Outcome of T-cell activating immunotherapy in mismatch repair deficient tumors and the predictive value of tumor-induced immune evasion mechanisms: a scoping review protocol
Creators: name: Rasmussen, Maria
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Neoplasms
subject: Chemicals and Drugs
subject: Diseases
subject: Medicine and Health Sciences
subject: Life Sciences
subject: Genetics and Genomics

description: Pregistration for a scoping review Review title and time scale Title Outcome of T-cell activating immunotherapy in mismatch repair deficient tumors and the predictive value of tumor-induced immune evasion mechanisms: a scoping review. Anticipated start date 01/03 2020 Anticipated completion date 01/01 2021 Stage of review at the time of submission The search string for the review was originallytested and approved on March 20, 2020. Minor alterations in the search string made in May 2020 After reviewing 100 hits, the search string was optimized, and a new search was performed on May 4, 2020. The optimization included deletion of the search terms “PD-1 antibody”, “PD-L1 antibody”, and “CTLA-4 antibody” under the identification of FDA and EMA approved immune checkpoint-based therapies. Review of title and abstracts of the identified articles are ongoing. Data extraction has not yet started. The new search string is: ((((((((Neoplasms[MeSH Terms]) OR (Neoplas*[Text Word])) OR (Tumor*[Text Word])) OR (Tumour*[Text Word])) OR (Cancer*[Text Word])) OR (Malignan*[Text Word])) OR (Carcinoma*[Text Word])) AND (((((((((((((((((((("Colorectal Neoplasms, Hereditary Nonpolyposis"[Mesh]) OR ("Lynch syndrome"[Text Word])) OR (HNPCC[Text Word])) OR (“Hereditary Nonpolyposis”[Text Word])) OR (“Hereditary Non polyposis”[Text Word])) OR (“Familial Nonpolyposis”[Text Word])) OR (“Familial Non polyposis”[Text Word])) OR (“DNA Mismatch Repair"[MeSH Terms])) OR (“Mismatch Repair”[Text Word])) OR (“DNA Mismatch”[Text Word])) OR (MMR[Text Word])) OR (dMMR[Text Word])) OR (d-MMR[Text Word])) OR (MMR-d[Text Word])) OR (MMRd[Text Word])) OR ("Microsatellite Instability"[MeSH Terms])) OR ("Replication Error Phenotype*"[Text Word])) OR (MSI[Text Word])) OR ("Microsatellite Instability"[Text Word])) OR ("Microsatellite unstable"[Text Word]))) AND ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((("Ipilimumab"[MeSH Terms]) OR (Ipilimumab[Text Word])) OR (Yervoy[Text Word])) OR (MDX010[Text Word])) OR (MDX-010[Text Word])) OR (MDX101[Text Word])) OR (MDX-101[Text Word])) OR (BMS734016[Text Word])) OR (BMS-734016[Text Word])) OR (Strentarga[Text Word])) OR ("pembrolizumab"[Supplementary Concept])) OR (Pembrolizumab[Text Word])) OR (SCH-900475[Text Word])) OR (SCH900475[Text Word])) OR (Keytruda[Text Word])) OR (MK-3475[Text Word])) OR (MK3475[Text Word])) OR (Lambrolizumab[Text Word])) OR ("Nivolumab"[MeSH Terms])) OR (Nivolumab[Text Word])) OR (Opdivo[Text Word])) OR (ONO-4538[Text Word])) OR (ONO4538[Text Word])) OR (MDX-1106[Text Word])) OR (MDX1106[Text Word])) OR (BMS-936558[Text Word])) OR (BMS936558[Text Word])) OR (Cmab819[Text Word])) OR (Cmab-819[Text Word])) OR ("atezolizumab"[Supplementary Concept])) OR (Atezolizumab[Text Word])) OR (MPDL3280A[Text Word])) OR (MPDL-3280A[Text Word])) OR (Tecentriq[Text Word])) OR (Tecntriq[Text Word])) OR (RG7446[Text Word])) OR (RG-7446[Text Word])) OR ("durvalumab"[Supplementary Concept])) OR (durvalumab[Text Word])) OR (MEDI4736[Text Word])) OR (MEDI-4736[Text Word])) OR (Imfinzi[Text Word]) OR ("avelumab"[Supplementary Concept])) OR (avelumab[Text Word])) OR (MSB0010682[Text Word])) OR (MSB-0010682[Text Word])) OR (MSB0010718C[Text Word])) OR (MSB-0010718C[Text Word])) OR (Bavenico[Text Word])) OR (MSB 10682[Text Word])) OR (MSB10682[Text Word])) OR (MSB 10718C[Text Word])) OR (MSB10718C[Text Word])) OR (pf 06834635[Text Word])) OR (pf06834635[Text Word])) OR (pf 6834635[Text Word])) OR (pf6834635[Text Word])) Review team details Contact person: Name: Maria Rasmussen Email Maria.Rasmussen.07@regionh.dk Phone number +4538627700 Organization Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Denmark. Working address Kettegård Allé 30, 2650 Hvidovre, Denmark Authors Ms Maria Rasmussen1, Dr. Jon Durhuus1, Prof. Ove Andersen1, Prof. Mef Nilbert1,2,3, Dr. Christina Therkildsen1. 1Clinical Research Centre, Copenhagen University Hospital, Denmark 2The Danish Cancer Society Research Center, Copenhagen, Denmark 3Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden Funding Danish Cancer Research Society (Knæk cancer fonden), R246-A14570. Conflicts of interest The authors have no conflicts of interest to declare. Review methods Rationale (optional) Checkpoint immunotherapy is administered based on disruption of tumor cell-induced inhibition of cytotoxic T cell mediated apoptosis. T cell re-activation is currently effectuated through the FDA and EMA approved drugs Ipilimumab, Atezolizumab, Avelumab, Pembrolizumab, Durvalumab, and Nivolumab, which target the PD1/PD-L1 or CTLA-4/B7.1/2 inhibitory mechanisms. These treatment strategies are tested in various organs, combinations, and lines of treatment. The drugs are highly efficient in patients with tumors that have a high mutation burden, mismatch repair deficiency/microsatellite instability, and high levels of tumor-infiltrating T cells, which are hallmarks of the hereditary cancer syndrome, Lynch syndrome. Though inclusion in clinical studies is based on patients having this tumor phenotype, up against 50% does not respond and predictive biomarkers are currently investigated to increase the response rates. Review questions This scoping review aims to: 1) Systematically map current knowledge and gaps in the literature on the outcome from the FDA and EMA approved T-cell activating drugs Ipilimumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, and Nivolumab in patients with mismatch repair deficient/microsatellite instable tumors? How is this outcome affected by tumor-induced immune evasion mechanisms? 2) Systematically map current knowledge and gaps in what is known in the literature on the outcome from the FDA and EMA approved T-cell activating drugs Ipilimumab, Pembrolizumab, Atezolizumab, Nivolumab in Lynch syndrome patients? How is this outcome affected by tumor-induced immune evasion mechanisms? Literature search Literature will be searched at the following electronic bibliographic databases: PubMed, EMBASE, and the Cochrane Library by an experienced librarian. The search string was assembled from MeSH and non-MeSH terms included in the three categories: [cancer] AND [Lynch syndrome/MSI/MMR-deficiency] AND [approved T-cell activating checkpoint inhibitors]: ((((((((Neoplasms[MeSH Terms]) OR (Neoplas*[Text Word])) OR (Tumor*[Text Word])) OR (Tumour*[Text Word])) OR (Cancer*[Text Word])) OR (Malignan*[Text Word])) OR (Carcinoma*[Text Word])) AND (((((((((((((((((((("Colorectal Neoplasms, Hereditary Nonpolyposis"[Mesh]) OR ("Lynch syndrome"[Text Word])) OR (HNPCC[Text Word])) OR (“Hereditary Nonpolyposis”[Text Word])) OR (“Hereditary Non polyposis”[Text Word])) OR (“Familial Nonpolyposis”[Text Word])) OR (“Familial Non polyposis”[Text Word])) OR (“DNA Mismatch Repair"[MeSH Terms])) OR (“Mismatch Repair”[Text Word])) OR (“DNA Mismatch”[Text Word])) OR (MMR[Text Word])) OR (dMMR[Text Word])) OR (d-MMR[Text Word])) OR (MMR-d[Text Word])) OR (MMRd[Text Word])) OR ("Microsatellite Instability"[MeSH Terms])) OR ("Replication Error Phenotype*"[Text Word])) OR (MSI[Text Word])) OR ("Microsatellite Instability"[Text Word])) OR ("Microsatellite unstable"[Text Word]))) AND ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((("Ipilimumab"[MeSH Terms]) OR (Ipilimumab[Text Word])) OR (Yervoy[Text Word])) OR (MDX010[Text Word])) OR (MDX-010[Text Word])) OR (MDX101[Text Word])) OR (MDX-101[Text Word])) OR (BMS734016[Text Word])) OR (BMS-734016[Text Word])) OR (Strentarga[Text Word])) OR ("CTLA-4 Antigen"[MeSH Terms])) OR (CTLA4[Text Word])) OR (CTLA-4[Text Word])) OR (CD152[Text Word])) OR ("Cytotoxic T-Lymphocyte-Associated Antigen 4"[Text Word])) OR ("Cytotoxic T Lymphocyte Antigen 4"[Text Word])) OR ("Programmed Cell Death 1 Receptor"[MeSH Terms])) OR (“Programmed Cell Death"[Text Word])) OR (“Programmed Death"[Text Word])) OR (PD-1[Text Word])) OR (PD1[Text Word])) OR (CD279[Text Word])) OR ("B7-H1 Antigen"[MeSH Terms])) OR (PD-L1[Text Word])) OR (PDL1[Text Word])) OR (PDL-1[Text Word])) OR (B7-H1[Text Word])) OR (B7H1[Text Word])) OR (CD274[Text Word])) OR ("B7 homolog 1"[Text Word])) OR ("B7 homologue 1"[Text Word])) OR (PDCD1[Text Word])) OR (PDCD1LG1[Text Word])) OR ("pembrolizumab"[Supplementary Concept])) OR (Pembrolizumab[Text Word])) OR (SCH-900475[Text Word])) OR (SCH900475[Text Word])) OR (Keytruda[Text Word])) OR (MK-3475[Text Word])) OR (MK3475[Text Word])) OR (Lambrolizumab[Text Word])) OR ("Nivolumab"[MeSH Terms])) OR (Nivolumab[Text Word])) OR (Opdivo[Text Word])) OR (ONO-4538[Text Word])) OR (ONO4538[Text Word])) OR (MDX-1106[Text Word])) OR (MDX1106[Text Word])) OR (BMS-936558[Text Word])) OR (BMS936558[Text Word])) OR (Cmab819[Text Word])) OR (Cmab-819[Text Word])) OR ("atezolizumab"[Supplementary Concept])) OR (Atezolizumab[Text Word])) OR (MPDL3280A[Text Word])) OR (MPDL-3280A[Text Word])) OR (Tecentriq[Text Word])) OR (Tecntriq[Text Word])) OR (RG7446[Text Word])) OR (RG-7446[Text Word])) OR ("durvalumab"[Supplementary Concept])) OR (durvalumab[Text Word])) OR (MEDI4736[Text Word])) OR (MEDI-4736[Text Word])) OR (Imfinzi[Text Word])) We will also scan the reference list of all relevant reviews and original articles in order to avoid selection bias. URL to search strategy Not applicable Condition or domain being studied Patients with mismatch repair deficient/microsatellite instable tumors treated with the FDA and EMA approved T-cell activating drugs Ipilimumab, Pembrolizumab, Avelumab, Atezolizumab, Durvalumab, and Nivolumab. Participants/Population All patients regardless of age have been pre-selected based on tumor phenotype showing microsatellite instability or mismatch repair deficiency through immunohistochemical loss of protein expression of the mismatch proteins MLH1, MSH2, MSH6 or PMS2. There are no selection criteria regarding tumor type. Concept All patients have been treated with the FDA and EMA approved T cell activating drugs Ipilimumab, Pembrolizumab, Avelumab, Atezolizumab, Durvalumab, or Nivolumab and tumor progression or regression (scored according to the RECIST criteria) and/or overall/progression-free survival have been collected in a medical setting. For some studies, biomarkers may have been investigated retrospectively to determine their predictive value. Context All periods of time and duration of follow-up before March 20, 2020, are eligible. Primary outcomes (optional) Primary outcomes include: objective response rate, overall survival, progression-free survival, progressive disease, resistance and biomarker analyses (protein analyses, gene expression analyses or DNA mutation analyses) on immune response and immune evasion pathways. Secondary outcomes (optional) Secondary outcomes include: all of the primary outcomes described above but specifically in Lynch syndrome patients. Data extraction The full set of titles and abstracts retrieved will be independently screened for eligibility by three authors (Maria Rasmussen and Christina Therkildsen) and the level of agreement will be discussed. A pilot search has been conducted to study the selection criteria and compare articles identified in the beginning and end of the screening process. A third reviewer (Jon Durhuus) will be consulted where agreement cannot be achieved. A standardized data extraction formula will be developed and pilot-tested among all reviewers. Data extraction will include: tumor type (e.g. location, organ, level of mismatch repair deficiency, level of microsatellite instability), treatment regimen (e.g. pharmaceutical drug used, line of treatment, combinational treatment, period), outcome (e.g. objective response rate, overall survival, progression-free survival, resistance), and biomarkers (e.g. name of the protein/genes, type of analyses, level of expression, percentage of positive tumors). All studies need to be on homo sapiens and written in English. Conference abstracts will be screened, but only included if all requested data are available. Risk of quality assessment Since this is a scoping review, quality assessment will not be conducted. Strategy of synthesis The synthesis will focus on providing: 1) mapping the outcomes from checkpoint-based immunotherapy in patients with mismatch repair deficient/microsatellite instable tumors and 2) describe the predictive value of immune response and immune evasion-related possible up-coming biomarkers associated with tumor-induced immune evasion mechanisms. Review general information Type of review Scoping review Language English Country Denmark Dissemination plans Results will be published in a peer-reviewed journal. Keywords Immunotherapy, mismatch repair deficient cancer, microsatellite instability, scoping review, predictive biomarkers Current review status Ongoing (reviewing title and abstract)