Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_119_библиотеки_им_акад_М_И_Перельмана
.pdf
Haidong Dong
https://t.me/med1917
Svetomir N. Markovic Editors
The Basics
of Cancer
Immunotherapy
Second Edition
The Basics of Cancer Immunotherapy
https://t.me/med1917
Haidong Dong • Svetomir N. Markovic
https://t.me/med1917
Editors
The Basics of Cancer
Immunotherapy
Second Edition
Editors
https://t.me/med1917
Haidong Dong
Department of Urology and Immunology
Mayo Clinic College of Medicine
Rochester, MN, USA
Svetomir N. Markovic
Division of Hematology/Oncology
Mayo Clinic
Rochester, MN, USA
ISBN 978-3-031-59474-8 ISBN 978-3-031-59475-5 (eBook)
https://doi.org/10.1007/978-3-031-59475-5
© Mayo Foundation for Medical Education and Research, a Minnesota charitable corporation 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specic statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional afliations.
Cover image: The image shows a region of interest (ROI) of a primary met (Lymph node metastasis)
from a patient who relapsed with immunotherapy. The patient had no response to the immune checkpoint
blocker. This is one facet of that tumor-immune interface. Credit: Markovic Lab, Mayo Clinic (https://
dimi-lab.github.io/)
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
If disposing of this product, please recycle the paper.
Acknowledgements
https://t.me/med1917
We are grateful to the pioneers, our mentors/mentees, and colleagues in the eld of
cancer immunology and immunotherapy. We dedicate our book to our patients and
their families for ghting cancer with us. Our research has been supported by the
National Institute of Health, the National Cancer Institute, and the Mayo Foundation.
We appreciate Sarah Lawler for the administration support and Crystal Lin for
graphing gures of some chapters. We apologize for not being able to cite all the
excellent studies and clinical trials in this eld due to space limitations.
v
Contents
https://t.me/med1917
1 Basic Concepts in Cancer Immunology and Immunotherapy . . . . . . 1
Laura M. Rogers and Haidong Dong
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Why Do We Have Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
How Does the Immune System Protect Us from Cancer? . . . . . . . . . . . 3
Why Does the Immune System Fail to Control Cancer Cells? . . . . . . . . 5
Strategies to Harness the Immune System to Fight Cancer Cells . . . . . . 6
Advantages and Side Effects of Cancer Immunotherapy . . . . . . . . . . . . 8
Future of Cancer Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2 Immune Checkpoint Inhibitors in Oncology . . . . . . . . . . . . . . . . . . . . 11
Katherine Smith and Svetomir N. Markovic
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Currently Approved Immune Checkpoint Inhibitors . . . . . . . . . . . . . . . 14
CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4)
Inhibitors
PD-1 (Programmed Death—1) Inhibitors . . . . . . . . . . . . . . . . . . . . . . 16
PD-L1 (Programmed Death Ligand 1) . . . . . . . . . . . . . . . . . . . . . . . . 17
LAG-3 (Lymphocyte Activation Gene—3) Inhibitors . . . . . . . . . . . . 17
Novel Immune Checkpoint Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Immune-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Special Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Patients with History of Autoimmune Disorders . . . . . . . . . . . . . . . . 20
Solid-Organ Transplant Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Take-Home Messages for Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
vii
viii
https://t.me/med1917
Contents
3 Immunotherapies for Cancer: Bi-specific T Cell
Engagers (BiTEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Richard C. Godby, Alex Niu, and Jonas Paludo
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
T Cell Signaling and BiTEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Approved Products and Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Adverse Events and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Cytokine Release Syndrome (CRS) . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Immune Effector Cell-Associated Neurotoxicity Syndrome
(ICANS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4 Tumor-Infiltrating Lymphocyte (TIL) Therapy . . . . . . . . . . . . . . . . . 33
Jeffrey E. Johnson, Velvet R. Van Ryan, and Arkadiusz Z. Dudek
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5 Cellular Therapies for Cancer: Chimeric Antigen Receptor
T Cells (CAR-T) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Richard C. Godby, Alex Niu, and Jonas Paludo
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
T Cell Signaling and CAR Constructs . . . . . . . . . . . . . . . . . . . . . . . . . . 42
CAR-T Production: Collection, Composition, Constructs,
and Manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Advanced Constructs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Approved Products and Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Adverse Events and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Cytokine Release Syndrome (CRS) . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Immune Effector Cell-Associated Neurotoxicity Syndrome
(ICANS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Cytopenias and Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Mechanisms of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6 Viral Immunotherapy Strategies in Clinical Practice . . . . . . . . . . . . . 57
Jeffrey Johnson and James Jakub
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Contents
https://t.me/med1917
7 Chemoimmunotherapy Combination for Solid Tumors . . . . . . . . . . . 63
Yiyi Yan
Mechanisms of Chemotherapy and Immunotherapy Combination . . . . 64
Chemoimmunotherapy in Solid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 65
Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Other Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Antibody-Drug Conjugate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Conclusion and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Immunomodulatory Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Strategies for Chemoimmunotherapy Combination . . . . . . . . . . . . . . 74
Potential Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
8 Melanoma Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Erica L. Andres and Matthew S. Block
Part 1: Melanoma and the Immune System . . . . . . . . . . . . . . . . . . . . . . 82
Inherent Immunogenicity of Melanoma . . . . . . . . . . . . . . . . . . . . . . . 82
Mechanisms of Immune Evasion and Immunosuppression
Employed by Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Part 2: Current Immunotherapy Treatments for Melanoma . . . . . . . . . . 85
Part 2a: Unresectable Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Interleukin 2 (IL-2) and Tumor-Inltrating Lymphocyte (TIL)
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Ipilimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Pembrolizumab and Nivolumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Combined Ipilimumab and Nivolumab . . . . . . . . . . . . . . . . . . . . . . . . 89
Nivolumab/Retlatinib Combination Therapy . . . . . . . . . . . . . . . . . . . 89
Comparison of CTLA-4 Monotherapy, PD-1 Monotherapy,
and Combination CTLA-4/PD-1 Therapy for Metastatic
Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Talimogene Laherparepvec (T-VEC) . . . . . . . . . . . . . . . . . . . . . . . . . 91
Tebentafusp for Uveal Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Part 2b: Resectable Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Adjuvant Immunotherapy in Resectable Melanoma . . . . . . . . . . . . . . 93
Neoadjuvant Immunotherapy in Resectable Melanoma . . . . . . . . . . . 96
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Part 3: New Treatments on the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . 99
TIL Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
TIGIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
ix
x
https://t.me/med1917
Contents
9 Significance of Immune Checkpoints in Lung Cancer . . . . . . . . . . . 109
Anastasios Dimou and Konstantinos Leventakos
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Staging and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Immunotherapy in Perioperative Treatment . . . . . . . . . . . . . . . . . . . . . . 111
Neoadjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Adjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Patients with Stage III Disease Receiving Concurrent
Chemotherapy and Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Patients with Advanced or Metastatic Disease . . . . . . . . . . . . . . . . . . 113
PD-1 and PD-L1 Inhibitors as Single Agents in Treatment-Naïve
Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
PD-1 or PD-L1 Inhibitors in Combination with Chemotherapy . . . . . 114
Combination of Anti-PD-1 and Anti-CTLA-4 Agents . . . . . . . . . . . . 115
Immunotherapy for Patients with EGFR and ALK Mutations . . . . . . 116
Immune Checkpoint Inhibitors in Later Lines of Treatment . . . . . . . 117
Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
PD-L1 Assessment and Companion Assays . . . . . . . . . . . . . . . . . . . . . . 119
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
10 Immunotherapy in Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Jenna Hoppenworth and Roberto A. Leon-Ferre
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Basics of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Breast Cancer Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Early-Stage Breast Cancer: Multidisciplinary Approaches
to Treatment
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
How Are the Different Treatment Modalities Integrated? . . . . . . . . . . . 129
Breast Cancer and the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . 130
Chemoimmunotherapy for Early-Stage Triple-Negative
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Chemoimmunotherapy for Metastatic Triple-Negative
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Atezolizumab + Chemotherapy in Metastatic TNBC . . . . . . . . . . . . . . . 135
Monoclonal Antibodies and Antibody-Drug Conjugates . . . . . . . . . . . . 135
Future Directions of Immunotherapy for Breast Cancer . . . . . . . . . . . . 138
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
11 Immunotherapy in Genitourinary Malignancies . . . . . . . . . . . . . . . . 141
Jacob Orme
Kidney/Renal Cell Carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Renal Cell Carcinoma Grade, Stage, and Risk . . . . . . . . . . . . . . . . . . 142
Contents
https://t.me/med1917
Immunotherapy in Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . 144
Bladder/Urothelial Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Immunotherapy in Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Prostate, Testicular, and Penile Cancers . . . . . . . . . . . . . . . . . . . . . . . . . 152
Immunotherapy in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Immunotherapy in Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 154
Immunotherapy in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
12 Immunotherapy for Gastrointestinal Malignancies . . . . . . . . . . . . . 157
Mojun Zhu
Colorectal, Appendiceal, and Small Bowel Cancer . . . . . . . . . . . . . . . . 157
Anal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Esophageal and Stomach Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Biliary Tract Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Neuroendocrine Tumor and Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . 162
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
xi
13 Immunotherapy in the Solid Organ Transplant Recipient . . . . . . . . 167
Alex Liu, Elena Barbir, Aleksandra Kukla, and Kymberly D. Watt
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Outcomes and Complications of ICI Use in Solid Organ Transplant
Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
General ICI Adverse Event Overview . . . . . . . . . . . . . . . . . . . . . . . . . 169
Outcomes and Adverse Effects by Organ . . . . . . . . . . . . . . . . . . . . . . . . 171
Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Heart and Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
14 Diagnosis and Management of Immune- Related Adverse Events
of Immune Checkpoint Inhibitor Therapy . . . . . . . . . . . . . . . . . . . . . 179
Casey Fazer-Posorske, Lisa Kottschade, and Anna Schwecke
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Grading of Immunotherapy Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Dermatologic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Gastrointestinal (GI) Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Hepatic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Endocrine Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Thyroid Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Соседние файлы в папке Библиотека им академика М.И. Перельмана