tbuckley/cabot-search huggingface dataset:
IOV-3001, a modified interleukin-2 fusion protein, for potential use in tumor-infiltrating lymphocyte cell therapy regimens.
Authors: Michelle R. Abelson, Sadie Johnson, Joanna Poprawski, Jamie L. Blauvelt, Sean Hall, Hequn Yin
Journal: Journal of Clinical Oncology (2024)

2552 Background: Tumor-infiltrating lymphocyte (TIL) cell therapy has shown promising efficacy in patients with solid tumor malignancies. Interleukin-2 (IL-2) administration after TIL infusion supports persistence and survival of infused TIL. Aldesleukin is a synthetic IL-2 with a short half-life administered every 8–12 hours, to support the expansion and persistence of the TIL in vivo. IOV-3001 is a modified dimeric IL-2 fused to palivizumab that has a longer half-life and potentially better safety profile, compared with aldesleukin. Here, we describe the preclinical activity, pharmacokinetics (PK), pharmacodynamics (PD), and in vivo safety profile of IOV-3001. Methods: Binding of IOV-3001 and aldesleukin to the IL-2 receptor (IL-2R), IL-2R-mediated activation via STAT5 phosphorylation, and T cell proliferation were assessed. Pharmacological activities of IOV-3001 and aldesleukin were evaluated in B16-F10 mice infused with pmel-1 T cells. Safety after a single dose of IOV-3001 (0.01–9.0 mg/kg) was assessed in cynomolgus monkeys across 3 independent studies. PK and PD parameters, clinical pathology, hematology, and histopathology were assessed. Results: Both IOV-3001 and aldesleukin induced comparable STAT5 phosphorylation and proliferation of T-cell subsets. Mice infused with pmel-1 T cells and subsequently treated with IOV-3001 or aldesleukin showed similar reductions in tumor burden. The half-life of IOV-3001 in cynomolgus monkeys ranged from 5–8 hours. IOV-3001 was well tolerated in monkeys across the dose range studied except for 1 animal administered IOV-3001 at the highest tested dose level, with recovery by Day 29. Inflammatory cytokines (IL-12 p40, IL-6, MCP-1) increased from 4 hours to ≤3 days after dosing and returned to baseline by Day 29. Fibrinogen, bilirubin, and triglycerides increased on Day 3 and returned to baseline by Day 29. No signs of capillary leak were observed. Increased numbers of hematopoietic cells were found in the bone marrow, spleen, and lymph nodes 3 days post dosing. During the 4-week recovery, these changes diminished or resolved, while bone marrow showed differential dose-dependent effects. IL-2–induced proinflammatory PD effects were observed, including &gt;10-fold peak CD8+ T cell expansion in peripheral blood mononuclear cells at Day 5 versus preacclimation in most cynomolgus monkeys treated with IOV-3001. Conclusions: IOV-3001 exhibited a similar mechanism of action (MoA) to that of aldesleukin in vitro and has a longer half-life in vivo. PD effects were consistent with the MoA of IL-2. IOV-3001 showed a favorable preclinical safety profile. These results suggest a potentially improved safety profile for IOV-3001 with less frequent dosing compared with aldesleukin. These features of IOV-3001 strongly advocate for its development in TIL cell therapy regimens.
INSIHGT: A scalable and homogeneous 3D multiplexed molecular mapping platform for spatial biology and precision medicine.
Authors: Hei Ming Lai, King Ngai Chow, Tin Shing Hung, Chun Ngo Yau, Shuk Ling Chan
Journal: Journal of Clinical Oncology (2024)

e15180 Background: The dynamic interplay between cancer cells and their microenvironment is a determinant of disease evolution and response to treatment. However, the current state of three-dimensional (3D) tumor microenvironment analysis is hindered by inadequate penetration of antibodies into thick tissue sections, leading to a substantial gap in acquiring unbiased, precise 3D multiplexed immunohistochemistry (IHC) images. Methods: We developed INSIHGT to surmount these limitations by enabling multi-round, multiplexed 3D IHC in standard formalin-fixed tissues. This fully automatable, fast-track method requires a simple series of chemical cocktail exchanges, translating to a tissue-to-image time of 6 days for 1 cm³ samples and as little as 6 hours for biopsy specimens. INSIHGT offers a scalable and efficient solution for detailed 3D spatial mapping of cancerous cells and their interactions within their native context. Results: 3D IHC with INSIHGT shows ideal penetration homogeneity, which quantitatively matches reference signals in 1cm 3 samples. We further validated INSIHGT with 309 commercially available primary antibodies and is compatible with simultaneous fluorescent in situ hybridization (FISH) to detect RNA transcripts or DNA chromosomal abnormalities. Notably, the quality of post-INSIHGT traditional histological analyses, such as H&amp;E and standard IHC, was not altered. We demonstrated a 3D mapping of over 20 markers in a 1 mm-thick tumor sample across seven INSIHGT cycles, and an atlas of multiple tumour samples with 3D IHC &amp; H&amp;E. The large datasets seamlessly integrates with single-cell segmentation and analysis workflows, yielding comprehensive maps that elucidate protein expression, cell morphology, spatial positioning, and potential cell-cell interactions. Conclusions: INSIHGT provides an unparalleled level of visualization and analytical detail concerning the spatial dynamics within the tumor microenvironment at a single-cell resolution. As a transformative next generation histopathology platform, it can uncover new structural and molecular details within clinical specimens, accelerating biomarker discovery and novel diagnostic assays development, thereby enriching the field of tumor biology and propelling the progress of personalized oncology treatments.
Unveiling a novel NKG2A inhibitor based on monoclonal antibody to HLAE-peptide complex.
Authors: Muhammad Khalid Abu Ahmad, Olga Radinsky, Angel Porgador, Frank Momburg
Journal: Journal of Clinical Oncology (2024)

e14677 Background: HLAE is a non-classical MHC class I molecule complexed with the VMAPRTLFL nonapeptide, derived from the leader sequence of HLAG (HLAE pHLAG ). HLAE pHLAG is overexpressed across a wide type of tumors prominently on Multiple Myeloma (MM). HLAE pHLAG complex is the ligand to CD94-NKG2A in the immune system which negatively regulates the activation of natural killer (NK) cells as well as NKG2A positive T cells. Harnessing of the HLAE-NKG2A axis by the cancer cells leads to evasion from the immune system attack resulting in cancer progression. Currently, several Immune Checkpoint Inhibitors (ICIs) target the NKG2A receptor which has a low specificity to cancer and high toxicity to the patient. Engineering a new ICI that targets the HLAE pHLAG complex can potentially yield improved outcomes in cancer therapy. Methods: Using the hybridoma system, a new mouse monoclonal antibody (mAb) called 4D7 that targets the HLAE pHLAG complex was developed. mAb 4D7 affinity was assessed in vitro with recombinant proteins and a panel of cell lines that expressed zero to high levels of HLAE. The functional impacts of the mAb 4D7 was examined in a system where various MM cell lines were separately co-cultured with primary NK (pNK) cells. pNK were isolated from the peripheral blood of 5 healthy donors, and their activity was examined in the presence of mAb 4D7 by CD107a degranulation assay. Also, the functional impacts of the mAb 4D7 on allogenic pNK and MM blast cells, isolated from the bone marrow of 6 MM patients were assessed. Results: mAb 4D7 was determined to be an IgG-kappa isotype showing a high specific binding to recombinant HLAE pHLAG . Cell lines with overexpression of membranal HLAE pHLAG : RPMI8226, U266, 721.221 HLAE, and 721.221 HLAG showed positive staining with the mAb 4D7. While cell lines with low to zero expression of HLA-E like 721.221 WT showed low or negative staining with the mAb 4D7. The degranulation of NKG2A + pNK subset cells against MM target cells increased in presence of mAb 4D7. However, adding mAb 4D7 to NKG2A - pNK subset cells co-cultured with MM target cells did not affect the pNK activity. Similar results were obtained when the target and effector cells were isolated from the bone marrow of active treatment-naive MM patients. Conclusions: MAb 4D7 demonstrates a remarkably high affinity for binding to the HLAE pHLAG complex, ensuring the safety of its application. The ability of 4D7 mAb to effectively block the HLAE pHLAG complex and counteract the inhibition signal in NK cells. mAb 4D7 is a promising monoclonal antibody with substantial potential to serve as an ICI for clinical use in MM patients.
<i>PIK3CA</i> testing and treatment patterns among patients with metastatic breast cancer in US community clinical practice.
Authors: Eunice Kim, Preet Kaur Dhillon, Peter Lambert, Anna Cheng, Reva K. Basho
Journal: Journal of Clinical Oncology (2024)

e13059 Background: PIK3CA mutations are present in ~35-40% of HR+/HER2- breast cancer patients. Targeted treatments are approved and in development for patients with advanced disease, and clinical guidelines recommend biomarker testing. This retrospective cohort study characterized PIK3CA mutation testing and treatment patterns among HR+/HER2- metastatic breast cancer (mBC) patients in United States (US) community clinical practices. Methods: We used the nationwide Flatiron Health electronic health record-derived de-identified database to select patients diagnosed with HR+/HER2- mBC from January 2011 to May 2023. We described baseline characteristics of patients tested and not tested for PIK3CA mutation. We captured rates of PIK3CA mutation testing (anytime and ≤1 year) prior to starting first-line (1L), second-line (2L), and third-line (3L) treatment; test and sample types; secular trends over time; and test turnaround time (TAT). Treatment patterns for patients with a PIK3CA-mutated tumor were also described from 2019 onwards. Results: Among 14,246 HR+/HER2- mBC patients treated at community sites, 4,537 had a PIK3CA mutation test result during the study period. 25% of patients had more than one PIK3CA mutation test. Test rates increased from 2011 to 2023 for all patients starting 1L, 2L, or 3L during the study period (Table). In 2023, the percentage of patients tested anytime prior to 1L, 2L, and 3L start dates were 11% (37 of 324 patients), 52% (140 of 271 patients), and 65% (133 of 204 patients), respectively. Among tested patients, those who were tested between 1L and 2L increased from 32% in 2018 to 45% in 2023. Median time from mBC diagnosis date to first test was variable across years: 8, 10, and 3 months in 2018, 2020, and 2022, respectively. During the study period, most PIK3CA mutation tests were next-generation sequencing (NGS) (88%) and used tumor tissue (72%). Median TAT decreased from 12 days in 2018 to 7 days in 2023. Among patients with a PIK3CA-mutated tumor in 2019 and onwards who received treatment, 36% of patients received alpelisib-containing regimens. Conclusions: PIK3CA mutation testing in HR+/HER2- mBC patients has increased over time in community clinical practice, and timing has shifted to earlier lines of therapy among tested patients. However, overall testing and subsequent treatment with pathway-directed therapy are still low despite clinical guidelines, which may reflect potential gaps in access to PIK3CA mutation testing and the continued unmet need regarding available targeted agents within the current treatment landscape. [Table: see text]
Characterizing clinical trials for CAR T targeting solid tumors from 2018 to 2023: A systematic review.
Authors: William Wesson, Fathima Shehnaz Ayoobkhan, Zahra Mahmoudjafari, Muhammad Umair Mushtaq, Al-Ola A. Abdallah, Weijing Sun, Faiz Anwer, Gary C. Doolittle, Joseph McGuirk, Raed Moh'd Taiseer Al-Rajabi, Joaquina Celebre Baranda, Nausheen Ahmed
Journal: Journal of Clinical Oncology (2024)

e15080 Background: In the last decade, there have been many advances in the treatment of solid tumors, including new chemotherapy agents, immunotherapy, and most recently, cellular therapies. Chimeric antigen receptor T-cell (CAR T) therapy, first approved for acute lymphoblastic leukemia in 2017, represented a paradigm shift in hematologic malignancies, producing response rates that dramatically outpaced alternative regimens in a relapsed/refractory patient setting. Approvals in large B-cell lymphomas and multiple myeloma followed. Excited by the potential of CAR T, investigators worldwide have initiated trials to investigate the use of CAR T in solid tumors. This review explores the trials conducted globally, evaluating the potential molecular targets and the status of current clinical trials. Methods: This systematic review identified CAR T clinical trials specifically targeting solid tumors starting in 2018 to 2023 registered at ClinicalTrials.gov as of January 8, 2024. Trial-related variables including trial phase, primary trial site location, primary endpoints, start and end dates, and molecular target were captured. Results: We screened 110 clinical trials, ultimately including 103 studies for analysis after excluding trials without a CAR T construct in the methods. The number of new clinical trials increased over time, with a significantly larger increase (440%) seen with non-US sponsors compared to US sponsors (100%), p&lt; 0.0001. Only 19 trials (18%) are/were being conducted in the United States in the studied time period. There were 33 unique molecular targets used, with mesothelin (17%), and the claudin protein family (13%) as the most frequented targets. Conclusions: The success that CAR T has demonstrated in hematologic malignancies has created great hope in solid tumor malignancies, although tempered by differences between the two categories. Unlike hematologic cancers, solid tumors exhibit significant biomarker variation, with interpatient biomarker expression varying greatly, even within the same tissue diagnosis. To deal with this issue, the majority of clinical trials that were reviewed here were not restricted to a single disease location such as breast cancer or esophageal cancer but were rather restricted by the expression of the targeted epitope, to allow for the heterogeneity inherent in these tumors. As presented here, substantial efforts are being made worldwide to improve these technologies, but the United States appears to be lagging in clinical trial efforts, compared to other nations. Further investigation is warranted into this topic, as the usage of CAR T quickly spreads from a therapy only used in hematology to one with promise in solid tumors, infectious diseases, and beyond.
Identification of HER2 ultra-low based on an artificial intelligence (AI)-powered HER2 subcellular quantification from HER2 immunohistochemistry images.
Authors: Wonkyung Jung, Taebum Lee, Sangwon SHIN, Biagio Brattoli, Mohammad Mostafavi, Gahee Park, Sukjun Kim, Hyunwoo Lee, Yoon Ah Cho, Eun Yoon Cho, So-Woon Kim, Sergio Pereira, Chang Ho Ahn, Siraj Mahamed Ali, Douglas E Mirsky, Chan-Young Ock
Journal: Journal of Clinical Oncology (2024)

1115 Background: HER2-targeted antibody-drug conjugates (ADCs) can effectively target tumor cells even in HER2-low breast cancers (1+ and 2+/no amp). We developed an AI-based whole-slide image (WSI) analyzer for immunohistochemistry (IHC)-stained slides, exploring a cutoff differentiating between true HER2 negative versus HER2 ultra-low. Methods: An AI-based IHC WSI analyzer was developed using 6,188 WSIs stained by 19 types of IHC including HER2 and from various cancers, annotated by 153 pathologists. The model predicts cells as tumor cells or non-tumor cells and generates HER2 expression continuous score (HER2ecs, 0-100%), quantifying IHC staining intensity of membrane, nucleus, cytoplasm, and membrane+cytoplasm separately for each cell. A total of 401 HER2 IHC WSIs were acquired from Samsung Medical Center (n=275), Kyung Hee University Hospital (n=78), and Commercial Biobank (n=48), scored as 0 (n=347) and 1+ (n=54) by pathologists. Results: In total, 67,169,114 tumor cells and 119,113,886 non-tumor cells from 401 WSIs were successfully evaluated. Comparing HER2 score 0 versus 1+ by pathologists, mean HER2ecs of nucleus (1.7% vs 4.1%), cytoplasm (6.5% vs 12.9%), and membrane (3.6% vs 8.2%) were comparable. In HER2 score 0 WSIs, membrane HER2ecs of tumor cell was 3.6 ± 7.8% (mean ± standard deviation), while that of non-tumor cell was 0.9 ± 2.9% (p &lt;0.001 vs. tumor cell), suggesting, even in HER2 score 0 cases, tumor cell exhibits HER2 expression beyond non-specific HER2 staining intensity. Based on our internal validation dataset, membrane-specific HER2ecs of 6.0% was the optimal threshold discriminating HER2 no-staining cells versus HER2 incomplete and faint/barely perceptible cells (AI-HER2-weak) per ASCO/CAP guideline. Among HER2 score 0 by pathologists, when applying this cutoff, the proportion of WSIs showing AI-HER2-weak or higher membrane-specific HER2ecs in over 10% of all tumor cells was 23.6% (82/347). Interestingly, that of WSIs among HER2 score 1+ by pathologists was 51.9% (28/54), which is comparable to 52.3%, objective response rate of trastuzumab deruxtecan in HER2-low patients in DESTINY-Breast04. Conclusions: AI-powered subcellular-level analysis enables identification of 23.6% HER2 ultra-low WSIs among HER2 score 0 by pathologist, which is defined by AI-HER2-weak or higher membrane-specific HER2 expression ≥ 10%. Clinical validation of the AI-powered HER2 ultra-low definition is warranted.
A single center retrospective cohort study of patients with metastatic breast cancer and leptomeningeal disease: Updated survival data and subgroup analyses by breast cancer subtype.
Authors: Samantha Catherine Fisch, Elene Tsopurashvili, Sai Sahitha Somepalle, Mia Salans, Harish Vasudevan, Amy Jo Chien, Melanie Majure, Hope S. Rugo, Ronald Balassanian, Lauren Boreta, Michelle E. Melisko, Laura Ann Huppert
Journal: Journal of Clinical Oncology (2024)

1108 Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapies. We previously reported data from our retrospective LMD registry; here we provide an update with additional pts and subgroup analyses highlighting differences in treatment and survival by breast cancer subtype. Methods: In this single center retrospective cohort study, we identified pts with MBC and LMD who received care from 2000-2024 and abstracted key clinical, treatment, and overall survival (OS) data. Results: We identified 111 pts with MBC and LMD, including pts with the following subtypes: HR+/HER2- (n=53, 47.7%), HER2+ (n=30, 27.0%), and triple negative breast cancer (TNBC; n=28, 25.2%). The majority of pts had concurrent brain metastasis (n=82, 73.9%). Median time from diagnosis of MBC to LMD was 16.4 months (mo) (range 0-101.3 mo). Pts received a median of 3 lines of therapy prior to the diagnosis of LMD (range 0-10) and 1 line after the diagnosis of LMD (range 0-4). Most pts received central nervous system-directed (CNS)-directed therapy (n=94, 84.7%), including intrathecal (IT) therapy (n=42, 37.8%) and/or CNS radiation (n=70, 63.1%). Median OS from the diagnosis of LMD to death was 4.1 mo (range 0.1-78.1 mo) and varied by subtype, with pts with HR+/HER2- or HER2+ MBC and LMD living longer than those with TNBC and LMD (4.2 and 6.8 mo respectively vs. 2.0 mo, p&lt;0.01, HR 2.15, 95% CI 1.36-3.39). There was no difference in OS by histology ductal vs. lobular or by presence or absence of concurrent parenchymal brain metastases. Pts who received IT therapy survived longer than those who did not (7.1 vs. 2.7 mo, p=0.01, HR 0.60, 95% CI 0.40-0.90). There was difference in OS by receipt of CNS-directed radiation therapy. Pts diagnosed with LMD from 2015-2024 lived longer than those diagnosed from 2000-2014 (6.4 vs. 2.9 mo, p=0.04, HR 0.67, 95% CI 0.46-0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p=0.004, HR 2.03, 95% CI 1.25-3.30). Conclusions: This study represents one of the largest case series of pts with MBC and LMD, including the most pts diagnosed after 2015 to our knowledge. Pts with lobular histology, HER2+ BC, TNBC, and those with de novo MBC were over-represented compared to the general MBC population. Pts with HR+/HER2- or HER2+ disease, LMD diagnosed after 2015, and those who received IT therapy survived longer than their respective cohorts. Novel diagnostic and therapeutic strategies for pts with MBC and LMD remains an area of unmet clinical need.
Real-world treatment patterns and clinical outcomes among patients with HR+/HER2- advanced/metastatic breast cancer receiving palbociclib in Brazil: IRIS study.
Authors: Patricia Simon, Alexandra Guarin, Ankita Jain, Luciana Piton, Julia Lima, Carla Fabrine Carvalho, Felipe Nazareth
Journal: Journal of Clinical Oncology (2024)

e13088 Background: Palbociclib was approved for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (aBC/mBC) in Brazil in 2018. Worldwide studies explore palbociclib's real-world use and outcomes; however, this data is not available for Brazilian patients. IRIS Brazil study aimed to describe demographic/clinical characteristics, treatment and clinical outcomes of adult female patients who have received palbociclib as first-line treatment for HR+/HER2- aBC/mBC in private healthcare institutions in Brazil. Methods: This retrospective descriptive study included females aged 18 years or older diagnosed with HR+/HER2- aBC/mBC and those who had received palbociclib as their initial line of therapy. The study analyzed variables such as demographics, clinical characteristics, treatment history, palbociclib combinations, and clinical outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimates at 6- and 12-month time points. Results: A total of 121 patients were included in the study. The mean age was 54.4 years, and 82 (67.7%) were menopausal at diagnosis. A total of 51 patients (42.1%) were treated with palbociclib + fulvestrant, while 67 (55.8%) were treated with palbociclib + aromatase inhibitors. The majority of patients (n = 79; 65.3%) did not require any dose adjustments. Among the 40 patients (33.1%) who required dose adjustments, the main reason was adverse events/toxicity (n = 36; 90%). The PFS rates at 6 and 12 months were 78% and 60%, respectively. The OS rates at 6 and 12 months were 86% and 70%, respectively. Conclusions: Results from this initial real-world assessment of clinical outcomes in Brazil suggest that Palbociclib combinations exhibit favorable effectiveness in treating HR+/HER2- aBC/mBC disease, as measured by PFS and OS rates.