高遺伝子異常性の小児がんに対する免疫チェックポイント阻害剤による免疫療法

//背景//-----
生殖細胞に由来する遺伝子異常は、
卵子が受精した時点で生じている可能性のある遺伝子異常です。
その遺伝子異常の中で
・DNA修復異常(MMRD)  
・ポリメラーゼ校正異常(PPD)
これらが生じると任意の遺伝子数に対する
変異の数が著しく高まるとされています(1)。
そうした中で癌ドライバー変異が生じれば、
細胞は癌化する事になります。
このような先天的な遺伝子異常によって生じる癌は
幼少期、青年期でも生じます。
これらの若い年代では
・脳(Malignant gliomas)
・胃腸(Gastrointestinal malignancies)
・血液(Hematological malignancies)
これらの部位に生じることが多いとされています(2)。
一番多いのが脳のグリア細胞が癌化するグリオーマです。
次に胃腸ということになります。
このように変異箇所が多い癌細胞は
基本的に抗がん剤が効きにくいと言われています(1)。
一方、ニボルマブ(オプジーボ)などの
免疫チェックポイント阻害剤は
癌細胞の遺伝子異常が多い時に効果を発揮するといわれており
実際に同様の免疫チェックポイント阻害剤の
Pembrolizumabは固形癌においては
Cancer mutation burdenが10/megabase以上の時に
FDAによって承認されています(3)。
上述したDNA修復、ポリメラーゼ校正機能に異常がある場合
この10倍以上の100/megabase以上になると考えられています。
従って、免疫チェックポイント阻害剤を使った
癌免疫療法が有効であると考えられます(4-6)。
一方、
一般的には免疫チェックポイント阻害剤を使った
小児癌、青年期に生じる癌においては有効ではないとされています(7-9)。

//主内容(1)//-----
Anirban Das, Sumedha Sudhaman, Daniel Morgenstern(敬称略)ら
国際的な医療研究グループは
先天的に遺伝子異常が生じる生殖細胞系において
DNAやポリメラーゼに異常がある幼児～青年期の
変異数が非常に多い癌の患者さんに対して
改めて免疫チェックポイント阻害剤を使った治療の有効性を
メタ分析しています(1)。
それによれば、6割から7割の患者さんにおいて
薬剤反応性を示しています。
薬剤：Nivolumab, Pembrolizumab
一番長い人で最大4年間以上生存が確認されています。
実際にはこのタイプのグリオーマでは
Post-relapse survivalの中央値が2.6カ月
という結果があります(10,11)。
このメタ分析では生存中央値が2年となっています。
従って、従来の認識を覆す顕著な効果と言えると思います。
このような高い遺伝子異常は
高い免疫原性があり、大人に比べて、
CD8+キラーT細胞の活性が高い若い人においては(12)
その免疫機能を生かす免疫チェックポイント阻害剤を使った
免疫療法が有効であると考えられます。

//Cell-type-specific delivery system//-----
遺伝子異常数の多い難治性の癌においては
免疫療法が有効ですが、
その治療をより少ない負担で実現するためには
免疫チェックポイント阻害剤を
iPS細胞などから作った特異的免疫細胞と複合体化して
脳、胃腸、血液の癌細胞の輸送することが考えられます。
そのためには、遺伝子異常数が多い癌において
特異的に発現されているタンパク質のメタデータの共有が必要です。
また、JOEL G. RURIK氏ら医療研究グループは
生体内でCAR-T細胞を作ることに
マウスのケースですが成功しています(13)。
このような細胞種特異的な免疫療法と
癌の免疫逃避を防ぐPD-1, PD-L1阻害の組み合わせによって
より体へのダメージの少ない治療の実現が可能かどうか？
ということです。
若い人は残された人生は長く、細胞の年齢の若いので
医療介入をできるだけ効率的に行うことで
予後の生活の質が大きく変わる可能性があります。

(参考文献)
(1)
Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C. Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, Hagay Ladany, David Chen, Matthew Zatzman, Vanja Cabric, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Lauren C, Sambira Nahum, Ayse B. Ercan, Arash Nabbi, Shlomi Constantini, Rina Dvir, Michal Yalon-Oren, Gadi Abebe Campino, Shani Caspi, Valerie Larouche, Alyssa Reddy, Michael Osborn, Gary Mason, Scott Lindhorst, Annika Bronsema, Vanan Magimairajan, Enrico Opocher, Rebecca Loret De Mola, Magnus Sabel, Charlotta Frojd, David Sumerauer, David Samuel, Kristina Cole, Stefano Chiaravalli, Maura Massimino, Patrick Tomboc, David S. Ziegler, Ben George, An Van Damme, Nobuko Hijiya, David Gass, Rose B. McGee, Oz Mordechai, Daniel C. Bowers, Theodore W. Laetsch, Alexander Lossos, Deborah T. Blumenthal, Tomasz Sarosiek, Lee Yi Yen, Jeffrey Knipstein, Anne Bendel, Lindsey M. Hoffman, Sandra Luna-Fineman, Stefanie Zimmermann, Isabelle Scheers, Kim E. Nichols, Michal Zapotocky, Jordan R. Hansford, John M. Maris, Peter Dirks, Michael D. Taylor, Abhaya V. Kulkarni, Manohar Shroff, Derek S. Tsang, Anita Villani, Wei Xu, Melyssa Aronson, Carol Durno, Adam Shlien, David Malkin, Gad Getz, Yosef E. Maruvka, Pamela S. Ohashi, Cynthia Hawkins, Trevor J. Pugh, Eric Bouffet & Uri Tabori
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Nature Medicine (2022)
---
Author information
Author notes
These authors contributed equally: Anirban Das, Sumedha Sudhaman, Daniel Morgenstern.
Affiliations
Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
Anirban Das, Daniel Morgenstern, Liana Nobre, Lauren C, Sambira Nahum, Anita Villani, David Malkin, Eric Bouffet & Uri Tabori
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Anirban Das, Sumedha Sudhaman, Jiil Chung, David Chen, Matthew Zatzman, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Ayse B. Ercan, Adam Shlien, David Malkin & Uri Tabori
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
Anirban Das, Sumedha Sudhaman, Jiil Chung, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Ayse B. Ercan, Peter Dirks, Michael D. Taylor & Uri Tabori
Department of Paediatric Haematology/ Oncology, Tata Medical Centre, Kolkata, India
Anirban Das
Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
Daniel Morgenstern, Vanja Cabric, Anita Villani, David Malkin, Eric Bouffet & Uri Tabori
Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada
Ailish Coblentz & Manohar Shroff
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Jiil Chung & Ayse B. Ercan
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Simone C. Stone, Shirin Soleimani, Arash Nabbi, Pamela S. Ohashi & Trevor J. Pugh
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Noor Alsafwani, Ola Abu Al Karsaneh & Matthew Zatzman
Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University (IAU), Dammam, Saudi Arabia
Noor Alsafwani
Department of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
Zhihui Amy Liu & Wei Xu
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Zhihui Amy Liu & Wei Xu
Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
Ola Abu Al Karsaneh
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Shirin Soleimani, David Malkin, Trevor J. Pugh & Uri Tabori
Biotechnology and Food Engineering, Technion – Israel Institute of Technology, Tel-Aviv, Israel
Hagay Ladany & Yosef E. Maruvka
Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel-Aviv, Israel
Shlomi Constantini
Department of Pediatric Hematology–Oncology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel
Rina Dvir
Department of Pediatric Hematology–Oncology, Sheba Medical Centre, Ramat Gan, Israel
Michal Yalon-Oren, Gadi Abebe Campino & Shani Caspi
Department of Paediatric Haematology/Oncology, Centre Hospitalier de Quebec-Universite Laval, Quebec City, Quebec, Canada
Valerie Larouche
Departments of Neurology and Pediatrics, University of California, San Francisco, CA, USA
Alyssa Reddy
Women’s and Children’s Hospital, North Adelaide, South Australia, Australia
Michael Osborn
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Gary Mason
Neuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA
Scott Lindhorst
Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg–Eppendorf, Hamburg, Germany
Annika Bronsema
Department of Paediatric Haematology–Oncology, Cancer Care Manitoba, Research Institute in Oncology and Haematology, University of Manitoba, Winnipeg, Manitoba, Canada
Vanan Magimairajan
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
Enrico Opocher
Pediatric Hematology-Oncology, Helen DeVos Children’s Hospital, Grand Rapids, MI, USA
Rebecca Loret De Mola
Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
Magnus Sabel
Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
Magnus Sabel
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
Charlotta Frojd
Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic
David Sumerauer & Michal Zapotocky
Department of Pediatric Oncology, Valley Children’s Hospital, Madera, CA, USA
David Samuel
Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelpha, PA, USA
Kristina Cole, Theodore W. Laetsch & John M. Maris
Paediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Stefano Chiaravalli & Maura Massimino
Department of Pediatrics, J.W. Ruby Memorial Hospital – West Virginia University, Morgantown, WV, USA
Patrick Tomboc
Kids Cancer Centre, Sydney Children’s Hospital, Randwick, New South Wales, Australia
David S. Ziegler
School of Women’s and Children’s Health, University of New South Wales, Sydney, New South Wales, Australia
David S. Ziegler
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
Ben George
Department of Paediatric Haematology and Oncology, Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
An Van Damme
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Irving Medical Centre, New York, NY, USA
Nobuko Hijiya
Atrium Health Levine Children’s Hospital, Charlotte, NC, USA
David Gass
Cancer Predisposition Division, Oncology Department, St Jude Children’s Research Hospital, Memphis, TN, USA
Rose B. McGee & Kim E. Nichols
Department of Pediatric Hematology Oncology, Rambam Health Care Campus, Haifa, Israel
Oz Mordechai
Department of Pediatrics, The University of Texas Southwestern Medical School, Dallas, TX, USA
Daniel C. Bowers
Department of Oncology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Alexander Lossos
Neuro-Oncology Service, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
Deborah T. Blumenthal
Lux Med Onkologia, Warsaw, Poland
Tomasz Sarosiek
Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
Lee Yi Yen
Division of Pediatric Hematology/ Oncology/ BMT, Medical College of Wisconsin, Milwaukee, WI, USA
Jeffrey Knipstein
Department of Pediatric Hematology-Oncology, Children’s Hospitals and Clinics of Minnesota, St Paul, MN, USA
Anne Bendel
Phoenix Children’s Hospital, Phoenix, AZ, USA
Lindsey M. Hoffman
Department of Pediatrics, Anschutz Medical Campus, Children’s Hospital of Colorado, Aurora, CO, USA
Sandra Luna-Fineman
Paediatric Haematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany
Stefanie Zimmermann
Paediatric Gastroenterology, Hepatology and Nutrition Unit, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
Isabelle Scheers
Children’s Cancer Centre, Royal Children’s Hospital, Murdoch Children’s Research Institute, University of Melbourne, Parkville, Victoria, Australia
Jordan R. Hansford
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Jordan R. Hansford
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada
Peter Dirks, Michael D. Taylor & Abhaya V. Kulkarni
Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
Peter Dirks & Michael D. Taylor
Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
Abhaya V. Kulkarni
Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Derek S. Tsang
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
Melyssa Aronson & Carol Durno
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Adam Shlien & Cynthia Hawkins
Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA, USA
Gad Getz
Broad Institute of Harvard and MIT, Cambridge, MA, USA
Gad Getz
Department of Immunology, University of Toronto, Toronto, Ontario, Canada
Pamela S. Ohashi
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
Cynthia Hawkins
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Cynthia Hawkins
Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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