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
5 Cellular Therapies forCancer: Chimeric Antigen Receptor T Cells (CAR-T)
https://t.me/med1917
51
Immune Effector Cell-Associated Neurotoxicity
Syndrome (ICANS)
After infusion of the CAR-T product, there is potential for rapid expansion, activation, and cytotoxic activity resulting in large amounts of cytokine release that may
also disrupt the blood-brain barrier (Morris etal., 2022). Clinically, this may manifest with depressed consciousness, seizures, motor changes, and cerebral edema
which are used to grade the ICANS and subsequently guide treatment (Lee etal.,
2019; Santomasso etal., 2021; NCCN, 2023). If this occurs, it usually takes place
relatively later than CRS typically does and lasts relatively longer, commonly occurring around 1 week after infusion and possibly persisting up to approximately 2
weeks (Santomasso etal., 2021; Morris et al., 2022; NCCN, 2023). Each CAR-T
product has product-specic recommendations for management of ICANS, but in
addition to supportive care, the rst-line treatment if clinically warranted is highdose steroids (e.g., dexamethasone) with the possible addition of antiepileptics;
anti-IL6 therapy is usually added only for the simultaneous presence of CRS
(Santomasso etal., 2021; NCCN, 2023; Jain etal., 2023a).
Cytopenias andInfections
Patients receiving cellular therapies often experience cytopenias that can arise from
various etiologies. By the time patients are eligible for CAR-T products, they have
already been exposed to cytotoxic chemotherapy and are reexposed to lymphodepleting therapy prior to infusion of CAR-T.While early cytopenias are often attributed to the lymphodepleting chemotherapy, there is a broad differential of diagnoses
requiring etiology-specic interventions depending on the clinical course, including
large granular lymphocytosis, thrombotic microangiopathies, disease relapse,
hemophagocytic lymphohistiocytosis, and more (Santomasso et al., 2021; Jain
etal., 2023b). Infections may also be an etiology for cytopenias but are often a consequence, requiring adequate antimicrobial prophylaxis, treatment, and vaccination
(Hill etal., 2018; Hill & Seo, 2020; Santomasso etal., 2021). Another consequence
of the cytopenias associated with CAR-T therapies, especially those products targeting CD19, is prolonged hypogammaglobulinemia often requiring intravenous
immunoglobulin support and predisposing to additional infections complications.
Mechanisms ofResistance
Resistance to CAR-T is complex with mechanisms related to the tumor itself, T cell
dysfunction, and/or the TME.
52
https://t.me/med1917
In a signicant portion of patients receiving CAR-T cell therapy, antigen escape
(partial or complete loss of target antigen expression by the tumor) is observed.
Clinical relapse due to antigen loss was rst reported with blinatumomab in MRDpositive B-ALL patients (Topp etal., 2011). Other possible mechanisms of antigen
loss include CAR-T trogocytosis, lineage switching, and antigen masking.
Trogocytosis is a process where the target antigen is transferred from the tumor cell
to T cells which ultimately promotes T cell fratricide and exhaustion. CAR-T trogocytosis has been observed as a mechanism of resistance in preclinical models of
CD19 CARs as well as CD22, BCMA, and mesothelin-directed CAR-T cells
(Hamieh et al., 2019). Antigen loss may also occur when the target cell lineage
switches from a lymphoid phenotype to a myeloid phenotype due to cellular reprograming and B-cell de-differentiation, which has been reported as a mechanism of
antigen escape after both CD19 CAR-T and blinatumomab therapy (DorantesAcosta & Pelayo, 2012; Gardner etal., 2016; Wöl etal., 2018). Antigen masking
was described in the accidental transduction of a leukemic cell during CAR-T manufacturing that presumably led to masking of the CD19 epitope which led to resistance to CAR-T therapy (Ruella etal., 2018).
Another important resistance mechanism, associated with lack of early molecular response in large B-cell lymphoma cases treated with axicabtagene ciloleucel,
was T cell exhaustion (Deng etal., 2020). T cell exhaustion may be an intrinsic T
cell defect inuenced by pretreatment factors or may be acquired via immunosuppressive ligands and immunosuppressive cells in the TME.T cell exhaustion immunophenotypes are characterized by increased expression of inhibitory receptors
(PD-1, CTLA-4, TIM-3, and LAG-3), altered metabolism, decreased proliferation
and cytokine production, and a distinct transcriptional signature (Long etal., 2015).
Activation-induced cell death (AICD), a mechanism of peripheral tolerance resulting in T cell death rather than activation through binding of the TCR to its antigen,
is another resistance mechanism (Green etal., 2003). Repetitive stimulation of the
TCR is a factor that can predispose T cells to AICD and has been observed in
CAR-T cells. Unlike T cell exhaustion, AICD is irreversible (Kuünkele etal., 2015).
The TME is composed of endothelial cells, extracellular matrix (ECM), myeloidderived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated broblasts (CAFs), which interact closely
with tumor cells and contribute to tumorigenesis (Quail & Joyce, 2013). Physical
barriers to tumor penetration by immune cells, upregulated checkpoint ligands, a protumor stromal niche, and presence of immunosuppressive cytokines/chemokines and
soluble factors are known mechanisms of TME-mediated T cell dysfunction.
R. C. Godby etal.
Future Directions
Allogeneic CAR-T cells, manufactured from an unrelated T cell donor, are an alternative to the current autologous CAR-T products that could overcome many logistical and manufacturing related barriers to current CAR-T practices. Allogeneic
5 Cellular Therapies forCancer: Chimeric Antigen Receptor T Cells (CAR-T)
https://t.me/med1917
53
CAR-T products are an attractive “off-the-shelf” approach given the shorter wait
times that patients currently experience, but they must be designed such that they
avoid graft versus host disease (GVHD) and graft rejection. GVHD might occur
when recipient antigens are recognized by the TCR of the allogeneic CART.Additionally, the host immune system may recognize the allogeneic CAR-T cells
via nonself HLAs resulting in rejection of the CAR-T product. Strategies to overcome these barriers include genome editing techniques during engineering of the
CAR construct, use of alternative effector cells (e.g., NK cells), invivo delivery of
the CAR construct, and more. These cellular technologies are also being studied in
various cancers, including solid tumor oncology, as well as in other elds of medicine, such as rheumatology and infectious diseases.
References
Abou-El-Enein, M., Elsallab, M., Feldman, S.A., etal. (2021). Scalable manufacturing of CAR T
cells for cancer immunotherapy. Blood Cancer Discovery, 2, 408–422.
Abramson, J.S., Palomba, M.L., Gordon, L.I., etal. (2020). Lisocabtagene maraleucel for patients
with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre
seamless design study. Lancet, 396, 839–852. https://doi.org/10.1016/S0140- 6736(20)31366- 0
Abramson, J.S., Solomon, S.R., Arnason, J., etal. (2023). Lisocabtagene maraleucel as second-
line therapy for large B-cell lymphoma: Primary analysis of the phase 3 TRANSFORM study.
Blood, 141, 1675–1684. https://doi.org/10.1182/blood.2022018730
Alabanza, L., Pegues, M., Geldres, C., etal. (2017). Function of novel anti-CD19 chimeric anti-
gen receptors with human variable regions is affected by hinge and transmembrane domains.
Molecular Therapy, 25, 2452–2465. https://doi.org/10.1016/j.ymthe.2017.07.013
Ansell, S.M. (2020). Fundamentals of immunology for understanding immunotherapy for lym-
phoma. Blood Advances, 4, 5863–5867.
Atsavapranee, E.S., Billingsley, M.M., & Mitchell, M.J. (2021). Delivery technologies for T cell
gene editing: Applications in cancer immunotherapy. eBioMedicine, 67, 103354.
Berdeja, J.G., Madduri, D., Usmani, S.Z., etal. (2021). Ciltacabtagene autoleucel, a B-cell matu-
ration antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or
refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet, 398,
314–324. https://doi.org/10.1016/S0140- 6736(21)00933- 8
Bersenev, A. (2017). CAR-T cell manufacturing: Time to put it in gear. Transfusion, 57, 1104–1106.
Bridgeman, J.S., Hawkins, R.E., Bagley, S., etal. (2010). The optimal antigen response of chi-
meric antigen receptors harboring the CD3ζ transmembrane domain is dependent upon incor-
poration of the receptor into the endogenous TCR/CD3 complex. Journal of Immunology, 184,
6938–6949. https://doi.org/10.4049/jimmunol.0901766
Cappell, K.M., & Kochenderfer, J.N. (2021). A comparison of chimeric antigen receptors con-
taining CD28 versus 4-1BB costimulatory domains. Nature Reviews. Clinical Oncology, 18,
715–727.
Ceppi, F., Rivers, J., Annesley, C., etal. (2018). Lymphocyte apheresis for chimeric antigen recep-
tor T-cell manufacturing in children and young adults with leukemia and neuroblastoma.
Transfusion, 58, 1414–1420. https://doi.org/10.1111/trf.14569
Chaplin, D.D. (2010). Overview of the immune response. The Journal of Allergy and Clinical
Immunology, 125, S3–S23. https://doi.org/10.1016/j.jaci.2009.12.980
Deng, Q., Han, G., Puebla-Osorio, N., etal. (2020). Characteristics of anti-CD19 CAR T cell infu-
sion products associated with efcacy and toxicity in patients with large B cell lymphomas.
Nature Medicine, 26, 1878–1887. https://doi.org/10.1038/s41591- 020- 1061- 7
54
https://t.me/med1917
Dorantes-Acosta, E., & Pelayo, R. (2012). Lineage switching in acute leukemias: A consequence of
stem cell plasticity? Bone Marrow Research, 2012, 1–18. https://doi.org/10.1155/2012/406796
Enblad, G., Karlsson, H., Gammelgård, G., etal. (2018). A phase I/IIa trial using CD19-targeted
third-generation CAR T cells for lymphoma and leukemia. Clinical Cancer Research, 24,
6185–6194. https://doi.org/10.1158/1078- 0432.CCR- 18- 0426
Eshhar, Z., Waks, T., Gross, G., & Schindler, D.G. (1993). Specic activation and targeting of
cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains
and the γ or ζ subunits of the immunoglobulin and T-cell receptors. Proceedings of the National
Academy of Sciences of the United States of America, 90, 720–724. https://doi.org/10.1073/
pnas.90.2.720
Fowler, N.H., Dickinson, M., Dreyling, M., etal. (2022). Tisagenlecleucel in adult relapsed or
refractory follicular lymphoma: The phase 2 ELARA trial. Nature Medicine, 28, 325–332.
https://doi.org/10.1038/s41591- 021- 01622- 0
Gardner, R., Wu, D., Cherian, S., etal. (2016). Acquisition of a CD19-negative myeloid phenotype
allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood,
127, 2406–2410. https://doi.org/10.1182/blood- 2015- 08- 665547
Green, D. R., Droin, N., & Pinkoski, M. (2003). Activation-induced cell death in T cells.
Immunological Reviews, 193, 70–81.
Gross, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chi-
meric molecules as functional receptors with antibody-type specicity. Proceedings of the
National Academy of Sciences of the United States of America, 86, 10024–10028. https://doi.
org/10.1073/pnas.86.24.10024
Guedan, S., Posey, A.D., Shaw, C., etal. (2018). Enhancing CAR T cell persistence through ICOS
and 4-1BB costimulation. JCI Insight, 3. https://doi.org/10.1172/jci.insight.96976
Hamieh, M., Dobrin, A., Cabriolu, A., etal. (2019). CAR T cell trogocytosis and cooperative
killing regulate tumour antigen escape. Nature, 568, 112–116. https://doi.org/10.1038/
s41586- 019- 1054- 1
Hill, J.A., & Seo, S.K. (2020). How I prevent infections in patients receiving CD19-targeted
chimeric antigen receptor T cells for B-cell malignancies. Blood, 136, 925–935. https://doi.
org/10.1182/blood.2019004000
Hill, J. A., Li, D., Hay, K. A., et al. (2018). Infectious complications of CD19-targeted chi-
meric antigen receptor-modied T-cell immunotherapy. Blood, 131, 121–130. https://doi.
org/10.1182/blood- 2017- 07- 793760
Hong, M., Clubb, J.D., & Chen, Y.Y. (2020). Engineering CAR-T cells for next-generation cancer
therapy. Cancer Cell, 38, 473–488.
Jacobson, C.A., Chavez, J.C., Sehgal, A.R., et al. (2022). Axicabtagene ciloleucel in relapsed
or refractory indolent non-Hodgkin lymphoma (ZUMA-5): A single-arm, multicentre, phase 2
trial. The Lancet Oncology, 23, 91–103. https://doi.org/10.1016/S1470- 2045(21)00591- X
Jain, M.D., Smith, M., & Shah, N.N. (2023a). How I treat refractory CRS and ICANS after CAR
T-cell therapy. Blood, 141, 2430–2442.
Jain, T., Olson, T.S., & Locke, F.L. (2023b). How I treat cytopenias after CAR T-cell therapy.
Blood, 141, 2460–2469.
Kershaw, M.H., Westwood, J.A., Parker, L.L., etal. (2006). A phase I study on adoptive immu-
notherapy using gene-modied T cells for ovarian cancer. Clinical Cancer Research, 12,
6106–6115. https://doi.org/10.1158/1078- 0432.CCR- 06- 1183
Kuünkele, A., Johnson, A. J., Rolczynski, L. S., et al. (2015). Functional tuning of CARs
reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due
to cell fas-FasL-Dependent AICD. Cancer Immunology Research, 3, 368–379. https://doi.
org/10.1158/2326- 6066.CIR- 14- 0200
Lee, D.W., Santomasso, B.D., Locke, F.L., etal. (2019). ASTCT consensus grading for cytokine
release syndrome and neurologic toxicity associated with immune effector cells. Biology of
Blood and Marrow Transplantation, 25, 625–638.
R. C. Godby etal.
5 Cellular Therapies forCancer: Chimeric Antigen Receptor T Cells (CAR-T)
https://t.me/med1917
Locke, F.L., Miklos, D.B., Jacobson, C.A., etal. (2022). Axicabtagene ciloleucel as second-line
therapy for large B-Cell lymphoma. The New England Journal of Medicine, 386, 640–654.
https://doi.org/10.1056/nejmoa2116133
Long, A.H., Haso, W. M., Shern, J. F., et al. (2015). 4-1BB costimulation ameliorates T cell
exhaustion induced by tonic signaling of chimeric antigen receptors. Nature Medicine, 21,
581–590. https://doi.org/10.1038/nm.3838
Maude, S.L., Laetsch, T.W., Buechner, J., etal. (2018). Tisagenlecleucel in children and young
adults with B-Cell lymphoblastic leukemia. The New England Journal of Medicine, 378,
439–448. https://doi.org/10.1056/nejmoa1709866
McGuirk, J., Waller, E.K., Qayed, M., etal. (2017). Building blocks for institutional preparation
of CTL019 delivery. Cytotherapy, 19, 1015–1024.
Milone, M. C., Fish, J. D., Carpenito, C., etal. (2009). Chimeric receptors containing CD137
signal transduction domains mediate enhanced survival of T cells and increased antileukemic
efcacy invivo. Molecular Therapy, 17, 1453–1464. https://doi.org/10.1038/mt.2009.83
Morris, E.C., Neelapu, S.S., Giavridis, T., & Sadelain, M. (2022). Cytokine release syndrome and
associated neurotoxicity in cancer immunotherapy. Nature Reviews. Immunology, 22, 85–96.
NCCN. (2023). Management of immunotherapy-related toxicities. In Guidelines. https://www.
nccn.org/guidelines/guidelines- detail?category=3&id=1486
Neelapu, S.S., Locke, F. L., Bartlett, N. L., et al. (2017). Axicabtagene ciloleucel CAR T-cell
therapy in refractory large B-Cell lymphoma. The New England Journal of Medicine, 377,
2531–2544. https://doi.org/10.1056/nejmoa1707447
Paroder, M., Le, N., Pham, H.P., & Thibodeaux, S.R. (2020). Important aspects of T-cell collec-
tion by apheresis for manufacturing chimeric antigen receptor T cells. Advances in Cell and
Gene Therapy, 3, e75. https://doi.org/10.1002/acg2.75
Qin, L., Lai, Y., Zhao, R., etal. (2017). Incorporation of a hinge domain improves the expansion
of chimeric antigen receptor T cells. Journal of Hematology & Oncology, 10, 68. https://doi.
org/10.1186/s13045- 017- 0437- 8
Quail, D. F., & Joyce, J.A. (2013). Microenvironmental regulation of tumor progression and
metastasis. Nature Medicine, 19, 1423–1437.
Raq, S., Hackett, C.S., & Brentjens, R.J. (2020). Engineering strategies to overcome the current
roadblocks in CAR T cell therapy. Nature Reviews. Clinical Oncology, 17, 147–167.
Ramos, C.A., Rouce, R., Robertson, C.S., etal. (2018). In vivo fate and activity of second- versus
third-generation CD19-specic CAR-T cells in B cell Non-Hodgkin’s lymphomas. Molecular
Therapy, 26, 2727–2737. https://doi.org/10.1016/j.ymthe.2018.09.009
Rodriguez-Otero, P., Ailawadhi, S., Arnulf, B., et al. (2023). Ide-cel or standard regimens in
relapsed and refractory multiple myeloma. The New England Journal of Medicine, 388,
1002–1014. https://doi.org/10.1056/nejmoa2213614
Ruella, M., Xu, J., Barrett, D.M., etal. (2018). Induction of resistance to chimeric antigen receptor
T cell therapy by transduction of a single leukemic B cell. Nature Medicine, 24, 1499–1503.
https://doi.org/10.1038/s41591- 018- 0201- 9
Rurik, J.G., Tombácz, I., Yadegari, A., etal. (2022). CAR T cells produced invivo to treat cardiac
injury. Science, 375, 91–96. https://doi.org/10.1126/science.abm0594
Santomasso, B. D., Nastoupil, L.J., Adkins, S., et al. (2021). Management of immune-related
adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guide-
line. Journal of Clinical Oncology, 39, 3978–3992. https://doi.org/10.1200/JCO.21.01992
Schuster, S.J., Tam, C.S., Borchmann, P., etal. (2021). Long-term clinical outcomes of tisagenle-
cleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): A mul-
ticentre, open-label, single-arm, phase 2 study. The Lancet Oncology, 22, 1403–1415. https://
doi.org/10.1016/S1470- 2045(21)00375- 2
Sehgal, A., Hoda, D., Riedell, P.A., etal. (2022). Lisocabtagene maraleucel as second-line ther-
apy in adults with relapsed or refractory large B-cell lymphoma who were not intended for
haematopoietic stem cell transplantation (PILOT): An open-label, phase 2 study. The Lancet
Oncology, 23, 1066–1077. https://doi.org/10.1016/S1470- 2045(22)00339- 4
55
56
https://t.me/med1917
Shah, B.D., Ghobadi, A., Oluwole, O.O., etal. (2021a). KTE-X19 for relapsed or refractory adult
B-cell acute lymphoblastic leukaemia: Phase 2 results of the single-arm, open-label, multi-
centre ZUMA-3 study. Lancet, 398, 491–502. https://doi.org/10.1016/S0140- 6736(21)01222- 8
Shah, K., Al-Haidari, A., Sun, J., & Kazi, J.U. (2021b). T cell receptor (TCR) signaling in health
and disease. Signal Transduction and Targeted Therapy, 6, 412.
Tokarew, N., Ogonek, J., Endres, S., etal. (2019). Teaching an old dog new tricks: Next-generation
CAR T cells. British Journal of Cancer, 120, 26–37.
Topp, M.S., Kufer, P., Gökbuget, N., etal. (2011). Targeted therapy with the T-cell- Engaging anti-
body blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute
lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free sur-
vival. Journal of Clinical Oncology, 29, 2493–2498. https://doi.org/10.1200/JCO.2010.32.7270
Turtle, C.J., Hana, L.A., Berger, C., etal. (2016a). CD19 CAR-T cells of dened CD4+:CD8+
composition in adult B cell ALL patients. The Journal of Clinical Investigation, 126,
2123–2138. https://doi.org/10.1172/JCI85309
Turtle, C.J., Hana, L.A., Berger, C., etal. (2016b). Immunotherapy of non-Hodgkin’s lymphoma
with a dened ratio of CD8+ and CD4+ CD19-specic chimeric antigen receptor- modied
T cells. Science Translational Medicine, 8, 355ra116. https://doi.org/10.1126/scitrans-
lmed.aaf8621
Wang, X., & Rivière, I. (2016). Clinical manufacturing of CAR T cells: Foundation of a promising
therapy. Molecular Therapy Oncolytics, 3, 16015.
Wang, M., Munoz, J., Goy, A., etal. (2020). KTE-X19 CAR T-Cell therapy in relapsed or refrac-
tory mantle-cell lymphoma. The New England Journal of Medicine, 382, 1331–1342. https://
doi.org/10.1056/nejmoa1914347
Wöl, M., Rasche, M., Eyrich, M., etal. (2018). Spontaneous reversion of a lineage switch fol-
lowing an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant
ALL. Blood Advances, 2, 1382–1385. https://doi.org/10.1182/bloodadvances.2018018093
Xia, A., Zhang, Y., Xu, J., etal. (2019). T cell dysfunction in cancer immunity and immunotherapy.
Frontiers in Immunology, 10, 1719.
Young, R.M., Engel, N.W., Uslu, U., etal. (2022). Next-generation CAR T-cell therapies. Cancer
Discovery, 12, 1625–1633. https://doi.org/10.1158/2159- 8290.CD- 21- 1683
Zhang, A., Sun, Y., Du, J., etal. (2021). Reducing hinge exibility of CAR-T cells prolongs sur-
vival invivo with low cytokines release. Frontiers in Immunology, 12, 724211. https://doi.
org/10.3389/mmu.2021.724211
R. C. Godby etal.
Chapter 6
https://t.me/med1917
Viral Immunotherapy Strategies
inClinical Practice
JeffreyJohnson andJamesJakub
Abstracts Viruses are a tool that can be used to help activate the immune system
against cancer. Viral genetics may be changed to make a virus less infectious or
toxic to patients and more effective at combating cancer. Viruses injected into
tumors help treat cancer by directly killing cancer cells as well as helping to activate
the immune response in a manner similar to a vaccine. A number of viral therapies
are being investigated for research. Currently, talimogene laherparepvec (T-VEC) is
the only viral therapy approved for clinical use for treating recurrent melanoma.
T-VEC is a genetically modied herpes simplex virus that is injected directly into
recurrent melanoma lesions in the skin or lymph nodes. A number of additional
viral therapies are in development to improve killing of cancer cells and activation
of the immune system.
Keywords Oncolytic virus · Talimogene laherparepvec (T-VEC) · T cell ·
Intralesional therapy · Intralesional injection · Herpes simplex virus · Metastatic
melanoma · In-transit disease
Viruses may be used as a tool for priming the immune system against cancer. Viruses
are an appealing tool for treating cancer as viral genomes may be manipulated to
coopt the evolutionary mechanisms the immune system has developed to combat
infection. The concept that the body’s response to infection may be used to prime
the immune system against cancer has been studied since the late nineteenth century. Most famously, William Coley, a surgeon at the NewYork Hospital, published
his results in using bacterial toxins injected into patients to treat inoperable sarcoma
(Coley, 1910). Research using viruses, and particularly viruses developed to target
J. Johnson (*)
Department of Surgery, Division of Breast and Melanoma Surgical Oncology, Mayo Clinic,
Rochester, MN, USA
e-mail: johnson.jeffrey5@mayo.edu
J. Jakub
Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Jacksonville, FL, USA
H. Dong, S. N. Markovic (eds.), The Basics of Cancer Immunotherapy,
https://doi.org/10.1007/978-3-031-59475-5_6
57© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
58
https://t.me/med1917
J. Johnson and J. Jakub
cancer, began in the middle of the twentieth century. Alice Moore, a physician
researcher also working in NewYork, was an early pioneer in the development and
characterization of viruses with oncolytic properties (Moore, 1952). However, it
was not until more sophisticated techniques had been developed in the latter twentieth century, which allowed targeted genetic engineering of viruses, that therapeutic use of viruses began to be considered for clinical trials (Martuza etal., 1991).
Over the last two decades, development of novel oncolytic virus therapy has
expanded rapidly and has entered standard of care clinical use.
Viruses can be made to replicate nearly exclusively in cancer cells, and the viral
genome can be modied to diminish its virulence and increase antitumor activity.
Promoters can be added into viral genes to reduce the expression of or delete the
genes that cause infection in normal cells (DeWeese et al., 2001; Brown et al.,
1997). Tumor cells that are selectively infected by a virus are killed by the cancer
cell rupturing secondary to viral replication, thereby releasing tumor antigens that
prompt a specic antitumor immune response (Kaufman etal., 2015). Also, some
oncolytic viruses can be designed to produce proteins that activate a T-cell immune
response (Hu etal., 2006; Liu etal., 2003; Fukuhara etal., 2005). One challenge
encountered in viral therapies is the risk of the immune system recognizing the virus
and clearing it from the body before it serves its purpose. This can be overcome by
methods that prevent the virus from being recognized by the host immune system,
including genetically modifying the virus to inhibit immune system recognition and
coating the outside of the virus so it is not recognized (Tesfay etal., 2013).
A number of viruses have been used in the development of oncolytic therapies,
including herpes simplex virus, measles virus, poliovirus, adenovirus, coxsackievirus, vaccinia virus, reovirus, Newcastle disease virus, and Seneca Valley virus
(Chiocca & Rabkin, 2014). While systemic administration of a virus has been considered in a model similar to vaccination, current oncolytic viral therapy is employed
using targeted delivery of viruses to the site of cancer, such as direct injection in
melanoma or urinary catheter-delivered irrigation in bladder cancer, to increase
local antitumor effects. In addition, novel oncolytic viruses are modied to further
enhance the immune response.
To date, the only FDA-approved virus for treatment of cancer is talimogene
laherparepvec (T-VEC), a modied oncolytic herpes simplex virus type 1. Approval
was granted in 2015 for treatment of unresectable, recurrent cutaneous melanoma.
This virus has been genetically modied for tumor cell selective infection, to
increase the immune system’s ability to recognize it and to diminish the ability to
divide in normal, nontumor cells (Liu etal., 2003). The coding sequence for granulocyte macrophage colony-stimulating factor (GM-CSF) has been inserted into its
genome, which enhances the immune response and increases therapeutic efcacy
(Liu etal., 2003; Toda etal., 2000).
FDA approval was granted on the results of a large, multicenter trial randomizing
patients with unresectable advanced stage melanoma to intralesional injection of
T-VEC or subcutaneous GM-CSF (Andtbacka etal., 2015). The study demonstrated
an improved durable response rate, dened as complete or partial response lasting
6 Viral Immunotherapy Strategies inClinical Practice
https://t.me/med1917
59
at least 6 months, in 16% of patients receiving T-VEC compared to 2% for those
receiving GM-CSF. The overall response rate was also higher for those receiving
T-VEC (26% vs. 6%). The treatment is well tolerated with the most common side
effects including fever, fatigue, nausea, and reaction at the injection site (Andtbacka
etal., 2015).
The indications for T-VEC remain relatively limited. It is generally used in the
setting of melanoma involving the skin, subcutaneous tissue, and/or lymph nodes
for which surgical removal is not advised. In-transit disease is the spread of melanoma in the lymphatics of the skin, which is the most common indication for using
T-VEC. T-VEC is one of several treatment options for patients with in-transit melanoma, including regional perfusion of high-dose chemotherapy into the circulation
of the limb, topical ointments that cause a local inammatory immune response or
act as a direct chemotherapy, radiation, and other injectable therapies, as well as
systemic treatment with immunotherapy. The decision for which therapy to use
depends on a number of clinical and institutional factors, and often these treatments
are used in series (Racz etal., 2019).
A number of subsequent studies have continued to demonstrate the efcacy and
tolerability of T-VEC (Louie et al., 2019, 2020). While there has been interest in
combining systemic immunotherapy with T-VEC, including laboratory research
suggesting a benet, the combination has been shown in randomized clinical trials
to improve response rate and local control without an improvement in overall survival or progression-free survival (Chesney etal., 2018, 2023a, b). However, T-VEC
may be used after failure of immunotherapy (Carr etal., 2022).
T-VEC is delivered as an injection directly into the tumor in the ofce setting.
T-VEC is generally contraindicated in patients with immunodeciency, on treatment with immunosuppressive medications including high-dose steroids, and
patients who are pregnant. Lesions may be injected under direct visualization or
with the use of ultrasound guidance, as necessary. T-VEC dose is determined by the
size of the lesion(s) with a set maximal total dose that can be administered with each
cycle. Injections are generally performed every 2 weeks. Progress is followed for a
minimum of 3 months, and injections may continue until there is a complete
response, progression of disease, or other clinical factors requiring cessation of
treatment (Collichio etal., 2018). The average time to achieve a complete response
is approximately 8 months (Andtbacka etal., 2015). In some cases, additional biopsies may be required to evaluate for the presence of viable melanoma cells in pigmented skin lesions, which can persist even with complete resolution of the cancer
(Park etal., 2022).
A wide number of additional oncologic viral therapies are in development and
actively being tested in clinical trials, both as monotherapy and in combination with
systemic therapies, including immunotherapy. The next generation of viral therapies will include additional genetic modications to enhance tumor cell killing and
the native immune response (Tripodi etal., 2023). Modications include adding
viral genes to increase tumor cell-specic viral effectiveness, antitumor activity, and
immune response (Thomas etal., 2019; Kontermann etal., 2021).
60
https://t.me/med1917
J. Johnson and J. Jakub
References
Andtbacka, R. H., Kaufman, H.L., Collichio, F., Amatruda, T., Senzer, N., Chesney, J., et al.
(2015). Talimogene laherparepvec improves durable response rate in patients with advanced
melanoma. Journal of Clinical Oncology, 33(25), 2780–2788.
Brown, S.M., MacLean, A.R., McKie, E.A., & Harland, J. (1997). The herpes simplex virus viru-
lence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear
antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34.
Journal of Virology, 71(12), 9442–9449.
Carr, M.J., Sun, J., DePalo, D., Rothermel, L.D., Song, Y., Straker, R.J., etal. (2022). Talimogene
Laherparepvec (T-VEC) for the treatment of advanced locoregional melanoma after failure of
immunotherapy: An international multi-institutional experience. Annals of Surgical Oncology,
29(2), 791–801.
Chesney, J., Puzanov, I., Collichio, F., Singh, P., Milhem, M. M., Glaspy, J., et al. (2018).
Randomized, open-label phase II study evaluating the efcacy and safety of talimogene laher-
parepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced,
unresectable melanoma. Journal of Clinical Oncology, 36(17), 1658–1667.
Chesney, J.A., Puzanov, I., Collichio, F.A., Singh, P., Milhem, M.M., Glaspy, J., etal. (2023a).
Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for
advanced melanoma: 5-year nal analysis of a multicenter, randomized, open-label, phase II
trial. Journal for Immunotherapy of Cancer, 11(5).
Chesney, J.A., Ribas, A., Long, G.V., Kirkwood, J.M., Dummer, R., Puzanov, I., etal. (2023b).
Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laher-
parepvec combined with pembrolizumab for advanced melanoma. Journal of Clinical
Oncology, 41(3), 528–540.
Chiocca, E.A., & Rabkin, S.D. (2014). Oncolytic viruses and their application to cancer immu-
notherapy. Cancer Immunology Research, 2(4), 295–300.
Coley, W.B. (1910). The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of
the Streptococcus erysipelas and the Bacillus prodigiosus). Proceedings of the Royal Society of
Medicine, 3(Surg Sect), 1–48.
Collichio, F., Burke, L., Proctor, A., Wallack, D., Collichio, A., Long, P. K., et al. (2018).
Implementing a program of talimogene laherparepvec. Annals of Surgical Oncology, 25(7),
1828–1835.
DeWeese, T.L., van der Poel, H., Li, S., Mikhak, B., Drew, R., Goemann, M., etal. (2001). A
phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the
treatment of locally recurrent prostate cancer following radiation therapy. Cancer Research,
61(20), 7464–7472.
Fukuhara, H., Ino, Y., Kuroda, T., Martuza, R.L., & Todo, T. (2005). Triple gene-deleted oncolytic
herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed
by bacterial articial chromosome-mediated system. Cancer Research, 65(23), 10663–10668.
Hu, J.C., Cofn, R.S., Davis, C.J., Graham, N.J., Groves, N., Guest, P.J., etal. (2006). A phase
I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus express-
ing granulocyte macrophage colony-stimulating factor. Clinical Cancer Research, 12(22),
6737–6747.
Kaufman, H.L., Kohlhapp, F.J., & Zloza, A. (2015). Oncolytic viruses: A new class of immuno-
therapy drugs. Nature Reviews. Drug Discovery, 14(9), 642–662.
Kontermann, R. E., Ungerechts, G., & Nettelbeck, D. M. (2021). Viro-antibody therapy:
Engineering oncolytic viruses for genetic delivery of diverse antibody-based biotherapeutics.
MAbs, 13(1), 1982447.
Liu, B.L., Robinson, M., Han, Z.Q., Branston, R.H., English, C., Reay, P., etal. (2003). ICP34.5
deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour
properties. Gene Therapy, 10(4), 292–303.
Соседние файлы в папке Библиотека им академика М.И. Перельмана