tbuckley/cabot-search huggingface dataset:
The use of cryoablation to overcome resistance to PD-1 blockade in unresectable melanoma.
Authors: Meghan Mooradian, Florian J. Fintelmann, Howard E. Kaufman, Mari Mino-Kenudson, Jaimie Lynn Barth, Aleigha Lawless, Tatyana Sharova, Riley Fadden, Krista M. Rubin, Donald P. Lawrence, Dennie T. Frederick, Moshe Sade-Feldman, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2021)

9538 Background: Percutaneous image-guided cryoablation (cryo) is an established minimally invasive oncologic treatment that modulates the immune microenvironment. We hypothesized that cryo can augment anti-tumor responses in melanoma patients progressing on immune checkpoint inhibitors (ICI). Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryo of an enlarging lesion and ICI continuation for a minimum of 2 additional cycles. Computed tomography was performed at 6-8 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-12 weeks. The primary endpoint was safety and feasibility. Secondary endpoints were overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analyses on pre- and post-cryo tumor biopsy and blood samples were performed. Results: From May 2018 through July 2020, 20 pts were screened, 18 enrolled and 17 treated per protocol. All pts received prior PD-1/PD-L1 monotherapy and 12 (67%) experienced primary resistance to ICI. Median follow-up was 8.5 months. Ablated lesions included lymph nodes (n = 4), lung/pleura (n = 4), soft tissue/bone (n = 3), adrenal (n = 3), chest wall (n = 1), and kidney (n = 1). Peri-procedural events occurred in 3 cases (pneumothorax, diaphragm puncture, osteomyelitis). One pt. with underlying ICI-induced hypophysitis experienced an adrenal crisis post-procedure, which rapidly corrected with stress-dose steroid administration; there were no de novo immune-related adverse events post-ablation and there were no grade 4/5 events. In evaluable pts (n = 17), ORR was 18% and DCR was 47% (3 PR, 5 SD). To investigate the inflammatory state of the tumor microenvironment prior to cryo, PD-1, CD8+ TIL IHC, was performed and will be presented at the meeting. Additional exploratory analyses (serial ctDNA analysis, single cell RNA sequencing, HLA-subtyping) are ongoing. Conclusions: Cryoablation in patients with unresectable melanoma following progression on ICI is feasible with an acceptable side effect profile. Efficacy data of this potentially synergistic approach in metastatic melanoma is encouraging. Correlative analyses are underway to identify biomarkers of response to this novel strategy. Clinical trial information: NCT03290677. [Table: see text]
Role of partial cystectomy for muscle invasive bladder cancer: Impact on morbidity and overall survival, a population-based study, 2006-2017.
Authors: Natasza Posielski, Hannah Koenig, Nathan Jung, On Ho, John Paul Flores, Christopher Porter
Journal: Journal of Clinical Oncology (2021)

e16530 Background: National Comprehensive Cancer Network (NCCN) guidelines state partial cystectomy (PC) may be offered in select patients with clinical T2 (cT2) muscle invasive bladder cancer (MIBC) utilizing neoadjuvant chemotherapy (NAC) and pelvic lymphadenectomy (PLND). Our objective was to investigate utilization and survival outcomes of PC in a large contemporary cohort. Methods: Propensity matching was used to compare pathological and surgical outcomes in non-metastatic MIBC patients in the National Cancer Database undergoing PC or radical cystectomy (RC). Multivariate logistic regression was used to determine predictors of NAC, LND, peri-operative morbidity and mortality outcomes. This analysis was repeated in the subset with cT2 MIBC. Results: Of 31,306 T2-T4N0M0 patients, 1543 (4.9%) underwent PC. PC use was higher in older patients and most often (85%) performed for cT2 disease. The PC group was less likely to receive standard of care including NAC (11.4 vs 27.9%, p&lt;0.001) and PLND (58.7 vs 92.5%, p&lt;0.001) than the RC group. Pathological ≥T3 disease (pT3) was found in 39.4% and pos. nodes in 6.9% of PCs. Positive margins were higher in PC, 15.7 vs 10.6%, p&lt;0.001. PC patients had shorter inpatient stay (4.2 vs 8.7 days, p&lt;0.001), lower 30-day readmission (6.7 vs 9.6%, p&lt;0.001), and decreased 30- and 90-day mortality (1.3 vs 1.8%, p&lt;0.001 &amp; 4.8 vs 4.9%, p=0.04). PC was an independent predictor of lack of NAC (OR 0.49, p&lt;0.001) and PLND (OR 0.11, p&lt;0.001), shorter LOS (b -4.66, &lt;0.001), readmission rate (OR 0.72, p&lt;0.001), and improved 30- and 90- day mortality (OR 0.55 &amp; 0.75, p&lt;0.001). In cT2 patients only: PLND and NAC were less utilized in PC (p&lt;0.001), 32% were ≥pT3 and 6.6% node pos. In both full cohort and cT2 subset, PC was associated with slight improvement in time to mortality (Table) and overall survival (OS) (OR 1.44, p&lt;0.001). Conclusions: PC is rarely used in treatment of MIBC. Despite guidelines, NAC and PLND are underutilized in PC. Care is required in selecting patients for PC as up to one third of cT2 patients have ≥pT3. In these likely highly selected patients, PC had lower peri-operative mortality and comparable OS to RC. Selection bias may play a role in these results and further investigation is needed to determine optimal candidates for PC.[Table: see text]
The impact of the COVID-19 pandemic on African American cancer survivors living in metropolitan Detroit.
Authors: Jennifer Lynn Beebe-Dimmer, Chrissy Lusk, Julie J. Ruterbusch, Tara Baird, Stephanie Pandolfi, Theresa A. Hastert, Felicity W. K. Harper, Hayley Thompson, Ann G. Schwartz
Journal: Journal of Clinical Oncology (2021)

12129 Background: COVID-19 has had profound direct and indirect effects on population health to date and long-term effects are anticipated. Vulnerabilities to the most serious consequences of infection include older age, obesity, African American race and the presence of comorbid conditions. African American cancer survivors represent a particularly high-risk group, therefore understanding the impact of the virus and our strategies to prevent its spread on this patient population is important. Methods: The Detroit Research on Cancer Survivors (ROCS) cohort is a unique effort to understand the determinants of poor outcomes in African American cancer survivors. Eligible participants were diagnosed with breast, prostate, colorectal, or lung cancer on or after 1/1/2013, or with endometrial or any other cancer before age 50 on or after 01/01/2016 and were identified through the Metropolitan Detroit Cancer Surveillance System cancer registry. To date, we have enrolled 4173 survivors. Full participation includes completion of a baseline survey, and collection of biospecimens, medical records and tumor tissue, if available. Participants are also followed annually for outcomes and changes in history. A supplemental survey focused on the impact of COVID-19 was offered to enrolled participants beginning in the spring of 2020. The results presented here include data from 890 survivors who also completed the ROCS COVID survey. Results: Nearly all ( &gt; 99%) survivors reported some change in their daily activities in an effort to reduce the risk of infection. At the time of survey, just over 1/3 of participants reported being tested for the virus and among those, 12% reported positive results. More than 40% of survivors reported some disruption in their access to medical care. A substantial ( &gt; 40%) proportion of survivors reported feeling anxious, depressed and/or isolated during the COVID-19 pandemic. Approximately 40% of patients reported changes in health behaviors as a direct result of the pandemic that are known to negatively affect survivorship outcomes (physical inactivity, smoking, alcohol use). Notably, 30% of survivors reported declines in physical activity and these declines were significantly associated with increased anxiety (p = 0.008), depression (p = 0.005) and poorer health-related quality of life (p &lt; 0.001). Conclusions: The influence of the COVID-19 pandemic on African American cancer survivors has been substantial, affecting both their physical and mental health and access to needed medical care. Coupled with changes in health behaviors as a direct result of the pandemic, these factors will likely affect outcomes in this high-risk patient population making further study and interventions necessary to mitigate the long-term impact of the pandemic on cancer outcomes.
HMBD-002 is a novel, neutralizing, anti-VISTA antibody exhibiting strong preclinical efficacy and safety, being developed as a monotherapy and in combination with pembrolizumab.
Authors: Leah DiMascio, Dipti Thakkar, Namita Gandhi, Siyu Guan, Eric Keith Rowinsky, Piers Ingram, Jerome Douglas Boyd-Kirkup
Journal: Journal of Clinical Oncology (2021)

e14569 Background: Inhibition of immune checkpoints has been an effective strategy against several cancers, but efficacy gaps remain. VISTA is an immunoregulatory protein expressed on both hematopoietic and tumor cells and has been shown to induce an immunosuppressive environment by repressing T-cell activation and cytokine production. VISTA expression has been shown to be upregulated following treatment with immune checkpoint inhibitors. Hummingbird Bioscience is developing HMBD-002, an IgG4 antibody against VISTA with high binding specificity across species (human, cyno and rodent) and low pM affinity to the region of VISTA required for engagement with interaction partners, including VSIG3. As HMBD-002 is an IgG4 isotype, it uniquely blocks the inhibitory function of VISTA and releases immune suppression without depleting VISTA+ cells. Here we establish the preclinical efficacy and safety of HMBD-002 along with the rationale for development of HMBD-002 as a monotherapy and in combination with PD1 inhibitors in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Methods: The effect of HMBD-002 in an in vitro model of human immune activation was evaluated using an allogenic Mixed Lymphocyte Reaction (MLR) assay. Tumor growth inhibition studies were conducted in syngeneic murine cell-derived xenograft (CDX) models. The PK and tolerability of HMBD-002 was evaluated in rats and cynomolgus monkeys with a 21 or 28-day observation period. The expression profile of VISTA was examined in different cancers by IHC staining of FFPE TMAs of various solid cancers. Results: HMBD-002 induced a significant dose dependent increase in the levels of inflammatory cytokines, IFN-γ and TNF- α and suppressed the expansion of CD14+ monocytes. Treatment with HMBD-002 significantly inhibited tumor growth and improved survival in CDX models. HMBD-002 is well tolerated in rats and cynomolgus monkeys with acceptable serum half-life, no HMBD-002 related morbidity/mortality or clinical signs, and no HMBD-002 related changes were observed in body weight, food consumption, clinical chemistry, or hematology parameters. HMBD-002 did not induce cytokine release in human PBMCs or whole blood. TNBC and NSCLC patients were found to harbor the highest VISTA expression across cancer types tested, providing a rationale for exploring these indications in upcoming clinical studies. Conclusions: These studies provide the rationale for development of HMBD-002 as a monotherapy and in combination with pembrolizumab to treat patients with solid tumors expressing VISTA in the tumor microenvironment. A Phase 1 study will be initiated in 2021.
Epigenetic and Transcriptomic Profiling of MLL Rearranged Infant Acute Lymphoblastic Leukemia
Authors: Tomoya Isobe, Aiko Sato, Kenichi Yoshida, Chika Kobayashi, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Shiro Fukuda, Shogo Yamamoto, Kenji Tatsuno, Shuichi Tsutsumi, Nobutaka Kiyokawa, Yuki Aoki, Takashi Ishihara, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Satoru Miyano, Seishi Ogawa, Hiroyuki Aburatani, Shuki Mizutani, Junko Takita, Masatoshi Takagi
Journal: Blood (2017)
BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease
Authors: Michelle M. Gonzalez, Adebowale O. Bamidele, Phyllis A. Svingen, Mary R. Sagstetter, Thomas C. Smyrk, Joseph M. Gaballa, Feda H. Hamdan, Robyn Laura Kosinsky, Hunter R. Gibbons, Zhifu Sun, Zhenqing Ye, Asha Nair, Guilherme P. Ramos, Manuel B. Braga Neto, Alexander Q. Wixom, Angela J. Mathison, Steven A. Johnsen, Raul Urrutia, William A. Faubion
Journal: Journal of Clinical Investigation (2021)

FOXP3+ Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3+ cells led to systemic inflammation. BMI1-deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17-like proinflammatory cells, a transition relevant to human Crohn's disease associated CD4+ T cells.
Subcutaneous daratumumab (DARA SC) plus lenalidomide versus lenalidomide alone as maintenance therapy in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are minimal residual disease (MRD) positive after frontline autologous stem cell transplant (ASCT): The phase 3 AURIGA study.
Authors: Nina Shah, Sharmila Patel, Huiling Pei, Ming Qi, Maria Krevvata, Thomas S. Lin, Vipin Khare
Journal: Journal of Clinical Oncology (2021)

TPS8054 Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM) and in combination with standard of care (SoC) in RRMM and NDMM. However, no clinical studies have yet compared DARA maintenance versus SoC maintenance. The ongoing phase 3 AURIGA study will evaluate the addition of DARA to lenalidomide maintenance among pts with NDMM who are MRD positive after SoC induction and ASCT. The primary endpoint is the conversion rate to MRD negativity after 1 year of maintenance therapy. Methods: This open-label, multicenter, randomized phase 3 study will enroll approximately 214 pts in the United States aged 18-79 years with NDMM who receive ≥4 cycles of induction followed by ASCT. Pts must enroll within 6 months of ASCT, be naïve for anti-CD38 treatment, have a very good partial response or better per IMWG criteria, and be MRD positive at a threshold of 10 –5 by next generation sequencing (NGS) within 30 days of screening. Pts will be stratified by cytogenetic risk (high vs standard/unknown) and randomized 1:1 to 28-day cycles of lenalidomide maintenance (10 mg PO; D1-28 [dose increasing to 15 mg if tolerated]) ± DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA; QW Cycle 1-2, Q2W Cycles 3-6, Q4W C7+). Treatment will continue for up to 36 cycles or until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint is MRD conversion rate after 12 months of maintenance treatment, defined as the proportion of pts who achieve MRD negativity (10 –5 ) by NGS. Additional MRD assessments occur after 18, 24, and 36 months of maintenance. While MRD negativity is associated with improved long-term outcomes for pts with MM and is an emerging, validated prognostic factor, this study is among the first to use MRD negativity as a primary study endpoint. Importantly, MRD negativity allows for earlier efficacy assessment than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD conversion rate at any time, sustained MRD negativity lasting ≥12 months, PFS, OS, response rates, duration of complete response, changes in health-related quality of life, and safety. Due to the COVID-19 pandemic, this study has been amended to improve enrollment access by allowing up to 12 months from start of induction therapy to ASCT to mitigate against ASCT delays and to allow greater flexibility for screening and laboratory assessments. Clinical trial information: NCT03901963.
Nodule net: A prospective safety net program to reduce loss to follow-up and increase early detection of lung cancer.
Authors: Harpreet Singh, Chinmay Jani, Arashdeep Rupal, Arti Tewari, Alexander Walker, Marcel Casasola, Joseph Khoory, Lynsie Ranker, Megan Koster, Carey Thomson
Journal: Journal of Clinical Oncology (2021)

1564 Background: Inadequate follow-up of suspicious lung nodules can result in a delay in diagnosis and potential progression to advanced staged lung cancer. A multidisciplinary lung nodule program entitled "Nodule Net" was implemented in 2017 to provide a safety net, increase the rate of follow-up, streamline management. The program consisted of a multidisciplinary team with EMR notification by the radiologist to a centralized nurse navigator for inclusion in a follow-up database, outreach with reminders to the primary care provider if follow-up was not completed, and referral for management where appropriate. In this study, we sought to evaluate program effectiveness in tracking and rate of follow-up imaging of suspicious pulmonary nodules. Methods: 2,398 chest CT scans were reviewed between January and May 2018 for the presence of a lung nodule that required follow-up. Nodules known to be inflammatory or associated with a metastatic malignancy were excluded. Baseline demographics, medical history, primary care affiliation, type of imaging scan, nodule characteristics, and presence and specifics of follow-up recommendations were collected. For reports that did not include a follow-up recommendation, Fleischner’s recommendations were applied or an independent pulmonologist’s review was completed. The rate of follow-up imaging was recorded and compared with historical rates prior to Nodule Net implementation. Prevalence ratios were generated for each comparison. Results: 1,367 (57%) reported lung nodules. Recommendations for follow-up imaging were recorded in 632 (46.2%), and 523 (82.8%) of these were reported to the program navigator. The rate of follow-up completion of those referred to the program was significantly higher [408 (78%)] than standard of care prior to program implementation [442/1202 (36.8%), (2.90, 95% CI: 2.65-3.18)]. Out of 408 patients who completed follow-up, nodule net outreach was required in 116 (28.4%). Of these 116, malignancy was identified in 4/116 (3.4%). Increased nodule size requiring referral was identified in 17 (14.7%). Out of 109 who were not transmitted to the program navigator and not present in the database, 57 (52.3%) had completed the recommended follow-up compared with 78% among those referred (1.49, 95% CI:1.23-1.79). Conclusions: Management of lung nodules is a complex process with poor follow-up completion reported in prior studies (29%-33%). Implementation of a multidisciplinary lung nodule care program for tracking lung nodules led to a significant increase in completion of recommended follow-up imaging. Developing a comprehensive lung nodule management program using software and navigation may further enhance detection, reduce human errors, augment the necessary follow-up for suspicious lung nodules, and ultimately the prevalence of advanced stage lung cancer.
Trichostatin A sensitivity signature across hematological cell lines.
Authors: Bartlomiej Przychodzen
Journal: Journal of Clinical Oncology (2021)

e19521 Background: Histone deacetylase inhibitors (HDACi) are small molecules that increase acetylation of lysine residues by blocking histone deactylases. These anticancer agents affect epigenetic and non-epigenetic gene expression resulting in cell cycle arrest of cancer cells. Furthermore HDACi can enhance its anti-tumor effects via the pharmacologic modulation of macrophage. Some HDACi’s such as Trichostatin A (TSA) can also affected the tumor immune microenvironment by suppressing the activity of infiltrating macrophages and inhibiting myeloid-derived suppressor cell recruiement (Li et al.,). Methods: We conducted a high throughput screen comparing gene expression profiles in known hematological cell lines to identify transcriptional signatures associated with TSA sensitivity obtained from GDSC. Results: We selected genes that showed at least 2fold expression difference and were statistically significant (p &lt; 0.05). We identified 49 genes that were upregulated and 85 that were downregulated. The most significant results include multiple genes known to be correlated with the B-cell maturation process. We found that CD24 a small GPI linked glycoprotein expressed at the surface of most B lymphocyte precursors, neutrophils, epithelial cells and frequently found to be highly expressed in various hematological and solid neoplasms, was up/downregulatred by XX. Interestingly, CD24 plays a role in the activation and differentiation of the cells as bone marrow samples lacking CD24 resulted in decreased numbers of both pre-B and immature B-cell populations. We also found that IKZF2, a transcription factor regulating lymphocyte development and queiesence and which is frequently deleted in hypodiploid B-ALLs. This result could revelent as other reports suggest a role of IKZF2 as a tumor suppressor with a central role regulating the balance of self-renewal and differentiation in leukemic stem cells. Conclusions: Our study identified transcriptional profiles which suggest that TSA sensitivity could be related to B cell maturation. Further experiments warrant replication of these findings which could prove useful in creating optimal, TSA-based treatments acting either as potent single agents or in combination enhancing anti-tumor effects of immunotherapies.