tbuckley/cabot-search huggingface dataset:
Using the tumor microenvironment to identify predictors of immunotoxicity to checkpoint inhibitors.
Authors: William Alexander, Kristopher Attwood, Kayla Catalfamo, Grace K. Dy, Saby George, Marc S. Ernstoff, Yara Abdou
Journal: Journal of Clinical Oncology (2021)

2545 Background: While Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, the benefits have come at the cost of serious side effects known as immune-related adverse events (irAEs). Approaches that can predict patients’ susceptibility to irAEs are key to their early detection and management. In the present study, we investigate the association between irAEs reported during ICI therapy across multiple cancer types and markers of tumor immune response. Our primary objective is to explore potential biomarkers for assessing patients’ risk of irAEs. Methods: 472 patients were evaluated who had tumor immune profiling performed paraffin embedded formalin fixed archival tumor biopsy samples using Omniseq Immune Report Card (IRC) and subsequently underwent ICI therapy. The IRC consisted of enumeration of tumor infiltrating lymphocytes (TILs) by immunohistochemistry (IHC) and TIL-associated genes by RNA-Seq, PD-L1 expression by IHC, and tumor mutational burden (TMB) by DNA-Seq. irAE type and grade were determined based on retrospective chart review. Fisher’s exact test was used to determined statistically significant associations between immune markers and irAE development. Results: Patients with lung (55%), ovarian (9%), and melanoma (5%) cancers constituted the majority of the cases. The median age of patients was 61, with 56% being female and 44% male. Most patients underwent treatment with (94%). irAEs developed in 36% of patients, with 2% of patients developing high-grade irAEs (Grade 3 or 4). Skin (11%), thyroid (10%), and GI (9%), were the most commonly affected organ systems. Increased TILs were associated with increased risk for any irAE (p = 0.04). A stronger association was noted in patients who underwent anti-PD-1/L1 monotherapy (p = 0.01) and/or in cases of lung cancer (p = 0.01). Interestingly, subanalyses by gender showed a statistically significant correlation between increased TILs and risk for any irAE in males (p = 0.006) but not in females (p = 0.63). High PD-L1 (defined as &gt; 70% by IHC) was also significantly associated with increased risk for any irAE (p = 0.03). Subanalyses by gender and age again showed a similar association in females (p = 0.0002) and/or patients &lt; 65 years (p = 0.04). high TMB and any irAE in female patients (p = 0.01) and in breast cancer cases (p = 0.03). On multivariate analysis, TILs by IHC appeared to be the strongest predictor of irAEs (p = 0.03). Conclusions: The tumor immune microenvironment (TME) has been shown to influence response to ICI, yet its association with irAEs has not been well studied. Our analysis sheds light on potential TME predictors for irAE in patients receiving ICI therapy. Further studies are needed to deepen our understanding of immune toxicity and to develop tools for identifying patients who are at risk.
Organotin compounds as effective antimetastatic substances in the treatment of epidermoid lung carcinoma Lewis (LLC) in an experiment.
Authors: Margarita Avdeevna Dodokhova, Inga Movlievna Kotieva, Andrej Vladimirovich Safronenko, Dmitriy Borisovich Shpakovsky, Elena Rudolfovna Milaeva, Alexander Albertovich Shtil, Ekaterina Fedorovna Komarova, Margarita Stefanovna Alkhuseyn-Kulyaginova
Journal: Journal of Clinical Oncology (2021)

e15054 Background: Lung cancer occupies one of the first places in the structure of oncological diseases in the world. Reducing the life expectancy of patients, as a rule, occurs as a result of metastatic complications, so the search for new antimetastatic agents is an urgent task for experimental pharmacology and oncology. The aim of our study is to assess the severity of metastatic lesion in the Lewis lung epidermoid carcinoma (LLC) model in the presence of an organotin compound. Methods: The study was conducted on experimental C57BL/6 mice (n = 24, each group contained 12 mice) with LLC (subcutaneous transplantation) in the presence of the cytotoxic organotin compound 2,6-bis (1,1-dimethylethyl) - 4 - [(triphenylstannyl)thio]phenol (Me5). All manipulations were carried out in accordance with the European Convention for the Protection of Vertebrates Used for Experimental and Other Scientific Purposes (ETS 123). Female mice (8 weeks of age, weighing 21-22 g) were intraperitoneally injected with a 1% aqueous gelatin solution of organotin Me5 daily for 5 days. The most effective total dose of Me5 was 250 mg / kg. The animals of the control group received saline solution in similar modes and volumes. In the experimental and control groups, the degree of metastatic lesion was assessed on the 21-day post-grafting period according to the scale proposed by D. Tarin and J. E. Price, which allows us to differentiate the severity of the lesion depending on the number of metastases and their size. The experiment describes three degrees of lesion: LCP-1 (metastases less than 10 pcs. with a diameter not exceeding 1 mm); LCP-2 (metastases from 10 to 30 pieces, some of them larger than 1 mm) and HCP-3 (metastases larger than 30 pieces of different sizes, but no drain). The pathohistological structure was studied by the light-optical method with hematoxylin and eosin staining. Results: When administered intraperitoneal to mice, Me5 did not inhibit the growth of the primary tumor site in the experimental group, but significantly reduced the severity of metastatic lesions in the lungs. In the control group, 75 % of mice with LLC had LCP - 2 (low colonization potential) and in 25% of HCP-3 (high colonization potential) metastatic lesions, in the experimental group only mild lesions were noted in all animals: 58% of mice had LCP – 1, 42% - LCP-2. Conclusions: It is concluded that the overall result of this study clearly demonstrates that the organotin compound 2,6-bis (1,1-dimethylethyl) - 4 - [(triphenylstannyl)thio] phenol (Me5) is an effective antimetastatic agent in the Lewis lung epidermoid carcinoma (LLC) model at a total dose of 250 mg/kg.
Prognostic subset of metastatic and non-metastatic luminal B breast cancer (LBBC) subtype based on Ki67 index.
Authors: Lalnun Puii, Lalram Sangi, Hrishi Varayathu, Samuel Luke Koramati, Beulah Elsa Thomas, Smruthy Ann Mathew, Shalaka Somayaji, Satheesh Chiradoni Thungappa, Sriniivas Bj, Vinayak Munirathnam, Shivakumar Swamy, Tejaswini BN, Suhail Sayeed Mufti, Radheshyam Naik, Basavalinga Sadasivaiah Ajaikumar
Journal: Journal of Clinical Oncology (2021)

e12570 Background: Gene expression profiling for breast cancer has classified ER positive subtype into luminal A and luminal B. Luminal B breast cancer (LBBC) have a higher proliferation and poorer prognosis than luminal A tumors. Ki-67 index is the commonly used proliferation marker in breast cancer; however Ki67 expression can also be used to identify a subset of patients among LB with a favorable prognosis. This study attempts to verify this subset of LBBC patients based on DFS and PFS in non-metastatic and metastatic patients respectively. Methods: We retrospectively analyzed 80 IDC breast cancer patients diagnosed in 2013-2016 with complete follow-up till January-2021. We defined LBBC as ER+, PR+ or PR- , HER2+ or HER2- with a Ki67 index &gt;20%. PFS was considered as the endpoint in patients presenting with metastatic disease whereas DFS was used in non-metastatic disease. The cut-off for ki67 was calculated using an X-tile plot (version 3.6.1, Yale University) by dividing Ki67 data into two populations: low and high, with randomized 1:1 “training” and “validation” cohorts. Results: Median age was 51.5 years. 18.7% (n=15) presented with metastasis at the time of diagnosis and their overall median PFS was found to be 25.8 months. The incidence of HER2 positive LBBC was found to be 15% (n=12) and none of them were found to be presented with metastasis. Survival and frequency of various sub groups in our study are enlisted in the given table. We estimated a Ki67 cut-off of 30% in patients with upfront metastatic disease and PFS was found to be higher in &lt;30% compared to a Ki67 index &gt;30% (38.9 months vs 19.7 months, p-0.002). Overall median DFS was not achieved in non-metastatic group (Mean DFS: 64.7 months) where as a statistically significant difference was observed in the survival of HER2 positive (median DFS: 53.5 months, mean DFS: 50.9) than HER2 negative patients (median DFS not achieved, mean: 66.97 months) ( p-0.021). We obtained a Ki67 cut-off of 32% in non- metastatic group and mean DFS was found to be higher in Ki67&lt;32% (69 months) compared to Ki67&gt;32% (61.4 months), however it failed to exhibit a statistically significant relationship ( p-0.373). Conclusions: Our study indicates that a subset of patients exists within metastatic and non-metastatic LBBC with differing prognosis based on Ki67. Larger studies are further required to confirm the findings and therapeutic implications.[Table: see text]
Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) (CaNI) for advanced renal cell carcinoma with variant histology (aRCCVH).
Authors: Bradley Alexander McGregor, Wanling Xie, Mehmet Asim Bilen, David A. Braun, Wenxin Xu, Praful Ravi, Elisabeth I. Heath, David F. McDermott, Rana R. McKay, Hans J. Hammers, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

TPS4592 Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment naïve or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Database Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1-sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123.
Metastasectomy in colorectal carcinoma (CRC) patients (pts) with mBRAF: Prospective database analysis.
Authors: Mikhail Fedyanin, Kheda Elsnukaeva, Irina Demidova, Daniil Stroyakovskiy, Yuri Shelygin, Alexey Tsukanov, Maria V Panina, Vitaliy Shubin, Fedor Vladimirovich Moiseenko, Elena Karpenko, Larisa Bolotina, Anna Kudryavtseva, Maxim Filipenko, Liubov Yu Vladimirova, Natalya N. Timoshkina, Oleg I. Kit, Anna Stroganova, Svetlana Dranko, Alexey Tryakin, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2021)

e15549 Background: Role of metastasectomy in pts with mBRAF metastatic CRC is still controversial. We performed analysis of prospective multicentric database of pts with mBRAF mCRC to evaluate the efficacy of metastasectomy in such group of pts in the real clinical practice. Methods: We analyzed a database of pts with mCRC in 7 cancer clinics in Russia and chose pts with metastasectomy with different mutational status. The primary endpoints were disease free survival (DFS) and overall survival (OS), which were calculated from the time of metastasectomy. Analysis was performed with the SPSS v.20 software package. Results: The study included 126 pts: 26 pts with mBRAF, 57 pts with mRAS and 43 pts with wtRAS/BRAF. Pts with mBRAF more often had synchronous metastases (50%/19,3/11,6%, p&lt;0,01), N2 status (38,5%/11%/19,6%, p=0,04). In mBRAF cohort all but 1 pt had V600 mutations; peritonectomy performed in 19,2%, liver resection – in 34,6%, lung resection, ovariectomy, metastasectomy in brain and retroperitoneal lymph nodes dissection with removal of the local relapse – over 11,5%; R0 resection was achieved in 88,5%. Median DFS was 7 months in mBRAF pts, 14 months in mRAS and not achieved in wtRAS/BRAF group treated (HR 2,1, 95%CI 1,5-3.1, p&lt;0.01). Median OS was 26 months in mBRAF, 38 months in mRAS and not achieved in wtRAS/BRAF group (HR 1,5, 95%CI 1,0-2,4, p=0.06). Perioperative chemotherapy didn’t improve DFS in pts with mBRAF (HR 1,9, 95%CI 0,67-5,7, p=0,2). The best median DFS were in pts after ovariectomy – 10 months, the worst - after retroperitoneal lymph nodes dissection with removal of the local relapse – 2 months. Conclusions: Prognosis of pts with mBRAF after metastasectomy is worse than with other mutational phenotypes. However in selected cases metastasectomy might be considered in such aggressive mCRC.
Donor-derived CD7 CAR T cells for T-cell acute lymphoblastic leukemia.
Authors: Jing Pan, Jing Pan, Biping Deng, Zhuojun Ling, Weiliang Song, Jinlong Xu, Jiajia Duan, Zelin Wang, Alex Chang, Xiaoming Feng
Journal: Journal of Clinical Oncology (2021)

10001 Background: Despite the success of chimeric antigen receptor T cell therapy in B cell malignances, there is currently no proved CAR T treatment for T cell neoplasms. We provide first evidence support the use of donor derived CAR T cells in T cell leukemia. Methods: In this phase 1 trial, CD7 CAR T cells were manufactured with T cells from prior SCT prior to a single infusion at doses of 5 × 10 5 or 1 × 10 6 (± 30%) cells per kilogram of body weight. donors, or from new donors who were HLA-matched or haploidentical, via leukopheresis and transduced with a lentiviral vector which carries a CD7 CAR construct. The primary endpoint was safety. Short-term efficacy was also assessed. Results: Results of 20 enrolled patients who received infusion are reported. Of 20 patients, 12 received previous HSCT-donor derived CAR T cells and 8 received fresh haplo-identical donor derived CAR T cells and plan to received transplantation as consolidation after remission.Adverse events included grade 3-4 hematologic toxicity in all (100%), grade 3-4 and grade 1-2 cytokine release syndrome in 2 (10%) and in 18 (90%), grade 1 neurotoxicity in 3 (15%), grade 1-2 graft-versus-host disease in 12 (60%), and grade 1 viral activation in 3 (15%) patients. Nineteen (95%) patients had a response, including 18 (90%) with complete remission and 1 (5%) with partial remission. Of 19 responders, 7 were bridged to SCT and remained minimal residual disease (MRD)-negative until last visit; 12 were followed up at a medium of 4.4 months, among whom 9 remained MRD-negative, 1 had a relapse, 1 discontinued for other treatment, and 1 died of pulmonary fungal infection at 5.5 months. CAR cells mostly persisted beyond 3 months. Patient CD7-positive healthy T cells were depleted, while CD7-negative T cells increased. Conclusions: We report the initial toxicity profile and anti-leukemia activity of a donor-derived CD7-targeted cellular immunotherapy for patients with relapsed or refractory T-ALL. (Funded by the National Key R&amp;D program; ChiCTR.org number, ChiCTR2000034762). Clinical trial information: ChiCTR2000034762. [Table: see text]
Baseline Cytogenetic Response Is a Predictor of Outcome of Third Line 2nd Generation TKI Treatment in Chronic Phase Chronic Myeloid Leukemia Patients
Authors: Natalia Lazorko, Elza Lomaia, Vasily Shuvaev, Irina Martynkevich, Mikhail Fominykh, Anna Silyutina, Katerina Ovsiannikova, Nadia Siordia, Andrey Zaritskey, Elena Machulaytene
Journal: Blood (2017)
Identifying gaps in the coverage of survivorship care services.
Authors: Anne Hudson Blaes, Maysa M. Abu-Khalaf, Catherine M. Bender, Susan Faye Dent, Chunkit Fung, Sophia Kustas Smith, Samantha Watson, Sweatha Katta, Janette K. Merrill, Shawna V. Hudson
Journal: Journal of Clinical Oncology (2021)

6583 Background: Despite advancements in reimbursement, anecdotal evidence suggests patients are not able to access guideline concordant survivorship care services due to a lack of coverage by payers. We present the results of a mixed methods study aimed to determine the practice-reported rates and sources of delay/denial on evidence-based, guideline concordant survivorship care services. Methods: A quantitative survey was developed by ASCO’s Cancer Survivorship Committee (CSC) to assess which services are being denied by payers for coverage/reimbursement. Questions were limited to disease sites for which practice guidelines exist. 533 ASCO members who provide survivorship care were surveyed, with a focus on obtaining representation from rural/urban, academic/private practice, pediatric/adult, and geographic location across the U.S. Semi-structured telephone interviews were conducted in October and November 2020 with geographic sub sample representation to further explore the nature of and extent to which coverage barriers are experienced for guideline-concordant care, specific to the provider or clinic’s primary disease site or specialty. Results: 120 responses from 50 states were included. Respondents were primarily clinicians (88%) with the majority treating patients with Medicare/Medicaid/CHIP (60%), followed by private/employer insurance (38%). There was little issue with coverage of hormone therapies. One-third reported issues some of the time with maintenance chemotherapy (38%) and immunotherapy (35%). Coverage denials for screening for recurrence for breast cancer (MRI, 63.5%), Hodgkin Lymphoma (PET/CT 47%; Breast MRI, 44.4%), and lung cancer (Low-dose CT 37.4%) were common. Half of the survey respondents reported denials for supportive care/symptom management services (Table). Private or employer-based insurance denials were most often the source of barriers (57.7%). Through interviews, denials were found to be the same across sites and not unique to a single payer or region. Most had a process to appeal denials for evidence-based services. Conclusions: Denial for survivorship care, particularly supportive care services, is common. There is a need for better advocacy with payers, improved policy, and support for providers/practices to implement protocols to obtain coverage for services, particularly in the face of burnout.[Table: see text]
Patient-derived micro-organospheres recapitulate tumor microenvironment and heterogeneity for precision oncology.
Authors: Shengli Ding, Zhaohui Wang, Marcos Negrete Obando, Grecia rivera Palomino, Tomer Rotstein, Ian Williamson, Shiaowen David Hsu, Xiling Shen
Journal: Journal of Clinical Oncology (2021)

3076 Background: Preclinical models that can recapitulate patients’ intra-tumoral heterogeneity and microenvironment are crucial for tumor biology research and drug discovery. In particular, the ability to retain immune and other stromal cells in the microenvironment is vital for the development of immuno-oncology assays. However, current patient-derived organoid (PDO) models are largely devoid of immune components. Methods: We first developed an automated microfluidic and membrane platform that can generate tens of thousands of micro-organospheres from resected or biopsied clinical tumor specimens within an hour. We next characterized growth rate and drug response of micro-organospheres. Finally, extensive single-cell RNA-seq profiling were performed on both micro-organospheres and original tumor samples from lung, ovarian, kidney, and breast cancer patients. Results: Micro-organospheres derived from clinical tumor samples preserved all original tumor and stromal cells, including fibroblasts and all immune cell types. Single-cell analysis revealed that unsupervised clustering of tumor and non-tumor cells were identical between original tumors and the derived micro-organospheres. Quantification showed similar cell composition and percentages for all cell types and also preserved functional intra-tumoral heterogeneity.. An automated, end-to-end, high-throughput drug screening pipeline demonstrated that matched peripheral blood mononuclear cells (PBMCs) from the same patient added to micro-organospheres can be used to assess the efficacy of immunotherapy moieties. Conclusions: Micro-organospheres are a rapid and scalable platform to preserve patient tumor microenvironment and heterogeneity. This platform will be useful for precision oncology, drug discovery, and immunotherapy development. Funding sources: NIH U01 CA217514, U01 CA214300, Duke Woo Center for Big Data and Precision Health