tbuckley/cabot-search huggingface dataset:
Inequities in timely treatment (Tx) initiation for patients (pts) with acute myeloid leukemia (AML) treated in a predominantly community setting in the United States (US).
Authors: Esprit Ma, Ann-Kathrin Eisfeld, Olatoyosi Odenike, Achal Patel, Rongrong Wang, Archibong Yellow-Duke, Melissa Montez, Yanqing Xu, Kaylee Miu, Andrew Hantel
Journal: Journal of Clinical Oncology (2024)

1574 Background: AML is a highly morbid but treatable cancer with several novel Tx available. This study evaluates associations between race/ethnicity and socioeconomic status (SES) on timely Tx initiation in pts with newly diagnosed (ND) AML in a routine clinical setting. Methods: This retrospective cohort study uses the Flatiron Health electronic health record-derived, US nationwide, de-identified database. Pts aged ≥18 years, with AML diagnosis (Dx) Jan 2014–Dec 2022, had ≥2 visits recorded ≤3 months after Dx, and who received first line (1L) active Tx were included. 1L Tx was categorized as intensive chemotherapy (IC) or non-IC. Timely Tx was defined as initiation ≤14 days after Dx. Race/ethnicity was defined as White or People of Color (POC; including Black, Latinx, Asian, or Other). Logistic regression assessed associations between race/ethnicity and Yost Index-based SES on timely Tx initiation (adjusted for age at Dx, sex, practice type, hydroxyurea as part of 1L Tx [proxy of disease burden], European LeukemiaNet 2017 risk, and secondary AML), with adjusted odds ratios (aOR) reported. Results: Overall, 5981 pts with ND AML were included; 58% received non-IC and 42% received IC. Median ages were 76 and 60 years; 80% and 66% were treated in community settings; and median time from Dx to 1L initiation was 11 and 4 days. In the IC cohort, POC vs White pts had similar delays in Tx initiation (13.3% vs 13.8%, aOR 1.22, p=.2); significantly fewer POC vs White pts underwent stem cell transplant (SCT) post-remission (30.8% vs 47.7%, aOR 0.44, p&lt;.001).In the non-IC cohort, numerically more POC had delayed Tx initiation vs White pts (40.6% vs 36.2%, aOR 1.19, p=.074). This disparity was larger in pts of low SES (POC vs White pts: 42.5% vs 34.4%, aOR 1.35, p=.077) vs high SES (38.7% vs 35.6%, aOR 1.16, p=.4) (Table). Conclusions: In a predominantly US community setting, numerical but non-significant race/ethnic disparities in timely 1L Tx initiation were observed for pts with ND AML. Fewer POC vs White pts receiving IC underwent SCT post-remission. Analyses are ongoing to assess mediators and impact on survival. [Table: see text]
Food for cancer health equity: The impact of a culturally tailored food voucher intervention on food insecurity among Latinx patients with cancer.
Authors: Maria T. Hanna, Emily Hayes Wood, Gerardo Villicana, Lesly Lopez Guzman, Kasandra Escobar, Jajaira Reynaga, Chardria Trotter, Zachary M. Koontz, Hilary K. Seligman, Manali I. Patel
Journal: Journal of Clinical Oncology (2024)

1544 Background: Food insecurity disproportionately impacts immigrant, low-income, and racial and ethnic minorities with cancer. In our prior qualitative work, Latinx and multiethnic patients with food insecurity emphasized the importance of culturally tailored food assistance interventions that could minimize stigma and maintain self-efficacy and autonomy. In collaboration with Latinx patients and community partners in Monterey County, California, we co-developed a culturally tailored food voucher intervention. In this study, we conducted a pilot of the intervention among multiethnic and Latinx patients with cancer and tested the impact on food insecurity and health-related quality of life. Methods: We recruited low-income, racial and ethnic minority adults &gt;18 years of age who screened positive for food insecurity using the 2-item Hunger Vital Sign while receiving cancer treatment in a clinic in Monterey County, CA between July 2023 until August 2023. All participants who consented to participate received $40 monthly grocery store gift cards redeemable at a variety of local retailers for 6 months in addition to usual care provided by trained community health workers who assisted with other health-related social needs. We conducted validated surveys at baseline (time of enrollment) and 6-month follow-up (post-intervention) assessing demographics, food behaviors, food insecurity, and health-related quality of life. We compared pre- and post-intervention proportions with food insecurity using McNemar's tests and change in health-related quality of life using paired t-tests. Results: Of the 30 study participants enrolled, 27 (90%) were Latinx; 24 (80%) spoke Spanish as their preferred language; 16 (53%) had advanced (stage 3 or 4) cancer; 12 (40%) were retired or unemployed; 10 (33%) were disabled; 20 (67%) reported a household income &lt;$35,000 USD. Of the 26 (87%) participants who completed post-intervention surveys, the proportion with food insecurity decreased from 100% to 65% (95% CI 0.60-0.77; p=0.01); 100% adhered to recommended treatment; and health-related quality of life scores increased by 8 points from 71.9 +/-16.1 to 79.5+/- 10.5 (p=0.02) from baseline. Conclusions: This culturally tailored food voucher intervention was associated with reductions in food insecurity and improvements in health-related quality of life among low-income Latinx patients with cancer. This intervention may represent an effective approach to overcome food insecurity in Latinx and multiethnic patients with cancer.
Non-clinical evaluation of NT-112, an autologous T cell product engineered to express an HLA-C*08:02-restricted TCR targeting KRAS G12D and resistant to TGF-b inhibition.
Authors: Jennifer Ma, Vanessa Tubb, Michelle Mojadidi, Kayla Meade, Xiangjun Kong, Paula Kroon, Aastha Sareen, Bas Stringer, Oscar Krijgsman, Yvonne Claasen, Jules Gadiot, Karen Buchner, Sander Eshuis, Ton Schumacher, Carsten Linneman, Thomas Kuilman, Jeroen van Heijst, Gavin Bendle, Arianne Perez
Journal: Journal of Clinical Oncology (2024)

e14533 Background: Adoptive transfer of T-cell receptor (TCR)-engineered T-cells to target shared cancer neoantigens is a promising new immunotherapy approach for patients harboring mutations in oncogenes such as KRAS. Activating mutations in KRAS are among the most prevalent oncogenic driver mutations in human cancers, with KRAS G12D being the most frequent KRAS mutation in colorectal carcinoma and pancreatic cancer. NT-112 is an autologous engineered T-cell product expressing an HLA-C*08:02-restricted TCR that specifically targets the KRAS G12D mutation. NT-112 is additionally engineered to lack TGF-β receptor II (TGFBR2) expression, rendering T-cells insensitive to TGF-b-mediated inhibition in the tumor microenvironment. Methods: For manufacturing of NT-112, CD4 and CD8 T-cells are enriched from leukapheresis material, activated in vitro and gene-edited to knock-out both endogenous TGFBR2 and TCR β constant 1/2 (TRBC1/2) and knock-in an HLA-C*08:02-restricted KRS G12D neoantigen-specific TCR at the TCR α constant (TRAC) locus using CRISPR-Cas9 technology. NT-112 product functionality was evaluated in both in vivo models and in vitro co-culture experiments with a panel of cell lines including those endogenously expressing the KRAS G12D mutation. T-cell reactivity was assessed by measuring cytotoxicity, proliferation, and cytokine production. For determination of NT-112 product safety, cross-reactivity and allo-reactivity assessments were carried out. A comprehensive analysis of potential off-target editing by CRISPR/Cas9 was performed to assess potential risk of genotoxicity in clinical grade NT-112. Results: High reactivity of the NT-112 TCR against KRAS G12D and HLA-C*08:02-expressing target cells was observed. T-cell activation and functionality was highly specific, as demonstrated by a lack of reactivity against KRAS WT, minimal cross-reactivity in Alanine and Glycine scans, and lack of T-cell activation in the absence of HLA-C*08:02. In vivo, NT-112 T-cells were able to induce tumor clearance in two independent models. Low frequency chromosomal translocation events (&lt;0.1%) between on-target and off-target Cas9 cleavage sites were detectable in NT-112 T-cells. However importantly, these did not result in autonomous cytokine-independent growth. Conclusions: Non-clinical studies revealed a favorable safety and efficacy profile for NT-112 and supported further clinical development of a TGF-β-resistant TCR-edited T-cell product for mutant KRAS-targeted cancer immunotherapy.
Tyrosine kinase inhibitors with and without upfront CNS radiation for brain metastases in oncogene-driven non-small cell lung cancer (TURBO-NSCLC).
Authors: Emily Miao, Luke R. G. Pike, Lillian A Boe, Tejas Patil, Nathaniel James Myall, Caressa Hui, Erqi L. Pollom, Vera Qu, Jacob Langston, Michael J Grant, Sarah B. Goldberg, Joshua David Palmer, Rahul Neal Prasad, Tony J. C. Wang, Albert Lee, Catherine A. Shu, Lanyi Nora Chen, Nicholas J. Thomas, David Ross Camidge, Chad G Rusthoven
Journal: Journal of Clinical Oncology (2024)

2019 Background: Newer generation tyrosine kinase inhibitors (TKI) for NSCLC with EGFR mutations and ALK rearrangements have demonstrated encouraging central nervous system (CNS) activity with CNS objective response rates, greatly improved from 1 st generation TKIs. In response to these data, guideline statements have acknowledged a strategy of CNS-penetrant TKI +/- upfront stereotactic radiosurgery (SRS) for the treatment of select patients with BM. However, optimal use of upfront SRS for BM in these patients is controversial since upfront CNS radiation has been the historical standard of care, and there are limited data guiding patient management with upfront TKI alone. Additionally, results from a large multi-institutional series reported inferior overall survival (OS) with the omission of SRS in patients with EGFR-mutated NSCLC treated with first-generation TKI. Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs +/- upfront SRS were retrospectively collected from 7 centers in the United States. Time to CNS progression (PD), local CNS PD, and OS were analyzed, with multivariable adjustment (MVA) in Fine and Gray and Cox proportional hazards models for baseline factors including age, sex, performance status, mutation, extracranial metastases, prior therapy, neurologic symptoms, and number and size of BM. Results: We identified 317 patients (200 TKI only and 117 TKI+SRS). 250 (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients who received TKI+SRS were more likely to have BM ≥1 cm (p&lt;0.001) and neurologic symptoms (p&lt;0.001) at baseline. The median follow-up from treatment of BM was 23 months and 26 months in the TKI and TKI+SRS groups, respectively. Median OS was similar between the TKI and TKI+SRS groups (median 41 months [95% CI: 35-NR] vs 40 months [95% CI: 40-NR], respectively; p=0.5). On MVA, TKI+SRS was associated with a significant improvement in time to CNS PD (HR 0.63; 95% CI: 0.42-0.96; p=0.033). Local CNS control was significantly improved with TKI+SRS (HR 0.30, 95% CI: 0.16-0.55; p&lt;0.001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated greater CNS control benefits with TKI+SRS in patients with BM ≥1 cm. Conclusions: This is the largest multi-institutional study comparing strategies of CNS-penetrant TKIs +/- upfront SRS in TKI-naïve patients with oncogene-driven NSCLC. The addition of SRS improved time to CNS PD and local CNS control but not OS. Patients with BM ≥1 cm may benefit the most from upfront integration of SRS. [Table: see text]
Emavusertib (CA-4948) in combination with ibrutinib in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL).
Authors: Christian Grommes, Han W. Tun, Adolfo de la Fuente Burguera, Anna Dabrowska-Iwanicka, Lucia Regales, Wanying Zhao, Dora Ferrari, Meaghan Fowles, Maureen E Lane, Catherine Wang, Reinhard W. Von Roemeling, Michal Taszner, Christopher D'angelo, Grzegorz S. Nowakowski
Journal: Journal of Clinical Oncology (2024)

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .
Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis.
Authors: Ruxuan Chen, Yujie Shi, Hui Huang, Mengzhao Wang, Yan Xu
Journal: Journal of Clinical Oncology (2024)

e14683 Background: Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies. Methods: We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed. In our study, patients with grade 1 or grade 2 CIPs were defined as low-grade CIPs, and patients with grade 3, grade 4 or grade 5 CIPs were defined as high-grade CIPs. Results: The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31-78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. Most of the patients were diagnosed with lung cancer (36 patients, 85.7%). There were 3 patients with esophageal squamous cell cancer, 1 patient with hepatic cell cancer, 1 patient with gastric signet ring cell cancer and 1 patient with pericardial malignant mesothelioma. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3 + CD4 + /CD3 + CD8 + lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs. Conclusions: The CD3 + CD8 + lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3 + CD8 + lymphocytes might be a treatment option for CIPs.
Effect of TT-816, a novel immune response modifier targeting cannabinoid CB<sub>2</sub> receptor, on antitumor immunity and cancer growth.
Authors: Peidong Fan, Elfatih Elzein, Lina Yao
Journal: Journal of Clinical Oncology (2024)

e14595 Background: The endocannabinoid system is widely expressed in the human body, including the innate and adaptive immune system, where endocannabinoids, Δ9-tetrahydrocannabinol and synthetic ligands regulate immune suppression. The effects of endocannabinoids on immune regulation are primarily mediated by G-protein coupled cannabinoid CB 2 receptors (CB 2 R) via several mechanisms, including immune cell development, migration, proliferation and T and NK cell effector functions. The upregulated expression of CB 2 R and elevated levels of endocannabinoids have been observed in a variety of tumor microenvironments and are associated with the aggressiveness of cancer. Methods: NK cell function was determined by co-culturing TT-816 pretreated NK cells with K562 cancer cells for 24 hours. The mixed lymphocyte reaction assay was conducted by co-culturing human CD4+ T cells with monocyte-derived dendritic cells. Cell viability was measured by FACS and IFN-g by MSD. The in vivo efficacy of TT-816 was determined in the murine syngeneic B16F10 melanoma and MC38 colorectal cancer models. Tumor-bearing C57BL/6 mice were randomized 6 days after inoculation and treated with vehicle (0.5% CMC, QD) or with TT-816 at 1, 4 or 10 mg/kg (QD) orally, or anti-PD1 (RMP1 14) at 5 mg/kg (Q3D), intraperitoneally. Tumor size and body weight were determined every 2 to 3 days. Data represent mean±SEM. Results: TT-816 concentration-dependently enhanced the functions of NK cells, dendritic cells and T cells. It increased NK cell killing of the human cancer cells and IFN-g production, significantly stimulated the expression of CD86, HLA-DR, IL-12 and TNF-a in monocyte-derived dendritic cells, and enhanced CD4+ T cell proliferation and IFN-g production in a mixed lymphocyte reaction assay. In B16F10 melanoma and MC38 colorectal cancer models, TT-816 dose-dependently inhibited the tumor growth. Furthermore, combination of TT-816 with anti-PD1 synergistically inhibited both tumor growth. In B16F10 model, treatment with TT 816 (4 mg/kg, QD) alone significantly inhibited the tumor growth by 45%. By contrast, anti-PD1 had little effect (TGI 5%). However, the combination of TT-816 with anti-PD1 resulted in a TGI of 72%. In the MC38 model, treatment with TT-816 (4 mg/kg, QD) and anti-PD1 alone, achieved TGI of 50% and 36%, respectively. When combined, TGI was increased to 88%. Conclusions: TT-816 is a novel, oral small molecule immune response modifier that selectively blocks CB 2 R on immune cells and cancer cells. Preclinical data have demonstrated that it stimulates antitumor immune response and inhibits cancer growth in both hot and cold tumor models. TT-816 is currently undergoing phase 1 clinical trials for the treatment of a broad range of solid tumors.
Predicting immunotherapy toxicity through single-cell sequencing of peripheral immune cells: A pilot study.
Authors: Jennifer Wen Ying Lim, Venessa T. Chin, Patricia Keith, Rachael McCloy, Drew Neavin, Angli Xue, Dominik Kaczorowski, Ellie Spenceley, Himanshi Arora, Anthony M. Joshua, Joseph Powell
Journal: Journal of Clinical Oncology (2024)

e14538 Background: Immune checkpoint inhibitors are widely used in oncology. However, immune-related adverse events (iRAEs) are idiosyncratic and can be severe. The overall incidence is 27%, with severe iRAEs occurring in 6% of patients. We hypothesised that distinct immune cell phenotypes (gene expression) correlate with immune-related toxicity from checkpoint inhibitor immunotherapy. Single-cell RNA sequencing (scRNA-seq) is a powerful tool that can assay the gene expression of thousands of individual cells. RPS26 expression mediates CD4/CD8 T cell activation through a known trans-expressive quantitative trait locus at rs1131017 and is linked with autoimmunity. FOS and JUN encode for c-Fos and c-Jun, which dimerise to create the activator protein-1 complex, a well-established transcriptional factor of the immune system. c-Fos is an immunoregulator known to suppress pro-inflammatory cytokines, suggesting that c-FOS deficiency plays a crucial role in developing autoimmunity. We aimed to analyse the transcriptomic differences of peripheral immune cells between patients who experienced severe checkpoint inhibitor therapy iRAE and those who did not. Methods: We identified a pilot cohort of eight patients who developed grade three or above toxicity due to immune checkpoint inhibitors and eight controls who were matched for age, cancer and treatment type. Peripheral blood mononuclear cells were collected prospectively at baseline and two subsequent treatment cycles. Cells were captured on the 10x Chromium platform, and libraries were sequenced to 30,000 reads per cell. Samples were demultiplexed, and the data was analysed with the Seurat package on R statistical software (version 4.3.0). Results: Five patients had baseline samples only, two patients had two samples from two cycles, and one patient had samples from three cycles. After quality control filtering, we identified 36,288 cells from 16 individuals and 24 samples. Immune cells were annotated with the Azimuth package into 29 subtypes. We identified differences in cell proportions of immune cell subsets in the toxicity vs control group, including B naive cells (5.57% vs 3.71% p=0.01) and reduced cytotoxic CD4 T lymphocyte cells (0.66% vs 2.26%, p=0.005). Differential gene expression analysis identified a significantly high expression of ribosomal genes, particularly RPS26, in multiple cell types at baseline (p&lt;0.01) and reduced expression of FOS and JUN-related genes in CD14 and CD16 monocytes, CD4 and CD8 T cells in the toxicity cohort (p&lt;0.01). Conclusions: Overexpression of ribosomal genes and reduced expression of FOS/ JUN genes amongst PBMCs at baseline are potentially predictive biomarkers of severe checkpoint inhibitor immunotherapy toxicity. Validation of these findings in a larger cohort is in progress.