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Correction to: BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Diskin, Brian; Adam, Salma; Soto, Gustavo Sanchez; Liria, Miguel; Aykut, Berk; Sundberg, Belen; Li, Eric; Leinwand, Joshua; Chen, Ruonan; Kim, Mirhee; Salas, Ruben D; Cassini, Marcelo F; Buttar, Chandan; Wang, Wei; Farooq, Mohammad Saad; Shadaloey, Sorin A A; Werba, Gregor; Fnu, Amreek; Yang, Fan; Hirsch, Carolina; Glinski, John; Panjwani, Angilee; Weitzner, Yael; Cohen, Deirdre; Asghar, Usman; Miller, George
PMID: 36707621
ISSN: 1476-5594
CID: 5419832

A pilot study of gut microbiome modulation to enable efficacy of neoadjuvant checkpointbased immunotherapy (IO) following chemotherapy in pancreatic ductal adenocarcinoma (PDAC) [Meeting Abstract]

Wu, L; Ang, C; Pintova, S; Sung, M W; Kozuch, P; Dharmapuri, S; Cohen, N A; Schwartz, M E; Mandeli, J P; Saxena, D; Cohen, D J
Background: Neoadjuvant therapy is now a standard strategy for localized PDAC, and this preoperative window provides an excellent opportunity in which to test novel therapeutic approaches. Trials using IO in PDAC have largely been unsuccessful, and immune tolerance is implicated as a major mechanism of IO resistance. The gut and tumor microbiome have emerged as key modulators of response to both IO and chemotherapy. High tumor microbial diversity has been linked to longer survival in PDAC, and gut microbiota may have the ability to colonize pancreatic tumors. There is preclinical evidence that endogenous microbiota promotes the immunosuppressive tumor microenvironment characteristic of PDAC through stimulation of pro-tumor regulatory T cells and myeloid-derived suppressor cells at the expense of anti-tumor activated CD4+ and CD8+ T cells. Further, preclinical data show that ablation of the gut microbiota may induce T cell activation, improve immune surveillance, and increase sensitivity to IO. We hypothesize that ablative antibiotics (abx) will activate tumor infiltrating T cells and enhance IO activity in PDAC.
Method(s): This is a multi-center, single-arm, open-label pilot study of pre-operative chemotherapy followed by abx and pembrolizumab to evaluate overall immune response to abx + IO. Eligible patients will have histologically confirmed, resectable PDAC, without probiotic consumption or use of immunosuppressive agents. Patients will be enrolled at diagnosis after undergoing a baseline biopsy. They will then receive mFOLFIRINOX every 2 weeks for 5 cycles. After completion of chemotherapy, ciprofloxacin 500 mg PO BID and metronidazole 500 mg PO TID will be administered for 21 days, and pembrolizumab 200 mg IV x1 will be given 7 days after initiation of abx. Patients will then undergo surgical resection and adjuvant therapy at the investigators' discretion. On-treatment biopsy will be obtained prior to cycle 5 of mFOLFIRINOX. Blood and stool will be collected at baseline, during mFOLFIRINOX therapy, before and after pembrolizumab administration, and postoperatively. The primary endpoint is the overall immune response, which will be measured as activation of one or more of the T cell markers HLA-DR, CD38, CD25, Ki67, and CD69, defined as an increase in expression level of at least 20% from the on-treatment specimen to the surgical specimen, before and after abx + IO. Key secondary endpoints will be the evaluation of adverse events, R0 resection rate, histologic regression score, objective response rate, and overall survival rate. Correlative studies will be carried out to evaluate immune and microbiome changes in the blood and tissue following abx and pembrolizumab. These findings will be correlated with clinical endpoints. The target study accrual is 25 patients
EMBASE:640368014
ISSN: 1527-7755
CID: 5513832

BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Diskin, Brian; Adam, Salma; Soto, Gustavo Sanchez; Liria, Miguel; Aykut, Berk; Sundberg, Belen; Li, Eric; Leinwand, Joshua; Chen, Ruonan; Kim, Mirhee; Salas, Ruben D; Cassini, Marcelo F; Buttar, Chandan; Wang, Wei; Farooq, Mohammad Saad; Shadaloey, Sorin A A; Werba, Gregor; Fnu, Amreek; Yang, Fan; Hirsch, Carolina; Glinski, John; Panjwani, Angilee; Weitzner, Yael; Cohen, Deirdre; Miller, George
Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.
PMID: 35948648
ISSN: 1476-5594
CID: 5286982

Prescreening to Increase Therapeutic Oncology Trial Enrollment at the Largest Public Hospital in the United States

Wu, Jennifer; Yakubov, Amin; Abdul-Hay, Maher; Love, Erica; Kroening, Gianna; Cohen, Deirdre; Spalink, Christy; Joshi, Ankeeta; Balar, Arjun; Joseph, Kathie-Ann; Ravenell, Joseph; Mehnert, Janice
PURPOSE/UNASSIGNED:The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS/UNASSIGNED:The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS/UNASSIGNED:Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non-English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION/UNASSIGNED:Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.
PMID: 34748371
ISSN: 2688-1535
CID: 5050262

SSAT State-of-the-Art Conference: Advancements in the Microbiome

Miller, Miquell O; Kashyap, Purna C; Becker, Sarah L; Thomas, Ryan M; Hodin, Richard A; Miller, George; Hundeyin, Mautin; Pushalkar, Smruti; Cohen, Deirdre; Saxena, Deepak; Shogan, Benjamin D; Morris-Stiff, Gareth J
The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.
PMID: 32989690
ISSN: 1873-4626
CID: 4651692

1-Year Outcomes following Bioprosthetic Valve Fracture to Facilitate Valve-in-Valve Transcatheter Aortic Valve Replacement

Chhatriwalla, A K; Allen, K B; Saxon, J T; Cohen, D J; Nguyen, T C; Loyalka, P; Whisenant, B; Yakubov, S J; Sanchez, C; Sathananthan, J; Stegman, B; Harvey, J; Garrett, H E; Tseng, E; Gerdisch, M; Williams, P; Kennedy, K F; Webb, J
Background: Bioprosthetic valve fracture (BVF) improves the hemodynamic results of valve-in-valve transcatheter aortic valve replacement (VIV TAVR) by facilitating optimal expansion of the transcatheter heart valve (THV). Long-term outcomes following BVF are unknown.
Method(s): Consecutive cases of VIV TAVR and BVF (n = 139) performed at 11 sites were analyzed retrospectively. Hemodynamic measurements and aortic valve area (AVA) were assessed during the procedure and by echocardiography at 30-day and 1-year follow-up.
Result(s): VIV TAVR and BVF resulted in significant improvements in mean valve gradient (42.3 +/- 17.1 vs. 9.4 +/- 5.8 mmHg, p < 0.001) and AVA (0.8 +/- 0.4 vs. 1.8 +/- 0.7 cm2, p < 0.001) compared with baseline. Mortality was 2.3% at 30 days and 8.7% at 1-year. In adjusted models, mean valve gradient was higher (+5.1 [3.7, 6.5] mmHg, p < 0.001) and AVA was lower (-0.3 [-0.4, -0.2] cm2, p < 0.001) at 1 month as compared to post-procedure. Between 30 days and 1 year, no significant changes in mean valve gradient (+1.4 [-0.5, 3.4] mmHg, p = 0.15) or AVA (-0.1 [-0.3, 0.03] cm2, p = 0.11) were observed. In a multivariable analysis, use of a CoreValve (compared with a SAPIEN) THV was an independent predictor of a lower mean valve gradient at 1 year (-6.0 mmHg, p = 0.01).
Conclusion(s): Survival is excellent following VIV TAVR and BVF and valve hemodynamics are stable between 30-day and 1-year follow-up. CoreValve use is a predictor of better hemodynamic results following VIV TAVR and BVF. Abbreviations: VIV TAVR: valve-in-valve transcatheter aortic valve replacement; THV: transcatheter heart valve; BSV: bioprosthetic surgical valve; PPM: patient prosthesis mismatch; BVF: bioprosthetic valve fracture; IQR: interquartile range; LVEF: left ventricular ejection fraction; AVA: aortic valve area; STS PROM: Society of Thoracic Surgeons predicted risk of mortality.
Copyright
EMBASE:2011256477
ISSN: 2474-8706
CID: 4909442

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

Wang, Wei; Marinis, Jill M; Beal, Allison M; Savadkar, Shivraj; Wu, Yue; Khan, Mohammed; Taunk, Pardeep S; Wu, Nan; Su, Wenyu; Wu, Jingjing; Ahsan, Aarif; Kurz, Emma; Chen, Ting; Yaboh, Inedouye; Li, Fei; Gutierrez, Johana; Diskin, Brian; Hundeyin, Mautin; Reilly, Michael; Lich, John D; Harris, Philip A; Mahajan, Mukesh K; Thorpe, James H; Nassau, Pamela; Mosley, Julie E; Leinwand, Joshua; Kochen Rossi, Juan A; Mishra, Ankita; Aykut, Berk; Glacken, Michael; Ochi, Atsuo; Verma, Narendra; Kim, Jacqueline I; Vasudevaraja, Varshini; Adeegbe, Dennis; Almonte, Christina; Bagdatlioglu, Ece; Cohen, Deirdre J; Wong, Kwok-Kin; Bertin, John; Miller, George
PMID: 33049209
ISSN: 1878-3686
CID: 4632692

Advances in the pharmacotherapeutic management of esophageal squamous cell carcinoma

Peng, Chengwei; Cohen, Deirdre J
INTRODUCTION/BACKGROUND:Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease. AREAS COVERED/UNASSIGNED:The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations. EXPERT OPINION/UNASSIGNED:Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.
PMID: 33034212
ISSN: 1744-7666
CID: 4651782

Ipilumumab for hepatocellular cancer in a liver transplant recipient, with durable response, tolerance and without allograft rejection

Pandey, Abhishek; Cohen, Deirdre J
Organ transplant recipients are not routinely included in clinical trials, and as a result there is a paucity of data to guide clinicians in the treatment of malignancies in this unique patient population. This is a case report and focused review of the treatment of hepatocellular carcinoma in patients with orthotopic liver transplants. We describe a single patient's treatment over a period of 4 years from the time of diagnosis to submission of this case report. We submit evidence that the anti-CTLA-4 antibody ipilimumab can produce a durable response, with a tolerable adverse event profile and without associated allograft rejection.
PMID: 32248723
ISSN: 1750-7448
CID: 4378692

A phase II, randomized, controlled trial of nivolumab in combination with BMS-986253 or cabiralizumab in advanced hepatocellular carcinoma (HCC) patients [Meeting Abstract]

Welling, T; Beri, N; Siolas, D; Cohen, D J; Becker, D J; Zhong, H; Wu, J J; Oberstein, P E; Karasic, T B
Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Method(s): Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue
EMBASE:630962090
ISSN: 1527-7755
CID: 4326202