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   Table of Contents - Current issue
April-June 2019
Volume 2 | Issue 2
Page Nos. 21-51

Online since Wednesday, April 10, 2019

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Moonshot for precision medicine p. 21
Jordi Rodon
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Tackling immunotherapy resistance: Developing rational combinations of immunotherapy and targeted drugs p. 23
Elena Cojocaru, Mariana Scaranti, Anna Minchom
Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential.
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Should we design clinical trials differently in the era of cancer immunotherapy? p. 36
Chia-Chi Lin
The oncology clinical trials are evolving in the era of cancer immunotherapy. In Phase I trials, some severe immune-related adverse events occur beyond the first cycle. This is important to determine the recommended Phase II dose if the treatment duration is long. If there is no dose–response/toxicity relationship, it will not be necessary to push to the maximum tolerated dose. In Phase II trials, companion predictive biomarkers are valuable in cancers with intermediate response rates. Randomized (comparison, selection, or discontinuation) Phase II trials are needed in cancer immunotherapy combination. In Phase III trials, milestone analysis and restricted mean survival time could serve as the alternatives to hazard ratio to fit the survival kinetics of cancer immunotherapy.
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Vedolizumab Achieved Clinical and Histologic Remission in a Patient with Lung Cancer Who Had a Steroid-Refractory Upper Gastrointestinal Injury Due to Nivolumab Treatment p. 40
Cynthia Nguyen Tran, Hamzah Abu-Sbeih, Wenyi Luo, Yang Lu, Yinghong Wang
Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed.
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5th Annual immuno-oncology 360° conference: Spanning science and business to bring new therapies to patients p. 46
Marie Recine
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