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Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies

Wan, Shanshan; Zhao, Ende; Freeman, Daniel; Weissinger, Daniel; Krantz, Benjamin A; Werba, Gregor; Khanna, Lauren G; Siolas, Despina; Oberstein, Paul E; Chattopadhyay, Pratip K; Simeone, Diane M; Welling, Theodore H
[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].
PMID: 37033968
ISSN: 1664-3224
CID: 5464042

Phase II study of lenvatinib plus pembrolizumab for patients with immunotherapy-naive advanced gastric cancer following first line therapy [Meeting Abstract]

Cohen, Deirdre Jill; Lee, Jonathan W; Becker, Daniel Jacob; Siolas, Despina; Beri, Nina; Ryan, Theresa; Kozuch, Peter; Yu, Shun; Levinson, Benjamin A; Goldberg, Judith D; Leichman, Lawrence P; Oberstein, Paul Eliezer
ISSN: 1527-7755
CID: 5515782

Elevated dietary carbohydrate and glycemic intake associate with an altered oral microbial ecosystem in two large U.S. cohorts

Monson, Kelsey R; Peters, Brandilyn A; Usyk, Mykhaylo; Um, Caroline Y; Oberstein, Paul E; McCullough, Marjorie L; Purdue, Mark P; Freedman, Neal D; Hayes, Richard B; Ahn, Jiyoung
The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 non-diabetic subjects from the NCI-PLCO and ACS-CPSII cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA-sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational MANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, BMI, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P-value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (p-trend=0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q=0.02) and genus Leptotrichia (q=0.01) and with lesser abundance of an Actinomyces OTU (q=4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q=0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.
PMID: 36567732
ISSN: 2767-9764
CID: 5592052

1229P A multicenter phase II study of sotigalimab (CD40 agonist) in combination with neoadjuvant chemoradiation for resectable esophageal and gastroesophageal junction (GEJ) cancers [Meeting Abstract]

Ko, A H; Noel, M; Chao, J; Sohal, D; Crow, M; Oberstein, P E; Scott, A; McRee, A; Rocha, Lima C; Fong, L; Keenan, B; Filbert, E; Hsu, F J; Shankaran, V
Background: Neoadjuvant chemoradiation (CRT) followed by surgical resection is a standard approach for patients (pts) with locally advanced esophageal/GEJ cancers. A pathologic complete response (pCR) is achieved in 22-23% of adenocarcinomas (AC) and 42-49% of squamous cell carcinomas (SCC) and is associated with improved survival outcomes. Sotigalimab (sotiga) is a high affinity, potent CD40 agonist mAb capable of inducing and expanding anti-tumor immune responses by activating dendritic cells (DCs), T cells, NK cells, B cells, and M1 macrophages. This study examined the safety and efficacy of combining sotiga with neoadjuvant CRT in pts with esophageal/GEJ cancers.
Method(s): Pts with resectable (T1-3, Nx) AC or SCC of the esophagus/GEJ were eligible. T1N0 and cervical tumors were excluded. Study treatment: carboplatin (AUC 2)/paclitaxel (PTX) (50 mg/m2) weekly x 5 with radiation 5040 cGy plus up to 4 doses of sotiga 0.3mg/kg IV prior to Ivor-Lewis esophagectomy. Primary efficacy endpoint was pCR.
Result(s): 34 pts were enrolled (safety pop). Histology: 76% AC, 24% SCC; clinical stage: II/III/IVA, 9%/68%/23%; location: GEJ 47%. AEs (> 20%) attributed to sotiga: nausea, chills, fatigue, cytokine release syndrome (CRS), pyrexia, vomiting, abnormal LFTs, thrombocytopenia, diarrhea, and pruritus; majority Grade 1-2. Grade >3 CRS was observed in 3 pts (9%). No pt withdrawals due to sotiga; no treatment-related deaths. 28 pts were evaluable for the primary endpoint (3 opted against surgery, 1 pt withdrew after PTX reaction, 1 unrelated death, 1 surgery still pending). Path responses: 10 pCR (36%), 16 pPR (57%), 18 major path resp (<10% residual tumor) (64%). 2 PD (7%), ORR 93%. pCR by histology: 7/23 AC (30%), 3/5 SC (60%). Post-tumor samples demonstrated increased infiltration and activation of DCs and monocytes compared to baseline.
Conclusion(s): Sotiga combined with neoadjuvant chemoradiation for esophageal/GEJ cancers was generally well tolerated and achieved pCR rates in both AC and SCC that compare favorably to historical data and are promising for this treatment strategy. Additional evaluations of clinical outcomes (including DFS, OS) and immune-based biomarkers are ongoing. Clinical trial identification: NCT03165994. Legal entity responsible for the study: Apexigen, Inc.
Funding(s): Apexigen, Inc. Disclosure: A.H. Ko: Financial Interests, Personal, Other, Member of Data Monitoring Committee: Imugene, Erytech, Roche/Genentech, Ipsen; Financial Interests, Personal, Other, Developed content for web-based platform as well as lecture materials on pancreatic cancer; speaker at multiple CME activities: Clinical Care Options; Financial Interests, Personal, Other, Member and now chair of Pancreatic Cancer Task Force: National Cancer Institute; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (pancreatic cancer): Celgene, Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (esophageal cancer): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, National PI for clinical trial (GI cancers): Abgenomics; Financial Interests, Institutional, Invited Speaker, National PI for clinical trial (esophageal cancer): Apexigen; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (gastric cancer): Leap Therapeutics, Astellas; Non-Financial Interests, Other, MemberMultiple prior committee/speaking roles for Annual MeetingAssociate Editor: American Society of Clinical Oncology; Non-Financial Interests, Sponsor/Funding, For Precision Promise clinical trials consortium. Funding paid directly to my institution.: Pancreatic Cancer Action Network; Non-Financial Interests, Sponsor/Funding, For clinical trials collaboration. Funding paid directly to my institution.: Parker Institute for Cancer Immunotherapy. M. Noel: Financial Interests, Personal, Advisory Role: Celgene, Taiho Pharma, Ipsen; Financial Interests, Personal, Speaker's Bureau: Celgene, Taiho Pharma, Daiichi Sankyo/ AstraZeneca; Financial Interests, Institutional, Funding: Apexigen. J. Chao: Financial Interests, Personal, Advisory Role: Lilly, Merck, AstraZeneca, Daiichi Sankyo, Ono Pharma, Bristol Myers Squibb, Astellas Pharma, Turning Point Thera, Roche, Silverback Thera, Novartis, Coherus Biosciences, Geneos; Financial Interests, Personal, Advisory Role, +travel: Foundation Medicine, Macrogenics, Amgen; Financial Interests, Personal, Speaker's Bureau, +travel: Merck; Financial Interests, Personal, Speaker's Bureau: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Merck, Novonco Thera, Brooklyn Immunotherapeutics, Apexigen. D. Sohal: Financial Interests, Personal, Advisory Role: Perthera, Ability Pharma, AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Incyte, Genentech; Financial Interests, Personal, Other, Honoraria: Foundation Medicine; Financial Interests, Institutional, Funding: Celgene, Genentech, Bristol-Myers Squibb, Incyte, Rafael Pharma, Apexigen, Amgen, Ability Pharma, AstraZeneca, FibroGen, Merck. M. Crow: Financial Interests, Personal, Funding: Merck, Incyte, Janssen; Financial Interests, Institutional, Funding: Apexigen. P.E. Oberstein: Financial Interests, Personal, Advisory Role, +travel: Merck; Financial Interests, Personal, Advisory Role: Rubius Thera, QED Thera, AstraZeneca, Delcath Systems; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Institutional, Funding: Merck, Roche/Genentech, Rafael Pharma, Arcus BioSciences. A. Scott: Financial Interests, Personal, Advisory Role, +travel: Exelixis, QED Pharma; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Stocks/Shares: Johnson johnson; Financial Interests, Personal, Funding: Exelixis, Genentech, Incyte, Five Prime, Merck; Financial Interests, Institutional, Funding: Apexigen. A. McRee: Financial Interests, Personal, Full or part-time Employment, recent move to industry: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson Johnson; Financial Interests, Institutional, Funding: Inovio Pharma, Novartis, Merck, Boston Biomedical, AstraZeneca, Rgenix, BioMed Valley Discoveries, Takeda. C. Rocha Lima: Financial Interests, Personal, Funding: Rafael Pharma, Boston Biomedical, Pharmacyclics; Financial Interests, Institutional, Funding: Apexigen. L. Fong: Financial Interests, Personal, Stocks/Shares: Actym, Allector, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, Scribe, Senti, Soteria, TeneoBio; Financial Interests, Personal, Ownership Interest: Keyhole; Financial Interests, Institutional, Funding: Abbvie, Bavarian Nordic, Dendreon, Janssen, Merck, Roche/Genentech; Financial Interests, Personal and Institutional, Funding: BMS; Financial Interests, Institutional, Invited Speaker: Corvus; Financial Interests, Personal, Funding: AstraZeneca, Merck KGA. B. Keenan: Financial Interests, Institutional, Funding: Partner Therapeutics. E. Filbert: Financial Interests, Personal, Full or part-time Employment: Apexigen; Financial Interests, Personal, Stocks/Shares: Apexigen. F.J. Hsu: Financial Interests, Personal, Full or part-time Employment: Apexigen; Financial Interests, Personal, Officer: Apexigen. V. Shankaran: Financial Interests, Personal, Other, Honoraria: Cambia Health Foundatio; Financial Interests, Institutional, Funding: Amgen, Merck, Bayer, Bristol Myer Squibb, AstraZeneca, Genentech/Roche, Apexigen.
ISSN: 1569-8041
CID: 5366412

Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting

Everett, Jessica N; Dettwyler, Shenin A; Jing, Xiaohong; Stender, Cody; Schmitter, Madeleine; Baptiste, Ariele; Chun, Jennifer; Kawaler, Emily A; Khanna, Lauren G; Gross, Seth A; Gonda, Tamas A; Beri, Nina; Oberstein, Paul E; Simeone, Diane M
BACKGROUND:Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. METHODS:Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum. RESULTS:Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. CONCLUSION/CONCLUSIONS:Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.
PMID: 35906821
ISSN: 2045-7634
CID: 5277102

A phase 1b study evaluating IL-1beta and PD-1 targeting with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1) [Meeting Abstract]

Oberstein, P E; Rahma, O E; Beri, N; Stoll-D'Astice, A C; Duliege, A -M; Nazeer, S; Squires, M; Bar-Sagi, D; Wolpin, B M; Dougan, S; Simeone, D M
Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy that is refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1beta was shown to be upregulated in pancreatic cancer tumors, and in mouse models, IL-1beta expression led to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We hypothesize that blockade of IL-1beta and PD-1 will result in alterations in myeloid, lymphoid, and fibroblast subsets within the pancreatic cancer microenvironment and add therapeutic benefit in combination with chemotherapy in PDA.
Method(s): We are conducting an open-label multicenter Phase Ib study evaluating a 4 drug regimen including gemcitabine and nabpaclitaxel with the addition of canakinumab (ACZ885), a high-affinity human anti-interleukin1beta (IL-1beta) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1). Eligible subjects have metastatic PDA without prior anticancer therapy for metastatic disease and RECIST measurable disease. The primary objective was to identify a recommended phase II/III dose of combination therapy by evaluating the incidence of dose limiting toxicities in the first 56 days (8 weeks) of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability of quadruple therapy and preliminary assessment of clinical activity.
Result(s): 10 subjects were enrolled between November 2020 and March 2021, and the first 6 subjects to complete 8 weeks of therapy were included in the dose confirmation analysis. There were no dose limiting toxicities and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) on day 1,8,15; nab-paclitaxel (125 mg/m2 IV) on day 1,8,15, canakinumab (250 mg via subcutaneous injection) on day 1, spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. The majority of subjects completed the on-treatment blood and tissue collection for correlative analysis. The study is ongoing with subjects remaining on therapy and all subjects will be evaluated for efficacy.
Conclusion(s): In this Phase Ib study, we demonstrated the feasibility and safety of adding canakinumab and spartalizumab to standard of care chemotherapy in first line metastatic PDA and established the recommended Phase II/III dose. This novel 4 drug combination will be tested in a randomized Phase II/III study through the Precision Promise clinical trial network. Preliminary correlative and efficacy data will be reported
ISSN: 0732-183x
CID: 5164502

Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil and Folinic Acid in Metastatic Pancreatic Cancer: the COMBAT/KEYNOTE-202 Trial

Bockorny, Bruno; Macarulla, Teresa; Semenisty, Valerya; Borazanci, Erkut; Feliu, Jaime; Ponz-Sarvise, Mariano; Gutierrez Abad, David; Oberstein, Paul; Alistar, Angela; Muñoz, Andres; Geva, Ravit; Guillen-Ponce, Carmen; Salgado, Mercedes; Peled, Amnon; Chaney, Marya; Gliko-Kabir, Irit; Shemesh-Darvish, Liron; Ickowicz, Debby; Sorani, Ella; Kadosh, Shaul; Vainstein, Abi; Hidalgo, Manuel
PURPOSE/OBJECTIVE:Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. EXPERIMENTAL DESIGN/METHODS:Multicenter, single arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined to chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week, pembrolizumab every 3 weeks, nanoliposomal irinotecan, fluorouracil and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate, safety and tolerability. RESULTS:A total of 43 patients were enrolled. The objective response rate according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The disease control rate was 63.2% with median duration of clinical benefit of 5.7 months. In the intention to treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated with toxicity comparable to the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection were 7%, lower than expected for this chemotherapy regimen. CONCLUSION/CONCLUSIONS:Triple combination of motixafortide, pembrolizumab and chemotherapy was safe, well tolerated and showed signs of efficacy in a population with poor prognosis and aggressive disease.
PMID: 34253578
ISSN: 1557-3265
CID: 4950402

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma

Everett, Jessica N; Burgos, Gabriela; Chun, Jennifer; Baptiste, Ariele; Khanna, Lauren G; Oberstein, Paul E; Simeone, Diane M
BACKGROUND:Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. METHODS:We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. RESULTS:Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. CONCLUSION/CONCLUSIONS:PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.
PMID: 33721345
ISSN: 1097-0142
CID: 4823462

Moving Beyond the Momentum: Innovative Approaches to Clinical Trial Implementation

Eng, Cathy; Chen, Emerson Y; Rogers, Jane; Lewis, Mark; Strosberg, Jonathan; Thota, Ramya; Krishnamurthi, Smitha; Oberstein, Paul; Govindarajan, Rang; Buchschacher, Gary; Patel, Sandip; Sohal, Davendra; Al-Toubah, Taymeyah; Philip, Philip; Dasari, Arvind; Kennecke, Hagan; Stein, Stacey
Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.
PMID: 33534616
ISSN: 2688-1535
CID: 4814682

The Double-Edged Sword of Chemotherapy: Single Cell RNA Sequencing of Human PDA Reveals T-Cell Activation With Simultaneous Priming of Inhibitory Macrophages [Meeting Abstract]

Werba, G.; Dolgalev, I.; Zhao, E.; Jing, X.; Gonda, T.; Oberstein, P.; Welling, T.; Tsirigos, A.; Simeone, D. M.
ISSN: 0885-3177
CID: 5236652