tbuckley/cabot-search huggingface dataset:
Novel specific TCRs targeting KRAS<sup>G12V</sup>-related cancers.
Authors: Xingwang Xie, Dong J, Jianghua Wang, Jiahui Zhai, Baoqi Yan, Jinglei Bi, Yunqiang Shi, Yonghong Li, Yaping Zhu
Journal: Journal of Clinical Oncology (2024)

e14528 Background: KRAS mutations act as oncogenic drivers in a variety of tumors, such as pancreatic, colorectal and lung cancer. Among these, the KRAS G12V mutation, being one of the most common mutations, is associated with adverse outcomes in patients. KRAS has been regarded as an “undruggable” target, and no clinical trials targeting tumors carrying shared KRAS G12V mutation have been initiated. Notably, KRAS G12D specific TCR-T has shown high effectiveness, including the regression of metastases in patients with pancreatic cancer. Therefore, TCR-engineered T cells could be a promising strategy for the treatment of solid tumors harboring G12V mutation. Methods: We have developed an innovative approach to rapidly and sensitively identify natural TCRs from single T cell derived from patients using CorreGene’s Single T cell TCR Cloning platform, thus obviating the requirement for NGS sequencing and TCR gene synthesis. Additionally, natural TCRs can be refined with SMART-TCR system, utilizing T cell reporter cell lines to construct a high-throughput T-cell Display Platform for functional screening of TCRs. This system is meticulously designed to enrich TCRs with superior potency and specificity from a natural TCR mutation library. We performed a thorough assessment of each TCR identified, evaluating them across both in vitro and in vivo settings. Results: In the present study, we identified three natural TCRs from patients' TILs, designated as KVA11-N01, KVA11-N02 and KVA11-N04 respectively, that specifically recognized the HLA-A*11:01-restricted KRAS G12V epitope. KVA11-N01 exhibited lower affinity and potency, prompting us to develop an affinity-optimized variant, KVA11-M01-231, using the SMART-TCR system. For comparison, we used the murine TCR TRAV3-301/BV401, identified by NCI from HLA-A11:01 transgenic mice immunized with KRAS G12V 7-16 , as a benchmark. Three of our TCRs, including KVA11-N02, KVA11-N04 and the engineered KVA11-M01-231, outperformed TRAV3-301/BV401 in both in vitro and in vivo assays. These three TCRs exhibited excellent expression intensity and stability on T cells, and notably, their IFN-γ release potency surpassed that of TRAV3-3*01/BV4*01. Furthermore, in vivo experiments confirmed the significant tumor suppression efficacy of our TCRs in a tumor-bearing mouse model, showing enhanced tumor growth inhibition compared to TRAV3-301/BV401. TCRs from Corregene’s platform exhibited exceptional specificity, with no allo-reactivity, no reaction to KRAS G12V -negative cell lines, and no off-target effects. Additionally, all our TCRs demonstrates favorable tolerance in mice during in vivo studies. Conclusions: TCRs via Corregene’s Single T cell TCR Cloning platform and SMART-TCR system showed significantly excellent anti-tumor activities with great specificity and offers a promising solution for the treatment of KRAS G12V -related cancers.
Chimeric antigen receptor T-cell therapy in B-cell malignancies and DNA-methylation–based biological aging.
Authors: Drew Robert Nannini, Rene Cortese, Gerhard Hildebrandt
Journal: Journal of Clinical Oncology (2024)

2562 Background: Chimeric antigen receptor T-cell (CAR T-cell) therapy, a type of cancer immunotherapy which leverages genetically altered T cells to target cancer cells, has shown to be an effective option for patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Despite its growing use, the effect of CAR T-cell therapy on the aging process remains limited and findings may have implications for disease relapse and age-related diseases among survivors. The purpose of this study was to investigate the association between CAR T-cell therapy and markers of biological aging. Methods: DNA methylation and clinical data from a publicly available dataset (GSE179414) were used in this analysis. Transduced and untransduced T cells from patients with ALL (n=77) and NHL (n=37) underwent DNA methylation profiling using the Illumina Infinium MethylationEPIC BeadChip. Six DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), telomere length attrition (TLA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear regression analyses were performed to examine the association between CAR T-cell therapy and the aging metrics by B-cell malignancy. Interaction and stratified analyses by chronological age was additionally performed. Results: DunedinPACE ( P=0.002) was positively associated with CAR T-cell therapy among patients with ALL with an approximately 1-month higher pace of aging in transduced T cells compared to untransduced T cells after adjusting for chronological age and sex. Moreover, chronological age significantly ( P=0.016) modified the association between CAR T-cell therapy and TLA among ALL patients. Specifically, transduced T cells exhibited a 0.46 higher ( P=0.053) and a 0.39 lower ( P=0.142) rate of TLA among patients 16 years of age or older and those younger than 16 years of age, respectively. Conclusions: We observed CAR T-cell therapy was associated with greater biological aging as estimated from DNA methylation among ALL patients and these associations are modified by chronological age. These findings suggest CAR T-cell therapy may be associated with age-related changes to the epigenome in ALL patients and strategies to limit or reverse this effect may have implications for the aging process in cancer survivors. [Table: see text]
A randomized, controlled, phase 2 trial of nivolumab plus standard-dose or low-dose bevacizumab for recurrent glioblastoma (NAVAL).
Authors: Manmeet Singh Ahluwalia, David M. Peereboom, Ahmad Ozair, Atulya Aman Khosla, Yasmeen Rauf, Lakshmi Nayak, Marci Ciolfi, Tyler Alban, Matthew Grabowski, Pat Rayman, Marcella Diaz, Justin Lathia, Eudocia Quant Lee, Patrick Y. Wen, David A. Reardon
Journal: Journal of Clinical Oncology (2024)

2072 Background: PD-1/PD-L1 inhibition has demonstrated limited efficacy for recurrent glioblastoma (rGBM) across prior RCTs. VEGF, a proangiogenic factor upregulated in rGBM, contributes to tumor-associated immunosuppression. Preclinical and observational clinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immune response. This RCT evaluated anti-PD-1 plus anti-VEGF therapy for rGBM. Methods: NAVAL was a multicenter, open label, phase 2 RCT that enrolled 90 patients (≥18 years) with GBM at first recurrence. Participants received nivolumab (240 mg IV Q2 weeks), and were 1:1 randomized to concurrent 10 mg/kg bevacizumab ( standard-dose arm) or 3 mg/kg bevacizumab ( low-dose arm) administered IV biweekly. Stratification factors included age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months (OS-12). Other outcomes were overall objective response rate (ORR), median progression-free survival (PFS), PFS at 6 months (PFS-6), and safety. Exploratory genomic and immune profiling using CITEseq was performed in 16 patients. Results: 90 patients were enrolled with median age of 60.6 years (range 27-86). 35 patients were MGMT methylated, 53 were unmethylated and 2 were indeterminate. Final analysis had 87 evaluable patients, with median follow-up of 146 days (range 7-1239). There were 3 complete responses (3.4%), 29 partial responses (33.3%), 37 stable disease (42.5%), and 18 progressive disease (20.7%). OS-12 was 41.1% and 37.7% in standard-dose and low-dose arms respectively, with PFS and ORR data in table. Post-hoc analysis demonstrated survival benefit for patients aged ≥60 years in standard-dose arm. Most frequent toxicities (&gt;20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Grade 3-4 toxicities included hypertension (7.8%), fatigue (5.6) and non-neurological toxicities. Differential changes across trial arms were seen in myeloid-derived suppressor cells (MDSCs) post-therapy. Network medicine identified VEGF as target to reduce MDSCs. VEGF was found expressed by MDSCs of mainly responder patients. Differential gene expression analysis identified increased pro-inflammatory gene signatures in standard-dose arm. Conclusions: Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen in standard-dose arm in elderly. Standard-dose bevacizumab was associated with increased systemic inflammatory response and reduced immunosuppressive MDSCs. Clinical trial information: NCT03452579 . [Table: see text]
Analysis of long-lasting tumor-specific antibodies from murine tumors treated with Aliya pulsed electric fields.
Authors: Chiara Pastori, Ebtesam Nafie, Robert Evans Neal
Journal: Journal of Clinical Oncology (2024)

e14543 Background: Pulsed electric field (PEF) tissue destruction has demonstrated meaningful systemic immune responses in mice that are superior to thermal ablation, and synergize effectively with systemic chemotherapy and checkpoint blockade (CPB) immunotherapy. Immune cell populations are increased by PEF, including tumor specific activated CD8 T-cells and plasma B-cells. Antitumor immunity can include the presence of circulating anti-cancer antibodies. However, the presence and role of circulating tumor specific antibodies induced by PEF have not been explored. Serological antibodies are often detected with the ELISA assay, where tumor-associated antigens are coated to a microtiter plate to attract the corresponding serum antibodies. Here, we quantify IgG tumor specific antibodies after PEF using an in-house ELISA. Methods: Mice bearing immune-warm (EMT6) and immune-cold (4T1) orthotopic murine breast tumors were treated with a biphasic PEF dose comparable to Aliya titrated for mouse tumors. To detect tumor specific circulating IgG1 immunoglobulin in serum, an ELISA plate was coated with EMT6 and 4T1 protein lysate, as well as with a known 4T1-expressed tumor-specific antigen (gp70). Serum draws from the treated, untreated, and naïve mice were exposed to the coated wells for 1 hour. Bound IgG were detected by anti-mouse IgG (HRP tagged) antibody added to the wells and incubated 1 hour. A TMB substrate was added and color development was allowed for 15 minutes. The optical density was quantified using a microtiter plate reader. Results: ELISA quantification of serum IgG at multiple timepoints show that 4T1 tumor-specific IgG antibodies were increased 14.3- and 2.6-fold by day 20 in the PEF-treated and untreated group survivors relative to Naïve mice, respectively, (OD=0.86 and 0.15 v. 0.06). Furthermore, IgG antibodies specific to the gp70 antigen of the 4T1 cell line were increased by 44.9- and 2.7-fold in the PEF-treated and untreated groups relative to naïve mice (OD=3.14 and 0.19 v. 0.07). In the EMT6 model, at 3 months post-treatment, only the PEF-ablated group mice survived, and showed 15.5-fold higher antibodies against EMT6 tumor antigens compared to naive mice (OD=0.62 v. 0.04). Conclusions: The specific form of PEF in this study generated tumor-specific IgG long-lived antibodies in mice for immune-warm and immune-cold tumor models, corroborating previous findings of increased murine B-cell and plasma cell populations. This effect has not been well-reported for other ablation technologies. Increases were evident by Day 20 post-PEF and persisted at least 3 months. These murine data suggest the PEF used may invoke potent, long-lived immune responses and anti-tumor immune surveillance, offering a potential approach for in situ tumor vaccination to improve metastatic disease outcomes. Future studies should determine response durability and its role in attaining distant tumor clearance.
Effect of targeting DDR pathway on the late-phase autophagy and the killing effect of CD8+ T cells.
Authors: Guo Li, Chenghao Xuan, Diansheng Zhong, Linlin Zhang
Journal: Journal of Clinical Oncology (2024)

e14646 Background: Deficiency in DDR signaling pathways has been reported to be associated with better response to immunotherapy. This study aims to investigate whether inhibition of the key mediator of DDR pathways ATR could enhance the function of CD8+ T cells and its underlying mechanism. Methods: The CD8+ T cell-killing experiment was conducted in vitro to demonstrate the efficiency in the presence of ATR inhibitors. To investigate the regulatory mechanism, RNA Sequencing analysis was performed to identify gene changes after ATR inhibition. Subsequently, Western blotting and immunofluorescence assays were performed to access the autophagy flux based on the results of the RNA sequencing analysis. Flow cytometry was used to detect the surface MHC-I expression to validate our speculation with the change of autophagy activity. Results: ATR inhibitor (VX970) had been shown to enhance the cytotoxic effect of CD8+ T cells on tumor cells. RNA-seq analysis revealed the enrichment of pathways related to autophagy and its regulation, as well as inflammatory factor pathways. Accumulation of p62/SQSTM1 and an increased LC3II/I ratio had been found, indicating the involvement of autophagy after the inhibition of ATR. No further increase in autophagy proteins was observed upon treatment with autophagy inhibitors, suggesting the late stage of autophagy inhibition was affected. In addition, increased MHC-I molecular expression has been found in accordance with autophagy inhibition, which could further explain the reason ATR inhibition could induce the accumulation of CD8+ T cells. Conclusions: Targeting DDR pathway leads to stimulated CD8+ T cells accumulation probably by increased MHC-I surface expression through inhibition of late-phase autophagy, which may in turn enhance the efficiency of immunotherapy.
Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial
Authors: Naoki Inui, Takahito Suzuki, Kazuki Tanaka, Masato Karayama, Yusuke Inoue, Kazutaka Mori, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Tomoyuki Fujisawa, Shun Matsuura, Koji Nishimoto, Takashi Matsui, Kazuhiro Asada, Dai Hashimoto, Masato Fujii, Mitsuru Niwa, Masahiro Uehara, Hiroyuki Matsuda, Keigo Koda, Masaki Ikeda, Nao Inami, Yutaro Tamiya, Masato Kato, Hideki Nakano, Yasuaki Mino, Noriyuki Enomoto, Takafumi Suda
Journal: Journal of Clinical Oncology (2024)

We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT
The rationale of reprogramming TREM2+ macrophages for overcoming the resistance to immune checkpoint inhibitors in pancreatic adenocarcinoma.
Authors: Harshitha Ravichandran, Heng-Chung Kung, Rui Zhang, Kai Chen, Juan Fu, Lei Zheng
Journal: Journal of Clinical Oncology (2024)

e14649 Background: Pancreatic ductal adenocarcinoma (PDAC) resists to immune checkpoint inhibitors as single agents. TAMs expressing the triggering receptor expressed on myeloid cells (TREM2) protein were found to be a dominant macrophage population in PDAC; targeting TREM2 has been found to enhance the efficacy of immune checkpoint inhibitor-based therapies in preclinical studies of other malignancies. Here, we studied the role of targeting TREM2 in PDAC by testing the combination of non-depleting anti-TREM2 antibody and anti-PD-1 antibody in a mouse model of PDAC. We also examined the relationship between TREM2 expression and effector T cells in surgically resected human PDAC collected from a previous clinical trial treated with the neoadjuvant combination therapy of nivolumab (anti-PD-1 antibody), urelumab (anti-CD137 agonist antibody), and the pancreatic cancer GVAX vaccine. Methods: C57BL/6 mice were orthotopically implanted with KPC tumors. Anti-TREM2 was injected intraperitoneally (i.p.) once a week and anti-PD-1 was injected i.p. twice a week. Tumor volume was measured by ultrasound. TREM2 was stained on slides which were previously obtained from surgically resected PDACs following the neoadjuvant combination treatment of nivolumab, urelumab, and GVAX and stained for multiple immune cell markers with a multiplex staining-striping immunohistochemistry (IHC) technique. Results: Tumor growth post-tumor implantation was found to be significantly decreased by the anti-PD-1 and anti-TREM2 combination compared with anti-PD-1 alone, anti-TREM2 alone, or control treatment (p &lt; 0.0001). Survival of tumor-bearing mice was significantly prolonged by the anti-PD-1 and anti-TREM2 combination when compared to anti-PD-1(p &lt; 0.05), anti-TREM2(p &lt; 0.05), and control (p &lt; 0.01). Multiplex IHC analysis of human PDACs following neoadjuvant immunotherapy showed a higher density of granzyme B+CD8+ effector T cells correlated with higher density of TREM2+ cells (p = 0.0357). Conclusions: Our study demonstrates the anti-tumor efficacy of anti-TREM2 antibody in combination with an immune checkpoint inhibitor in mouse PDAC. However, the analysis of human PDAC following neoadjuvant immunotherapy suggests that TREM2 on TAMs may be activated following the activation of effector T cells. Taken together, our results suggest that TREM2+ TAMs should be reprogrammed instead of being depleted in the design of anti-TREM2-based therapy for PDAC.
Using exponential decay to model survival curves in immunotherapy trials.
Authors: Tarquin Dean Opperman, David J. Stewart, Abdullah Nasser
Journal: Journal of Clinical Oncology (2024)

e14698 Background: In oncology trials, survival outcomes, specifically overall survival (OS) and progression-free survival (PFS), are commonly assessed using the Kaplan–Meier estimator. Survival curves in immunotherapy trials for advanced solid tumors frequently display first-order kinetics, suitable for exponential decay modeling. This study utilizes such models on early trial data to predict median OS and PFS, aiming to yield earlier actionable insights. Methods: we searched PubMed to identify immunotherapy trials focusing on advanced solid tumors. Survival curves, along with actual OS and PFS data, were extracted and segmented into immunotherapy and control groups. An exponential decay model was fitted to the initial quartile of events, from which median OS and PFS were extrapolated. These forecasts were then benchmarked against documented trial results. Results: Our analysis included 347 subsets from 122 immunotherapy trials. We observed strong correlation coefficients between actual and predicted OS (0.882 for the immunotherapy group, 0.784 for the control group) and PFS (0.746 for the immunotherapy group, 0.791 for the control group). The predictive models were formulated as follows: Immunotherapy: OS = 0.867 × predicted OS (pOS) + 2.623 ⋅ Control: OS = 0.623 × pOS + 3.731; and Immunotherapy: PFS = 0.583 × predicted PFS (pPFS) + 1.827 ⋅ Control: PFS = 0.519 × pPFS + 1.901. Conclusions: The notable correlation between the actual and predicted survival outcomes supports the efficacy of exponential decay models in forecasting median OS and PFS from preliminary trial data. The consistency observed across trials underscores the model's potential as a predictive tool in clinical research. Further prospective studies are warranted to validate these predictive models and explore their implications for trial design and therapeutic decision-making in oncology.
Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer.
Authors: Malek Shatila, Antonio Pizuorno Machado, Parvir Aujla, Ryan W Huey, Yinghong Wang, Anusha Thomas
Journal: Journal of Clinical Oncology (2024)

e14708 Background: Immune checkpoint inhibitors (ICI) are successfully used to treat microsatellite instability-high (MSI-H) tumors. While immune checkpoint inhibitor related colitis is a frequent and devastating immune related adverse event (irAE) of these agents, the incidence and characteristics of this inflammatory toxicity in patients with MSI-H colorectal cancers has not been examined. We aimed to describe the characteristics and clinical profile of patients diagnosed with luminal gastrointestinal irAE in patients treated with ICI for colorectal cancer in a tertiary cancer care center. Methods: This is a retrospective analysis that included adult cancer patients diagnosed with colorectal cancer that received ICI between 6/1/2014 and 12/31/2022. We report data on those that developed colitis as an irAE up to 3 months after the last dose of ICI confirmed by laboratory and/or imaging report. We included patients’ demographic characteristics, oncologic profile and outcomes as well as clinical course, endoscopic features as well as treatment and outcomes in terms of luminal gastrointestinal irAEs. Results: Out of 474 patients with colorectal cancer on ICI in our study period, only 18 developed a gastrointestinal irAE with an incidence of 3.8%. Patients were primarily Caucasian (88.8%) males (61.1%) with a median age of 69.5 years. The majority of these patients received combination therapy with anti-PD1/L1 and CTLA-4 (50%). 66.6 % received ICI for MSI-H colorectal cancer. 11.1% of our sample were noted to have a second cancer-melanoma. The major-ity of patients had grade 1-2 colitis (61.2%) and grade 1-2 diarrhea (88.8%). Only 5 patients underwent endoscopic evaluation of whom, 2 had ulcerative inflammation necessitating use of selective immunosuppressive therapy with biologics. 61.1% had to withhold cancer treatment due toxicity. With regards to other gastrointestinal irAEs among this population, 41.4% and 5.8% were noted to have liver and pancreas toxicity respectively, with a median CTCAE grade of severity 2. The most common treatment for these toxicities were steroids. Conclusions: Luminal gastrointestinal irAEs seem to occur less frequently and at a lower severity among patients with MSI-H colorectal cancer after checkpoint inhibitors exposure compared to the overall incidence of the same among other cancers reported in literature. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of immune related adverse events of the GI organ system. [Table: see text]