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Article: Immunotherapy in Gastrointestinal Malignancies.

Surana, Rishi / Pant, Shubham

Advances in experimental medicine and biology

2021 Volume 1342, Page(s) 259–272

Abstract: Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment ... ...

Abstract	Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment also varies within each GI malignancy and can portend prognosis and response to therapy. Treatment with immune checkpoint inhibitors has changed the treatment landscape of various solid tumors including (but not limited to) renal cell carcinoma, melanoma, and lung cancer. Advances in the understanding between the interplay between the immune system and tumors cells have led to the integration of immunotherapy as standard of care in various GI malignancies. For example, immunotherapy is now a mainstay of treatment for tumors harboring defects in DNA mismatch repair proteins and tumors harboring a high mutational load, regardless of primary site of origin. Data from recent clinical trials have led to the integration of immunotherapy as standard of care for a subset of gastroesophageal cancers and hepatocellular carcinoma. Here, we outline the current landscape of immunotherapy in GI malignancies and highlight ongoing clinical trials that will likely help to further our understanding of how and when to integrate immunotherapy into the treatment of various GI malignancies.
MeSH term(s)	Clinical Trials as Topic ; Esophageal Neoplasms/therapy ; Gastrointestinal Neoplasms/therapy ; Humans ; Immunotherapy ; Tumor Microenvironment
Language	English
Publishing date	2021-12-06
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-79308-1_8
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Article ; Online: Pancreatic cancer.

Mizrahi, Jonathan D / Surana, Rishi / Valle, Juan W / Shroff, Rachna T

Lancet (London, England)

2020 Volume 395, Issue 10242, Page(s) 2008–2020

Abstract: Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, ... ...

Abstract	Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.
MeSH term(s)	Administration, Intravenous ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; BRCA1 Protein/drug effects ; BRCA1 Protein/genetics ; BRCA2 Protein/drug effects ; BRCA2 Protein/genetics ; Chemotherapy, Adjuvant/methods ; Contrast Media/administration & dosage ; DNA Damage/drug effects ; Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods ; Humans ; Immunotherapy/methods ; Middle Aged ; Mutation ; Neoplasm Staging ; Pancreatic Neoplasms/diagnostic imaging ; Pancreatic Neoplasms/epidemiology ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/therapy ; Risk Factors ; Survival Rate ; Tomography, X-Ray Computed/methods ; Tumor Microenvironment/drug effects
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Contrast Media
Language	English
Publishing date	2020-06-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(20)30974-0
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Article ; Online: Utility of Established Prognostic Scoring Systems for Patients with Advanced Pancreatic Adenocarcinoma Enrolled in Immunotherapy-Based Early-Phase Clinical Trials.

Surana, Rishi / Gonzalez, Graciela Nogueras / Rogers, Jane / Hong, David S / Yap, Timothy A / Rodon, Jordi / Naing, Aung / Wolff, Robert A / Smaglo, Brandon G / Bernstam, Funda Meric / Subbiah, Vivek / Pant, Shubham

Journal of gastrointestinal cancer

2023 Volume 54, Issue 4, Page(s) 1308–1315

Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy for which multiagent chemotherapy is the mainstay of treatment resulting in limited survival and symptomatic benefit. Treatment with immune checkpoint inhibitors (ICI) has proven ...

Abstract	Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy for which multiagent chemotherapy is the mainstay of treatment resulting in limited survival and symptomatic benefit. Treatment with immune checkpoint inhibitors (ICI) has proven effective in a growing number of solid tumors but has yet to show clinical benefit in patients with PDAC. Given the growing number of ICI-based clinical trials in development for patients with PDAC and lack of clinical benefit thus far with ICI-based therapies in these patients, we sought to (1) determine the outcomes of patients with PDAC treated with ICI-based therapies as part of an early phase clinical trial, (2) validate the utility of established prognostic scoring systems, and (3) identify novel prognostic factors in an attempt to better identify patients that would benefit from enrollment onto an ICI-based early phase clinical trial. Methods: We conducted a single-center retrospective analysis of patients with advanced PDAC who were treated with ICI-based therapy as part of an early-phase clinical trial. Results: Patients were only able to stay on study for a limited time due to disease progression and/or a change in performance status and had a poor overall survival. Established prognostic scoring systems were not effective in predicting outcomes in this patient population, but factors such as pre-treatment albumin neutrophil to lymphocyte ratio (NLC) may be helpful in patient selection. Conclusions: This study underscores the need for larger studies to help identify patient and tumor intrinsic factors that predict response to ICI-based therapies in patients with PDAC.
MeSH term(s)	Humans ; Pancreatic Neoplasms/drug therapy ; Adenocarcinoma/drug therapy ; Prognosis ; Retrospective Studies ; Carcinoma, Pancreatic Ductal/drug therapy ; Immunotherapy/methods
Language	English
Publishing date	2023-04-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2452514-5
ISSN	1941-6636 ; 1559-0739 ; 1941-6628 ; 1537-3649
ISSN (online)	1941-6636 ; 1559-0739
ISSN	1941-6628 ; 1537-3649
DOI	10.1007/s12029-023-00930-7
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Article: Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma.

Huffman, Brandon M / Ellis, Haley / Jordan, Alexander C / Freed-Pastor, William A / Perez, Kimberly / Rubinson, Douglas A / Sethi, Nilay / Singh, Harshabad / Surana, Rishi / Wolpin, Brian M / Aguirre, Andrew J / Cleary, James M

Cancers

2022 Volume 14, Issue 24

Abstract: The aggressive biology of pancreatic ductal adenocarcinoma (PDAC), along with its limited sensitivity to many systemic therapies, presents a major challenge in the management of patients with metastatic PDAC. Over the past decade, the incorporation of ... ...

Abstract	The aggressive biology of pancreatic ductal adenocarcinoma (PDAC), along with its limited sensitivity to many systemic therapies, presents a major challenge in the management of patients with metastatic PDAC. Over the past decade, the incorporation of combinatorial cytotoxic chemotherapy regimens has improved patient outcomes. Despite these advances, resistance to cytotoxic chemotherapy inevitably occurs, and there is a great need for effective therapies. A major focus of research has been to identify molecularly defined subpopulations of patients with PDAC who may benefit from targeted therapies that are matched to their molecular profile. Recent successes include the demonstration of the efficacy of maintenance PARP inhibition in PDAC tumors harboring deleterious
Language	English
Publishing date	2022-12-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14246223
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Article: Outcomes of patients with metastatic pancreatic cancer who progress on first restaging imaging.

Rogers, Jane E / Mizrahi, Jonathan D / Nogueras Gonzalez, Graciela M / Surana, Rishi / Shroff, Rachna T / Wolff, Robert / Varadhachary, Gauri R / Javle, Milind M / Overman, Michael / Raghav, Kanwal / Pant, Shubham

Journal of gastrointestinal oncology

2021 Volume 12, Issue 5, Page(s) 2268–2274

Abstract: Background: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging ... ...

Abstract	Background: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging imaging. With patients' short life expectancy, it is crucial for clinicians to be prudent when deciding whom and when to treat. Our study aimed to evaluate outcomes of patients that progressed on their first restaging imaging on 1 Methods: We retrospectively analyzed patients diagnosed between 2010-2017 whose first restaging imaging demonstrated PD. The primary outcome was overall survival (OS) from metastatic diagnosis date to death. Patients who were lost to follow-up were excluded. Results: Out of 262 total patients reviewed, 98 patients (37%) were included. Sixty-five (66%) received 2 Conclusions: Although likely biased due to better performance status and younger age, our patients who progressed rapidly on 1
Language	English
Publishing date	2021-11-02
Publishing country	China
Document type	Journal Article
ZDB-ID	2594644-4
ISSN	2219-679X ; 2078-6891
ISSN (online)	2219-679X
ISSN	2078-6891
DOI	10.21037/jgo-20-569
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Article ; Online: Monoclonal antibodies for the treatment of cancer.

Shuptrine, Casey W / Surana, Rishi / Weiner, Louis M

Seminars in cancer biology

2012 Volume 22, Issue 1, Page(s) 3–13

Abstract: Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune ...

Abstract	Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Antibody-Dependent Cell Cytotoxicity/drug effects ; Cytotoxicity, Immunologic/drug effects ; Drug Resistance/immunology ; Humans ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/immunology ; Neoplasms/drug therapy ; Neoplasms/immunology
Chemical Substances	Antibodies, Monoclonal ; Immunologic Factors
Language	English
Publishing date	2012-01-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2011.12.009
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Article: Phase II Study of Ipilimumab in Men With Metastatic Prostate Cancer With an Incomplete Response to Androgen Deprivation Therapy.

Graff, Julie N / Stein, Mark N / Surana, Rishi / Al Rabadi, Luai / Liu, Eric / Fong, Lawrence / Bailey, Shawna / Latour, Emile / Newby, Timothy A / Moran, Amy E / Beer, Tomasz M

Frontiers in oncology

2020 Volume 10, Page(s) 1381

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2020-08-07
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.01381
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Article ; Online: Vaccine prevention of cancer: can endogenous antigens be targeted?

Weiner, Louis M / Surana, Rishi / Murray, Joseph

Cancer prevention research (Philadelphia, Pa.)

2010 Volume 3, Issue 4, Page(s) 410–415

Abstract: This perspective on the report by Beatty et al. in this issue of the journal (beginning on page 438) discusses the prevention of cancer through vaccination strategies that target antigens associated with tumor promotion and progression. Such approaches ... ...

Abstract	This perspective on the report by Beatty et al. in this issue of the journal (beginning on page 438) discusses the prevention of cancer through vaccination strategies that target antigens associated with tumor promotion and progression. Such approaches were first developed for treating cancer. We address cancer vaccination in the context of a mouse model of inflammatory bowel disease expressing MUC1, an epithelial mucin aberrantly expressed during chronic inflammation and in colorectal carcinogenesis, and in a broader context that includes the potential of targeting the tumor microenvironment for immunoprevention in humans. Obstacles in developing effective cancer vaccines, including antigen selection, immunoediting, and tumor-mediated immunosuppression, are also discussed.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Cancer Vaccines/immunology ; Humans ; Neoplasms/immunology ; Neoplasms/prevention & control
Chemical Substances	Antigens, Neoplasm ; Cancer Vaccines
Language	English
Publishing date	2010-03-23
Publishing country	United States
Document type	Comment ; Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2434717-6
ISSN	1940-6215 ; 1940-6207
ISSN (online)	1940-6215
ISSN	1940-6207
DOI	10.1158/1940-6207.CAPR-10-0040
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Article ; Online: Monoclonal antibodies: versatile platforms for cancer immunotherapy.

Weiner, Louis M / Surana, Rishi / Wang, Shangzi

Nature reviews. Immunology

2010 Volume 10, Issue 5, Page(s) 317–327

Abstract: Antibodies are important therapeutic agents for cancer. Recently, it has become clear that antibodies possess several clinically relevant mechanisms of action. Many clinically useful antibodies can manipulate tumour-related signalling. In addition, ... ...

Abstract	Antibodies are important therapeutic agents for cancer. Recently, it has become clear that antibodies possess several clinically relevant mechanisms of action. Many clinically useful antibodies can manipulate tumour-related signalling. In addition, antibodies exhibit various immunomodulatory properties and, by directly activating or inhibiting molecules of the immune system, antibodies can promote the induction of antitumour immune responses. These immunomodulatory properties can form the basis for new cancer treatment strategies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/therapeutic use ; Antibody-Dependent Cell Cytotoxicity ; Antigens, CD/immunology ; CD40 Antigens/antagonists & inhibitors ; CTLA-4 Antigen ; Cancer Vaccines/therapeutic use ; Complement System Proteins/immunology ; Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes/immunology
Chemical Substances	Antibodies, Monoclonal ; Antigens, CD ; CD40 Antigens ; CTLA-4 Antigen ; CTLA4 protein, human ; Cancer Vaccines ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2010-04-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/nri2744
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Article ; Online: Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

Singh, Harshabad / Keller, Rachel B / Kapner, Kevin S / Dilly, Julien / Raghavan, Srivatsan / Yuan, Chen / Cohen, Elizabeth F / Tolstorukov, Michael / Andrews, Elizabeth / Brais, Lauren K / da Silva, Annacarolina / Perez, Kimberly / Rubinson, Douglas A / Surana, Rishi / Giannakis, Marios / Ng, Kimmie / Clancy, Thomas E / Yurgelun, Matthew B / Schlechter, Benjamin L /

Clark, Jeffrey W / Shapiro, Geoffrey I / Rosenthal, Michael H / Hornick, Jason L / Nardi, Valentina / Li, Yvonne Y / Gupta, Hersh / Cherniack, Andrew D / Meyerson, Matthew / Cleary, James M / Nowak, Jonathan A / Wolpin, Brian M / Aguirre, Andrew J

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 22, Page(s) 4627–4643

Abstract: Purpose: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for ... ...

Abstract	Purpose: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. Experimental design: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. Results: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. Conclusions: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.
MeSH term(s)	Humans ; Middle Aged ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Protein-Tyrosine Kinases/genetics ; Proto-Oncogene Proteins/genetics ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Mutation ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; KRAS protein, human
Language	English
Publishing date	2023-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-3930
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