Magda Golyska, Sarah Richman. Spatiotemporal Regulation of Chimeric Antigen Receptor T-cells Using Focused Ultrasound Therapy to Enable Use of High-Affinity Binders [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A021.