Добавил:

Sekretar kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.

Вуз:

Ростовский Государственный Медицинский Университет

Предмет:

Медицина общая

Файл:

Книга_104_библиотеки_им_акад_М_И_Перельмана

.pdf

Скачиваний:

Добавлен:

30.08.2026

Размер:

42 Мб

Скачать

☆

<<< < Предыдущая 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 4142 / 4542 43 44 45 > Следующая >>>

CAR- T cell therapy 393

https://t.me/med1917

Milone, M.C., Fish, J.D., Carpenito, C. etal. (2009). Chimeric receptors

containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy invivo. Mol. Ther. 17 (8): 1453–1464. https://doi.org/10.1038/mt.2009.83.

Mock, U., Nickolay, L., Philip, B. etal. (2016). Automated manufacturing

of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy. Cytotherapy 18 (8): 1002–1011. https:// doi.org/10.1016/j.jcyt.2016.05.009.

Morris, E.C., Neelapu, S.S., Giavridis, T., and Sadelain, M. (2022).

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat. Rev. Immunol. 22 (2): 85–96. https://doi.org/

10.1038/s41577-

Mullanfiroze, K., Lazareva, A., Chu, J. et al. (2022). CD34+-

stem cell boost can safely improve cytopenias following CAR Ttherapy. Blood Adv. 6 (16): 4715–4718. https://doi.org/10.1182/ bloodadvances.2022007572.

Munshi, N.C., Anderson, L.D. Jr., Shah, N. etal. (2021). Idecabtagene

vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384 (8): 705–716. https://doi.org/10.1056/NEJMoa2024850.

Neelapu, S.S., Locke, F.L., Bartlett, N.L. etal. (2017). Axicabtagene cilole-

ucel CARJ. Med. 377 (26): 2531–2544. https://doi.org/10.1056/NEJMoa1707447.

Neelapu, S.S., Tummala, S., Kebriaei, P. etal. (2018). Chimeric antigen

receptor TNat. Rev. Clin. Oncol. 15 (1): 47–62. https://doi.org/10.1038/nrclinonc.

2017.148.

Neelapu, S.S., Jacobson, C.A., Ghobadi, A. etal. (2023). Five-

low- up of ZUMA- 1 supports the curative potential of axicabtagene ciloleucel in refractory large B-

2315. https://doi.org/10.1182/blood.2022018893.

Newick, K., O’Brien, S., Sun, J. etal. (2016). Augmentation of CAR-

cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol. Res. 4 (6): 541–551. https://doi.org/

10.1158/2326-

Nia, H.T., Munn, L.L., and Jain, R.K. (2020). Physical traits of cancer.

Science 370 (6516). https://doi.org/10.1126/science.aaz0868.

Norelli, M., Camisa, B., Barbiera, G. et al. (2018). Monocyte-

IL- 1 and IL- 6 are differentially required for cytokine- release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24 (6): 739–748. https://doi.org/10.1038/s41591-

Obaid, G., Bano, S., Thomsen, H. etal. (2022). Remediating desmopla-

sia with EGFR- targeted photoactivable multi- inhibitor liposomes doubles overall survival in pancreatic cancer. Adv. Sci. (Weinh). 9 (24): e2104594. https://doi.org/10.1002/advs.202104594.

Park, J.H., Riviere, I., Gonen, M. etal. (2018). Long-

CD19 CAR- therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378 (5): 449–459. https://doi.org/10.1056/NEJMoa1709919.

Patel, U., Abernathy, J., Savani, B.N. etal. (2022). CAR- T cell therapy in

solid tumors: a review of current clinical trials. EJHaem 3 (S1): 24–

31. https://doi.org/10.1002/jha2.356.

Pilcher, W., Thomas, B., Bhasin, S. et al. (2021). Characterization of

T- cell exhaustion in rapid progressing multiple myeloma using cross center Scrna- Seq study. Blood 138: 401–401. https://doi.org/10.1182/ blood- 2021- 153863.

Ping, N., Qu, C., Li, M. etal. (2022). Overall survival benefits provided by

lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B- cell lymphoma. Ann. Transl. Med. 10 (6): 298. https://doi.org/10.21037/atm- 22- 20.

021- 00547- 6.

selected

cell

T- cell therapy in refractory large B- cell lymphoma. N. Engl.

cell therapy– assessment and management of toxicities.

year fol-

cell lymphoma. Blood 141 (19): 2307–

T-

6066.CIR- 15- 0263.

derived

018- 0036- 4.

term follow- up of

Popat, R., Zweegman, S., Cavet, J. et al. (2019). Phase 1 first-

study of AUTO2, the first chimeric antigen receptor (CAR) T cell targeting APRIL for patients with relapsed/refractory multiple myeloma (RRMM). Blood 134: 3112. https://doi.org/10.1182/blood-

Porter, D.L., Levine, B.L., Kalos, M. et al. (2011). Chimeric antigen

receptor–modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365 (8): 725–733. https://doi.org/10.1056/NEJMoa1103849.

Priceman, S.J., Tilakawardane, D., Jeang, B. etal. (2018). Regional deliv-

ery of chimeric antigen receptor–engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin. Cancer Res. 24 (1): 95–105. https://doi.org/10.1158/1078-

Prommersberger, S., Reiser, M., Beckmann, J. (2021). etal. CARAMBA:

a first-

in- human clinical trial with SLAMF7 CAR- T cells prepared by

free Sleeping Beauty gene transfer to treat multiple myeloma.

virusGene Ther. 28 (9): 560–571. https://doi.org/10.1038/s41434-

00254- w

021-

Pulè, M.A., Straathof, K.C., Dotti, G. etal. (2005). A chimeric T cell

antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12 (5): 933–941. https://doi.org/10.1016/j.ymthe.2005.04.016.

Qin, L., Lai, Y., Zhao, R. etal. (2017). Incorporation of a hinge domain

improves the expansion of chimeric antigen receptor T cells. J. Hematol. Oncol. 10 (1): 68. https://doi.org/10.1186/s13045- 0437- 8.

Qin, H., Ramakrishna, S., Nguyen, S. etal. (2018). Preclinical develop-

ment of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther. Oncolytics 11: 127–137. https://doi.org/10.1016/j. omto.2018.10.006.

Raje, N., Berdeja, J., Lin, Y. etal. (2019). Anti- BCMA CAR T- cell ther-

apy bb2121in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380 (18): 1726–1737. https://doi.org/10.1056/NEJMoa1817226.

Rajkumar, S.V. (2022). Multiple myeloma: 2022 update on diagnosis,

risk stratification, and management. Am. J. Hematol. 97 (8): 1086–

1107. https://doi.org/10.1002/ajh.26590.

Razeghian, E., Nasution, M.K.M., Rahman, H.S. etal. (2021). A deep

insight into CRISPR/Cas9 application in CARimmunotherapies. Stem Cell Res. Ther. 12 (1): 428. https://doi.org/

10.1186/s13287-

Rejeski, K., Burchert, A., Iacoboni, G. etal. (2022). Safety and feasibility

of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR Torg/10.1182/bloodadvances.2022007776.

Rodriguez-

standard regimens in relapsed and refractory multiple myeloma. N. Engl. J. Med. 388 (11): 1002–1014. https://doi.org/10.1056/ NEJMoa2213614.

Roma- Rodrigues, C., Mendes, R., Baptista, P.V., and Fernandes, A.R.

(2019). Targeting tumor microenvironment for cancer therapy. Int. J. Mol. Sci. 20 (4): 840.

Roybal, K.T., Rupp, L.J., Morsut, L. etal. (2016). Precision tumor recog-

nition by T cells with combinatorial antigen- sensing circuits. Cell 164 (4): 770–779. https://doi.org/10.1016/j.cell.2016.01.011.

Russell, B.M. and Avigan, D.E. (2023). Immune dysregulation in multi-

ple myeloma: the current and future role of cell- based immunotherapy. Int. J. Hematol. 117 (5): 652–659. https://doi.org/10.1007/ s12185- 023- 03579- x.

Samur, M.K., Fulciniti, M., Aktas Samur, A. etal. (2021). Biallelic loss of

BCMA as a resistance mechanism to CAR T cell therapy in a patient

021- 02510- 7.

cell therapy. Blood Adv. 6 (16): 4719–4725. https://doi.

Otero, P., Ailawadhi, S., Arnulf, B. etal. (2023). Ide- cel or

0432.CCR- 17- 2041.

T cell- based tumor

in- human

2019- 126689.

017-

本书版权归John Wiley & Sons Inc.所有

394 Molecular Hematology

https://t.me/med1917

with multiple myeloma. Nat. Commun. 12 (1): 868. Published 2021 Feb 8. https://doi.org/10.1038/s41467-

Sandler, R.D., Tattersall, R.S., Schoemans, H. et al. (2020). Diagnosis

and management of secondary HLH/MAS following HSCT and CAR-

T cell therapy in adults; a review of the literature and a survey of practice within EBMT centres on behalf of the autoimmune diseases working party (ADWP) and transplant complications working party (TCWP). Front. Immunol. 11: 524. Published 2020 Mar 31. https://doi.org/10.3389/fimmu.2020.00524.

Sasaki, K., Jabbour, E.J., Ravandi, F. et al. (2016). Hyper- CVAD plus

ponatinib versus hyperpatients with Philadelphia chromosomeleukemia: a propensity score analysis. Cancer 122 (23): 3650–3656. https://doi.org/10.1002/cncr.30231.

Schuster, S.J., Svoboda, J., Chong, E.A. etal. (2017). Chimeric antigen

receptor T cells in refractory B(26): 2545–2554. https://doi.org/10.1056/NEJMoa1708566.

Schuster, S.J., Bishop, M.R., Tam, C.S. etal. (2019). Tisagenlecleucel in

adult relapsed or refractory diffuse large BMed. 380 (1): 45–56. https://doi.org/10.1056/NEJMoa1804980.

Schuster, S.J., Tam, C.S., Borchmann, P. etal. (2021). Long-

outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive Bsingledoi.org/10.1016/S1470- 2045(21)00375- 2.

Sehn, L.H. and Gascoyne, R.D. (2015). Diffuse large B- cell lymphoma:

optimizing outcome in the context of clinical and biologic heterogeneity. Blood 125 (1): 22–32. https://doi.org/10.1182/blood 05- 577189.

Selli, M.E., Landmann, J.H., Terekhova, M. etal. (2023). Costimulatory

domains direct distinct fates of CAR141 (26): 3153–3165. https://doi.org/10.1182/blood.2023020100.

Shadman, M. (2023). Diagnosis and treatment of chronic lymphocytic

leukemia: a review. JAMA 329 (11): 918–932. https://doi.org/10.1001/ jama.2023.1946.

Shah, N.N. and Fry, T.J. (2019). Mechanisms of resistance to CAR- T cell

therapy. Nat. Rev. Clin. Oncol. 16 (6): 372–385. https://doi. org/10.1038/s41571-

Shah, N.N., Johnson, B.D., Schneider, D. etal. (2020). Bispecific anti-

CD20, anti- CD19 CAR- T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat. Med. 26 (10): 1569–

1575. https://doi.org/10.1038/s41591- 020- 1081- 3.

Shah, N.N., Highfill, S.L., Shalabi, H. etal. (2020). CD4/CD8 T- cell selec-

tion affects chimeric antigen receptor (CAR) T- cell potency and toxicity: updated results from a phase I anti- CD22 CAR T- cell trial. J. Clin. Oncol. 38 (17): 1938–1950. https://doi.org/10.1200/JCO.19.03279.

Shah, B.D., Ghobadi, A., Oluwole, O.O. et al. (2021). KTE- X19 for

relapsed or refractory adult B- cell acute lymphoblastic leukaemia: phase 2 results of the singlestudy. Lancet 398 (10299): 491–502. https://doi.org/10.1016/ S0140- 6736(21)01222- 8.

Shah, B.D., Ghobadi, A., Oluwole, O.O. etal. (2022). Two- year follow-

up of KTE- X19in patients with relapsed or refractory adult B- cell acute lymphoblastic leukemia in ZUMA- 3 and its contextualization with SCHOLAR- 3, an external historical control study. J. Hematol. Oncol. 15 (1): 170. Published 2022 Dec 10. https://doi.org/

10.1186/s13045- 022- 01379- 0.

cell lymphomas (JULIET): a multicentre, open- label,

arm, phase 2 study. Lancet Oncol. 22 (10): 1403–1415. https://

CVAD plus dasatinib as frontline therapy for

019- 0184- 6.

arm, open- label, multicentre ZUMA- 3

021- 21177- 5.

positive acute lymphoblastic

cell lymphomas. N. Engl. J. Med. 377

cell lymphoma. N. Engl. J.

term clinical

2014-

driven T- cell dysfunction. Blood

Siddiqi, T., Maloney, D.G., Kenderian, S.S. et al. (2023). Lisocabtagene

maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study. Lancet. 2023 Aug 19; 402(10402): 641–654. https://doi.org/10.1016/S0140-6736(23)01052-8. Epub 2023 Jun 6. PMID: 37295445.

Siebzehnrubl, F.A., Silver, D.J., Tugertimur, B. etal. (2013). The ZEB1 path-

way links glioblastoma initiation, invasion and chemoresistance. EMBO Mol. Med. 5 (8): 1196–1212. https://doi.org/10.1002/emmm.201302827.

Simsek, H. and Klotzsch, E. (2022). The solid tumor microenvironment-

breaking the barrier for T cells: how the solid tumor microenvironment influences T cells: how the solid tumor microenvironment influences T cells. Bioessays 44 (6): e2100285. https://doi.org/10.1002/bies.202100285.

Smith, S.M., Godfrey, J., Ahn, K.W. etal. (2018). Autologous transplan-

tation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer 124 (12): 2541–2551. https://doi.org/10.1002/cncr.31374.

Sommermeyer, D., Hudecek, M., Kosasih, P.L. etal. (2016). Chimeric

antigen receptorCD4+ subsets confer superior antitumor reactivity invivo. Leukemia 30 (2): 492–500. https://doi.org/10.1038/leu.2015.247.

Sommermeyer, D., Hill, T., Shamah, S.M. et al. (2017). Fully human

CD19- specific chimeric antigen receptors for T- cell therapy. Leukemia 31 (10): 2191–2199. https://doi.org/10.1038/leu.2017.57.

Song, D.-

Sotillo, E., Barrett, D.M., Black, K.L. et al. (2015). Convergence of

St Martin, Y., Franz, J.K., Agha, M.E., and Lazarus, H.M. (2023). Failure

Sterner, R.C. and Sterner, R.M. (2021). CAR- T cell therapy: current

Sterner, R.M., Sakemura, R., Cox, M.J. etal. (2019). GM-

Stewart, A.G. and Henden, A.S. (2021). Infectious complications of

Suhoski, M.M., Golovina, T.N., Aqui, N.A. et al. (2007). Engineering

Summers, C., Annesley, C., Bleakley, M. etal. (2018). Long term follow-

Sun, C., Shou, P., Du, H. etal. (2020). THEMIS- SHP1 recruitment by

G. and Powell, D.J. (2012). Pro- survival signaling via CD27 costimulation drives effective CAR- T- cell therapy. OncoImmunology 1 (4): 547–549. https://doi.org/10.4161/onci.19458.

acquired mutations and alternative splicing of CD19 enables resistance to CART- 19 immunotherapy. Cancer Discov. 5 (12): 1282–1295. https://doi.org/10.1158/2159- 8290.CD- 15- 1020.

of CAR-

T cell therapy in relapsed and refractory large cell lymphoma and multiple myeloma: an urgent unmet need. Blood Rev. 60: 101095. https://doi.org/10.1016/j.blre.2023.101095. Epub 2023 Apr 29. PMID: 37173224

limitations and potential strategies. Blood Cancer J. 11: 69. https:// doi.org/10.1038/s41408-

reduces cytokine release syndrome and neuroinflammation but enhances CARhttps://doi.org/10.1182/blood- 2018- 10- 881722.

CAR T- cell therapy: a clinical update. Ther. Adv. Infect. Dis. 8:

20499361211036773. Published 2021 Aug 24. https://doi. org/10.1177/20499361211036773.

artificial antigen- presenting cells to express a diverse array of costimulatory molecules. Mol. Ther. 15 (5): 981–988. https://doi. org/10.1038/mt.sj.6300134.

up after SCRI- CAR19v1 reveals late recurrences as well as a survival advantage to consolidation with HCT after CAR- T cell induced remission. Blood 132: 967.

4- 1BB tunes LCK- mediated priming of chimeric antigen receptor-

modified T cells derived from defined CD8+ and

021- 00459- 7.

CSF inhibition

T cell function in xenografts. Blood 133 (7): 697–709.

本书版权归John Wiley & Sons Inc.所有

CAR- T cell therapy 395

https://t.me/med1917

redirected T cells. Cancer Cell 37 (2): 216–225.e6. https://doi.org/

10.1016/j.ccell.2019.12.014.

Turtle, C.J., Hanafi, L.-

defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 126 (6): 2123–2138. https://doi.org/10.1172/JCI85309.

Turtle, C.J., Hay, K.A., Hanafi, L.A. et al. (2017). Durable molecular

remissions in chronic lymphocytic leukemia treated with CD19specific chimeric antigen receptor- modified T cells after failure of ibrutinib. J. Clin. Oncol. 35 (26): 3010–3020. https://doi.org/10.1200/ JCO.2017.72.8519.

Uslu, U., Da, T., Assenmacher, C.-

receptor T cells as adjuvant therapy for unresectable adenocarcinoma. Sci. Adv. 9 (2). https://doi.org/10.1126/sciadv.ade2526.

Van Oekelen, O., Nath, K., Mouhieddine, T.H. e tal. (2023). Interventions

and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA- directed CAR T therapy. Blood 141 (7): 756–

765. https://doi.org/10.1182/blood.2022017848.

Wang, Y., Zhang, W.Y., Han, Q.W. etal. (2014). Effective response and

delayed toxicities of refractory advanced diffuse large Bphoma treated by CD20modified T cells. Clin. Immunol. 155 (2): 160–175. https://doi. org/10.1016/j.clim.2014.10.002.

Wang, X., Popplewell, L.L., Wagner, J.R. etal. (2016). Phase 1 studies of

central memoryogous HSCT in patients with B- cell NHL. Blood 127 (24): 2980–2990. https://doi.org/10.1182/blood- 2015- 12- 686725.

Wang, M., Munoz, J., Goy, A. etal. (2020). KTE- X19 CAR- T- cell ther-

apy in relapsed or refractory mantle- cell lymphoma. N. Engl. J. Med. 382 (14): 1331–1342. https://doi.org/10.1056/NEJMoa1914347.

Wang, Y., Qi, K., Cheng, H. etal. (2020). Coagulation disorders after

chimeric antigen receptor T cell therapy: analysis of 100 patients with relapsed and refractory hematologic malignancies. Biol. Blood Marrow Transplant. 26 (5): 865–875. https://doi.org/10.1016/ j.bbmt.2019.11.027.

Wang, B., Iriguchi, S., Waseda, M. etal. (2021). Generation of hypoim-

munogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells. Nat. Biomed. Eng. 5 (5): 429–440. https://doi.org/10.1038/s41551-

Wang, Y., Cao, J., Gu, W. etal. (2022). Long- term follow- up of combina-

tion of B- cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple myeloma. J. Clin. Oncol. 40 (20): 2246–2256. https://doi.org/10.1200/JCO.21.01676.

Wang, M., Munoz, J., Goy, A. et al. (2023). Three-

KTE- X19in patients with relapsed/refractory mantle cell lymphoma, including high- risk subgroups, in the ZUMA- 2 study. J. Clin. Oncol. 41 (3): 555–567. https://doi.org/10.1200/JCO.21.02370.

Weber, E.W., Parker, K.R., Sotillo, E. et al. (2021). Transient rest

restores functionality in exhausted CAR- T cells through epigenetic remodeling. Science 372 (6537). https://doi.org/10.1126/science. aba1786.

Wee, B., Pietras, A., Ozawa, T. et al. (2016). ABCG2 regulates self-

renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells. Sci. Rep. 6: 25956. https://doi. org/10.1038/srep25956.

Whatcott, C.J., Posner, R.G., Von Hoff, D.D. etal. (2012). Desmoplasia

and chemoresistance in pancreatic cancer. In: Pancreatic Cancer and Tumor Microenvironment (eds. P.J. Grippo and H.G. Munshi).

A., Berger, C. etal. (2016). CD19 CAR–T cells of

A. et al. (2023). Chimeric antigen

cell lym-

directed chimeric antigen receptor-

derived CD19 CAR- T- cell therapy following autol-

021- 00730- z.

year follow- up of

Trivandrum, India: Transworld Research Network (Chapter 8. Available from: https://www.ncbi.nlm.nih.gov/books/NBK98939/.

Whilding, L., Halim, L., Draper, B. etal. (2019). CAR-

the integrin αvβ6 and coCXCR2 demonstrate enhanced homing and efficacy against several solid malignancies. Cancers 11 (5): 674. https://doi.org/10.3390/ cancers11050674.

Wittmann Dayagi, T., Sherman, G., Bielorai, B. et al. (2021).

Characteristics and risk factors of infections following CD28- based CD19 CARorg/10.1080/10428194.2021.1881506.

Wu, C.-

therapeutic T cells through a small molecule–gated chimeric receptor. Science 350 (6258). https://doi.org/10.1126/science.aab4077.

Yang, S., Huang, X., and Gale, R.P. (2022). Cell therapy of chronic

lymphocytic leukaemia: Transplants and chimeric antigen receptor (CAR)-T cells. Blood Rev. 2022 Jan; 51:100884. https://doi.org/

10.1016/j.blre.2021.100884. Epub 2021 Sep 1. PMID: 34489116.

Yarmarkovich, M., Marshall, Q.F., Warrington, J.M. et al. (2021).

Cross- HLA targeting of intracellular oncoproteins with peptidecentric CARs. Nature 599 (7885): 477–484. https://doi.org/10.1038/ s41586- 021- 04061- 6.

Zah, E., Nam, E., Bhuvan, V. et al. (2020). Systematically optimized

BCMA/CS1 bispecific CARmultiple myeloma. Nat. Commun. 11 (1): 2283. Published 2020 May 8. https://doi.org/10.1038/s41467-

Zhang, L., Kerkar, S.P., Yu, Z. et al. (2011). Improving adoptive T cell

therapy by targeting and controlling ILenvironment. Mol. Ther. 19 (4): 751–759. https://doi.org/10.1038/ mt.2010.313.

Zhang, L., Morgan, R.A., Beane, J.D. etal. (2015). Tumor-

lymphocytes genetically engineered with an inducible gene encoding interleukinCancer Res. 21 (10): 2278–2288. https://doi.org/10.1158/1078- 0432. CCR- 14- 2085.

Zhang, Y., Zhang, X., Cheng, C. et al. (2017). CRISPR-

LAG- 3 disruption in CAR- T cells. Front. Med. 11 (4): 554–562. https://doi.org/10.1007/s11684- 017- 0543- 6.

Zhang, W.Y., Liu, Y., Wang, Y. etal. (2017). Long- term safety and effi-

cacy of CARTnon- Hodgkin lymphoma: 5- years follow- up results of the phase I and IIa trials. Signal. Transduct. Target. Ther. 2: 17054. Published 2017 Oct 9. https://doi.org/10.1038/sigtrans.2017.54.

Zhang, X., Lv, X., and Song, Y. (2018). Short- term culture with IL- 2 is

beneficial for potent memory chimeric antigen receptor T cell production. Biochem. Biophys. Res. Commun. 495 (2): 1833–1838. https://doi.org/10.1016/j.bbrc.2017.12.041.

Zhang, Z., Liu, S., Zhang, B. etal. (2020). T cell dysfunction and exhaus-

tion in cancer. Front. Cell. Dev. Biol. 8: 17. Published 2020 Feb 11. https://doi.org/10.3389/fcell.2020.00017.

Zhang, A., Sun, Y., Du, J. et al. (2021). Reducing hinge flexibility of

CAR- T cells prolongs survival in vivo with low cytokines release. Front. Immunol. 12. https://doi.org/10.3389/fimmu.2021.724211.

Zhang, C., He, J., Liu, L. etal. (2022). Novel CD19 chimeric antigen

receptor T cells manufactured next- day for acute lymphoblastic leukemia. Blood Cancer J. 12 (6): 96. https://doi.org/10.1038/ s41408- 022- 00688- 4.

T cells. Leuk. Lymphoma 62 (7): 1692–1701. https://doi.

Y., Roybal, K.T., Puchner, E.M. etal. (2015). Remote control of

12 for the immunotherapy of metastatic melanoma. Clin.

20 cells in patients with refractory or relapsed B- cell

expressing the chemokine receptor

T cells robustly control heterogeneous

020- 16160- 5.

12 expression to the tumor

T- cells targeting

Cas9mediated

infiltrating

本书版权归John Wiley & Sons Inc.所有

396 Molecular Hematology

https://t.me/med1917

Zhao, Z., Condomines, M., van der Stegen, S.J.C. etal. (2015). Structural

design of engineered costimulation determines tumor rejection kinetics and persistence of CARhttps://doi.org/10.1016/j.ccell.2015.09.004.

Zhao, W.H., Liu, J., Wang, B.Y. etal. (2018). A phase 1, open-

of LCARagainst B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J. Hematol. Oncol. 11 (1): 141. Published 2018 Dec 20. https://doi.org/10.1186/s13045-

B38M, a chimeric antigen receptor T cell therapy directed

T cells. Cancer Cell 28 (4): 415–428.

label study

018-0681- 6.

Zhong, X.-

Zhou, J., Jin, L., Wang, F. et al. (2019). Chimeric antigen receptor T

S., Matsushita, M., Plotkin, J. etal. (2010). Chimeric antigen receptors combining 4- 1BB and CD28 signaling domains augment PI3kinase/AKT/Bcleradication. Mol. Ther. 18 (2): 413–420. https://doi.org/10.1038/ mt.2009.210.

(CAR-

T) cells expanded with IL- 7/IL- 15mediate superior antitumor effects. Protein Cell 10 (10): 764–769. https://doi.org/10.1007/s13238- 019-

0643- y.

XL activation and CD8+ T cell- mediated tumor

本书版权归John Wiley & Sons Inc.所有

Chapter26

https://t.me/med1917

Molecular basis oftransplantation

Pramila Krishnamurthy1, Victoria Potter1 and Francesco Dazzi

King’s College Hospital NHS Trust, London, UK

School of Cancer Sciences, King’s College London, UK

Introduction and definition, 397 Principles and clinical indications of HCT, 397 Exploiting HCT for resetting the immune system, 398 Basic concepts in the immunology of allogeneic HCT, 398 Graft- versus- host and graft- versus- leukemia, 402

Introduction and definition

Transplantation is a successful therapeutic modality for a variety of diseases of different etiologies and pathogenesis. Liver, heart, and kidney failures are common indications that would be even more widely pursued should the donor availability not be so limited. Although the basic general principle underlying transplantation is the replacement of a malfunctioning tissue with a healthy one, in the case of hemopoietic cell transplantation (HCT), the procedure is associated with a number of other beneficial effects which can be exploited not only to restore hemopoietic failure itself but also for treating cancer and autoimmune diseases.

Principles and clinical indications of HCT

Hematopoietic progenitor cells (HPCs) have the capacity to self- renew and give rise to all formed elements in the blood (see Scadden DT: “Stem Cells.” Molecular Hematology (ed: D Provan, HM Lazarus). 5th edition, Wiley- Blackwell, Hoboken, NJ, 2023). Because of this property, they can be used to rescue the hemopoietic system from the intensification of anti- cancer cytotoxic therapies. HPC can be autologous when donor and recipient are the same individual or allogeneic if another individual is selected as HPC donor. Mobilization of stem cells is routinely performed by administration of granulocyte colonystimulating factor (G- CSF) regardless of whether autologous or allogeneic donors are being harvested. Plerixafor (a smallmolecule inhibitor of chemokine receptor type 4 [CXCR4]) and more recently motixafortide, a novel cyclic- peptide CXCR4inhibitor with extended invivo activity have been utilized in combination with G- CSF to increase the efficacy of mobilization from autologous donors.

The pathogenesis of GvHD, 405 Can GvHD and GvL be dissected?, 407 New directions, 410 Conclusions, 410 Further readings, 410

In autologous HCT, patients can be subjected to lethal doses of

radiotherapy to eradicate the tumor and then receive

chemotheir own HPC harvested before to restore the otherwise permanently ablated hemopoietic system. Although autologous HCT is useful in some solid tumors, its efficacy in the treatment of hemopoietic malignancies is limited by the contamination of the harvested stem cells by the original tumor and/or by the insufficient activity of the chemotherapy in eliminating the tumor itself. However, such an approach maintains some efficacy because normal HPCs have a temporary growth advantage at repopulating the recipient as compared to neoplastic stem cells.

A more recent application of autologous HCT has been the treatment of severe autoimmune diseases whereby the repopulation of the immune system with primitive HPC is believed to re- educate the ill immune system. Phase I/II trials have reported high response rates in systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and multiple sclerosis. Randomized studies are ongoing to compare these achievements to conventional immunosuppressive therapies.

When a compatible donor is available, the use of allogeneic HCT has profoundly modified the outcome of several hematological malignancies. The conditioning regimen contributes to the eradication of the abnormal cells and ensures sustained engraftment of the healthy allogeneic stem cells. However, the efficacy of this approach cannot simply be ascribed to the chemo-

radiotherapy and either to the administration of healthy HPC but is greatly dependent on the immune recognition of the tumor by the lymphocytes contained in the donor cell preparation. Additionally, HCT is associated with several other beneficial effects which can be exploited, not only to restore hemopoietic failure itself, but also for treating cancer, autoimmune diseases, and inborn errors (or genetic defects).

From these preliminary considerations, it is clear how sev-

eral mechanisms contribute to the outcome of HCT and

本书版权归John Wiley & Sons Inc.所有

397

398 Molecular Hematology

https://t.me/med1917

these involve HPC engraftment, expansion, and differentiation as well as, in the case of allogeneic HCT, the interplay between donor and recipient immune responses.

Exploiting HCT for resetting theimmune system

While the long- term efficacy of autologous HCT in malignancies is confined to a minority of tumors, the fact that HPC are also the precursors of immune cells has prompted investigators to test the ability of autologous HCT to treat conditions characterized by abnormal immune responses. In support of this initiative is the evidence that the maturation of new T- cells in the thymus continues, albeit at a decreased rate, also in adult life.

Autologous HCT is currently being explored with remarkable success in severe forms of autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Crohn’s disease. The main rationale for applying HCT to autoimmune diseases has been the idea that intensive immune depletion could eliminate the pathogenic repertoire, and that reconstitution of a new immune system from hematopoietic precursors could restore immune tolerance, halting ongoing inflammatory activity and preventing relapses.

Recent studies have confirmed the notion that HCT induces alterations of the immune system, which are beyond the effects of a dose- escalating immunosuppressive approach. HCT has been shown not only to affect the B cell populations associated with the production of auto- antibodies, but also to profoundly perturb the T- cell compartment, as illustrated by the normalization of the deregulated T- cell receptor (TCR) repertoire in multiple sclerosis. Furthermore, it appears that following, a subset of T- cells (regulatory T- cells) with the specific function of controlling immunity to selfantigen selectively expands and could contribute to the control of the underlying autoimmune disease.

On the contrary, the immune reconstitution following allogeneic HCT remains incomplete for several months or years depending on the histocompatibility differences between donor and recipient. This is one of the several problems associated with the various immune responses generated in an allogeneic setting.

Basic concepts in the immunology ofallogeneic HCT

allogeneic SCT, they are profoundly inhibited by the conditioning regimen. The immunologically competent cells, present in the HPC preparation, play a more important role because they mediate a reaction against the host, which targets recipient normal tissues (grafteffect at the basis of the eradication of residual neoplastic cells (graft- versus- leukemia, GvL).

versus- host, GvH), but also mediate the

The major histocompatibility complex

The major histocompatibility complex (MHC) defines a genetic region that includes genes encoding class I and class II membrane- bound cell surface glycoproteins. The function of MHC proteins is to present peptide antigens to T- cells, a vital part of initiating an antigen- specific immune response. MHC proteins are also involved in the recognition of virally infected cells, or those cells in which genetic anomalies arise, by natural killer (NK) cells.

There are two major classes of genes within the MHC region, namely class I and class II MHC genes. In addition to these, the MHC class III region encodes other proteins of the immune system, such as certain complement and cytokine genes. In humans, the MHC region is found on the short arm of chromosome 6 and encodes for the human leukocyte antigens (HLA). Different loci are designated by a letter; thus, the major class I loci are HLA- A, HLA- B, and HLA- C. HLA class II genes are collectively designated HLA- D, and individual loci identified by a second letter, HLA- DR, HLA- DP, and HLA- DQ. In addition to the “classical” class I and class II MHC genes, there exists a number of nonclassical MHC genes, including HLA- E, HLA- F, and HLA- G with functions that have not yet been fully elucidated.

The role of MHC molecules is to present peptide antigens to T- cells. Class I molecules present endogenous peptides, which may include virus- or tumor- derived peptides that are generated in the cytosol, transported to the endoplasmic reticulum (ER), and finally presented to the cell surface. HLA class II molecules are assembled in the ER, then transported through the Golgi to endosomal compartments where they load peptides that have entered the cell via endocytosis or receptorof peptides by MHC molecules is dictated by the sequence of the MHC antigen- binding groove. Although MHC molecules have limited polymorphism as compared to TCRs, they exhibit varying avidity for different peptides, thus accounting for individual variability of responses to the same antigen and against different moieties.

mediated internalization. The selection

Allogeneic HCT triggers a network of immune responses, which fundamentally affects the outcome of the procedure both in terms of complications and therapeutic success. Whereas recipient anti- donor immune responses (host- versusgraft, HvG) are important in solid organ transplantation, in

本书版权归John Wiley & Sons Inc.所有

Mechanisms ofallorecognition: lessons fromsolid organ transplantation

Allorecognition is a particular form of antigen presentation, occurring only after transplantation of tissues between

Molecular basis oftransplantation 399

Direct presentation

MHC complex

T-cells

Recipient

Indirect presentation Semi-direct presentation

https://t.me/med1917

genetically disparate individuals of the same species (or after in vitro simulation of such). HvG reactions refer to the immune response of the host to disparate antigens expressed on donor cells, which result in graft rejection. Current understanding of HvG responses derives mainly from studies of solid organ transplantation in which the host does not receive any conditioning prior to the transplant and thus maintain the ability to reject it.

Three pathways of allorecognition have been described, namely direct, indirect, and the most recently described semi- direct allorecognition (Figure 26.1). The term direct allorecognition was initially used to describe the recognition by host T- cells of intact donor MHC–peptide complex directly on the surface of donor antigen presenting cells (APC), but it has also later been extended to include the recognition of other donor- derived transplantation antigens (minor histocompatibility antigens) presented on donor APC by an MHC molecule that is shared between donor and recipient. The frequencies of alloreactive T- cells using this pathway has been estimated between 0.1% and 10% as compared to approximately 10−5 for nominal peptide antigens. An explanation for such a high frequency is that direct allorecognition arises as a consequence of cross reactivity of self MHC- restricted T- cells.

Indirect allorecognition is the recognition of donorderived antigens that have been processed and are presented on the cell surface of host APC in the context of self- MHC. Therefore, the distinction between direct and indirect presentation is thus the source of the APC on which alloantigens are presented. The mechanism of indirect allorecognition is indistinguishable from the physiological processing and presentation of pathogen- derived peptide antigens. Donor MHC molecules can be processed, and peptide fragments presented to T- cells by host APC. Although only approximately 5–10% of alloreactive T- cells are specific for indirectly presented donor antigens, they are still thought to

play a major role in chronic solid organ transplant rejection, which occurs at a time when donor APC are no longer thought to be present. The mechanisms by which indirectly primed T- cells mediate graft rejection are unclear. Following organ transplantation, the donor endothelial layer is repopulated with recipient T- cells. One theory is that donor antigen is presented to direct pathway T- cells by recipient MHC I by the recipient endothelium. An alternative hypothesis is that graft destruction is the result of bystander killing following re- encounter of antigen on the surface of graft infiltrating APC.

More recently, a predominant role of CD4+ T- cells has been advocated, whereby they orchestrate both the production of donor- specific antibodies and the initiation of inflammatory signals through myeloid cells. Following the presentation of donor- derived antigens, host B- cells are induced to produce specific antibodies by CD4+ T- cells. Donor organ injury is ultimately mediated through opsonization and activation of host NK and macrophages. Host macrophages can also interact with CD4+ T- cells as host APCs.

A further mechanism of allorecognition has been described as the semi- direct presentation of donor antigens and the underlying mechanisms identified very recently. The original hypothesis assumed that intact donor- derived MHC complexes were transferred to and presented by host- derived

T- cells through the indirect pathway and specific CD8+ T- cells through the direct pathway. It was recently found that high numbers of “cross- dressed” recipient APCs, that have acquired intact, donor MHC–peptide complexes from graft cells, are present in the lymph nodes draining the graft. Donor MHCs are derived from allogeneic exosomes, which can induce proinflammatory allo- responses even without transplantation. The contribution of this pathway to the rejection of the transplanted organ is yet to be elucidated.

本书版权归John Wiley & Sons Inc.所有

Figure26.1 Mechanisms of allo- recognition.

TCR

Donor

400 Molecular Hematology

Recipient thymus

Peripheral anergy

Donor stem cells

https://t.me/med1917

Transplantation tolerance: clonal deletion

The establishment of tolerance to antigens expressed by donor tissues is a major goal of allogeneic transplantation. There are three main mechanisms that contribute to transplantation tolerance: clonal deletion, anergy, and peripheral regulation (Figure26.2).

During T- cell ontogeny, intrathymic clonal deletion of selfreactive T- cells is the primary process for the selection of the mature T- cell repertoire. The transplantation of donor HPC into sublethally or lethally myeloablated recipients gives rise to an immune system that is immunologically tolerant to donor antigens. The chimerism is established not only at the level of the bone marrow but also in the thymus where recipient T- cells learn to recognize the donor as “self” after interaction with donor- derived professional APCs, which orchestrate the continuous depletion of alloreactive T and B cells. Since mainly based on clonal deletion, such tolerance is long- term and does not require immunosuppression but for the first months of the transplant. There is now plenty of anecdotal evidence that patients undergoing allogeneic HCT can subsequently receive an organ from the original HCT donor without the need for lifelong immunosuppression, with induction of allograft tolerance through HCT in both HLA- matched and mismatched kidney transplants. Encouraging outcomes for these dual transplantation procedures have been reported, with at least half of recipients able to discontinue long- term immune suppression and low incidence of severe graftversus- host disease (GvHD) or solid organ graft rejection. Notably, although in most cases, hematopoietic chimerism

was achieved during the induction phase of the treatment, it was often not durable, thus questioning its requirement in the maintenance of the allograft tolerance in the long term. A better understanding of the underlying mechanisms of tolerance induction after HCT and the improvement of the safety of the protocols used will certainly extend the success of this approach to solid organ transplantation from non-

living

donors.

Clonal deletion can also occur at extra- thymic sites and can account for the removal of mature alloreactive T- cells, thus leading to the establishment and maintenance of donorspecific tolerance in experimental models of mixed chimerism induction following MHC- mismatched HCT. T- cells are deleted in the periphery by either activation- induced cell death or by passive cell death, both leading to apoptosis. Indeed, improved technical applications, such as the use of

throughput Vβ TCR chain CDR3 sequencing by next-

highgeneration sequencing approaches has enabled tracking of donor- derived alloreactive T- cell clones within transplant recipients. In the context of renal transplantation, gradual deletion of alloreactive donor T- cell clones within the patient following grafting was associated with tolerance and graft acceptance.

T- cell anergy describes a persistent state of unresponsiveness of T- cells to their cognate antigen. This functional inactivation occurs as a consequence of TCR engagement in absence of full co- stimulatory signals. T- cells receive costimulatory signals via ligation of surface CD28with B7molecules expressed on APC. Other co- stimulatory pathways

本书版权归John Wiley & Sons Inc.所有

Recipient bone marrow

Clonal deletion

Selection of

mature T cell

repertoire

Naïve and

memory T cells

Natural T

reg

Induced T

Figure26.2 Mechanisms of transplant tolerance.

Molecular basis oftransplantation 401

https://t.me/med1917

include CD40/CD40ligand (CD154). Furthermore, signaling through CTLA- 4 (CD152) has also been implicated in the generation of hyporesponsive T- cells. Anergic T- cells fail to produce sufficient interleukin (IL)- 2 and to proliferate in response to antigen, but the unresponsive state can be overcome by the exogenous addition of IL- 2, or if anergic T- cells are cultured in the absence of their cognate antigen. The blockade of co- stimulatory pathways has been widely exploited as a mechanism to induce tolerance in solid organ and hematopoietic stem cell transplantation. In the context of experimental models of allogeneic HCT, the administration of anti- CD154 mAb was shown to induce mixed lympho- hematopoietic chimerism and subsequent permanent skin graft acceptance if used as a single agent, in combination with reduced intensity HCT, or in combination with the antagonists of CTLA- 4. However, there is little evidence in support of a role for anergy in the induction of transplantation tolerance.

Transplantation tolerance: peripheral regulation

Since the demonstration that tolerance to allogeneic organ grafts can be transferred to naïve recipients by T- cells derived from tolerant hosts, induction and maintenance of transplantation tolerance has largely been ascribed to immunoregulation. The initial problems in the identification of a suppressor T- cell in the 70s have been partially overcome more recently with the discovery of a distinct CD4+ T- cell subset constitutively expressing CD25. Besides CD25, regulatory T- cells (T

) are characterized by the expression of the

reg

transcription factor Foxp3, crucially involved in suppressing overactive immune responses, as demonstrated by the high incidence of self- reactive lymphocytes in Immune Dysregulation, Polyendocrinopathy, Enteropathy, X- Linked (IPEX) syndrome in humans and scurfy in mice. Further markers to identify T

cells include the expression of CTLA-

reg

4, glucocorticoid- induced tumor necrosis factor receptor (GITR), folate receptor- 4 (FR4), and the absence of CD127. CD4+CD25+ naturally occurring T

cells are thymic derived

reg

and have been shown to be important for maintaining selftolerance, regulating the homeostasis of the peripheral T- cell pool, and contributing to tolerance induction in various models of solid organ transplantation as well as in allogeneic HCT. In vivo depletion of T

cells in animal models increases

reg

the incidence of autoimmune diseases and immune responses to tumors. It has also been observed that in the condition of full or mixed donor chimerism after HCT, there is a selective advantage in the homeostatic expansion of T

cells as com-

reg

pared to effector T- cells. The presence of donor antigens during this phase skews the T

repertoire toward the prefer-

reg

ential expansion of those recognizing the donor antigens, thus contributing to the induction of transplantation tolerance. The use of conditioning regimens aimed at expanding

cells invivo or the infusion of T

reg

cells expanded invitro

reg

and co- transplanted with HPC has been proven efficacious in prolonging the survival of the allograft.

The mechanisms underlying naturally occurring Treg cell immunosuppression require cell- to- cell contact. However, adaptive CD4+CD25+ regulatory cells with similar phenotype have been described that derive from mature effector T- cells and exert their suppressive activity via inhibitory cytokines such as transforming growth factor (TGF)- β or IL- 10. It is likely that a combination of naturally occurring and adaptive regulatory cells are involved in transplantation tolerance depending on the time and the conditioning regimens.

The use of low- dose IL- 2has been demonstrated to effectively increase the number of T

cells and, by activating their

reg

immunoregulatory activity, ameliorate cGvHD. The therapeutic efficacy of IL- 2 could also be enhanced by the combination with rapamycin that synergizes in increasing the proliferation and expansion of T

. These data are consistent

regs

with the poor experience of using IL- 2 receptor antibodies to control the expansion of activated alloreactive T- cells responsible for GvHD.

A few studies in animal models have documented that the adoptive transfer of T GvHD. There are also suggestions that T

cells can prevent and partially treat

reg

may preserve the

regs

GvL activity, but data obtained in patients after HCT have failed to show a significant correlation with GvHD and found that leukemia relapses are associated with an increment in the number of T Similarly, the degree of T

in the peripheral blood of patients.

regs

infiltration seems to correlate

reg

with bad prognosis in ovarian cancer.

However, only a small proportion of T

cells specifically

reg

recognize alloantigens, thus making their contribution to suppressing effector cells recognizing alloantigens limited. Furthermore, they can be implicated in inhibiting also the beneficial virus- or tumor- specific immunity. Therefore, alloantigen- specific T

cells are the most promising approach

reg

for their therapeutic application in the context of transplantation. This can be achieved by stimulating Treg cells in vitro with the alloantigen (or mHAg), but the efficiency and purity of the method is rather poor. Gene editing provides a much better tool. Antigen- specific Treg cells can be generated either by transducing genes encoding specific TCRs recognizing the antigen or by harnessing the CAR platform. While the TCR approach is complicated by the limitation of MHC restriction, the second scenario has the advantage of a broader application by targeting either the alloantigen or an antigen that is expressed at the site where effector T cells are concentrated. CAR- T

cells can therefore be engineered to migrate

reg

and concentrate their immunosuppressive activity at sites of GvHD. The CAR construct can be additionally modified to stabilize its function, thus avoiding the interference of an inflammatory microenvironment.

本书版权归John Wiley & Sons Inc.所有

402 Molecular Hematology

https://t.me/med1917

Graft- versus- host andgraft- versus- leukemia

A unique and prominent feature of allogeneic HCT as compared to solid organ transplantation is the presence, in the graft, of immunologically competent T- cells, which can recognize normal and malignant recipient tissues. Consequently, donor lymphocytes mediate a reaction against normal tissues, which is defined as GvHD, but also mediate the fundamental therapeutic effect at the basis of the eradication of residual neoplastic cells, the GvL effect. It is not surprising therefore that the molecular targets of GvH and GvL largely overlap.

The immunological targets of GvHD and GvL

We have previously discussed how differences between donor and recipient at the MHC level produce vigorous immune responses. Since genetic differences are the major factors influencing the outcome of allogeneic HCT, selection of the donor is of crucial importance. Given the extensive existing experience and outcome data associated with the use of MHCidentical sibling or MHC- matched unrelated donors, these remain the donors of choice. However, given the low probability (1/4) of any single sibling being MHC- identical and the fact that only approximately 40% of patients will have fully MHCmatched donor options identified via international donor registries, alternative MHC mismatched donors are increasingly being utilized. These include related haploidentical donors and cord blood units, and are of particular importance in the context of ethnic minority transplant recipients, since historical uptake of voluntary donation by minority ethnic communities has been relatively low– although this is changing with increasingly targeted donor recruitment drive efforts.

MHC matching is by itself insufficient for long- term graft survival and/or to prevent GvH reactions without the use of potent immunosuppressive regimens. The existence of additional histocompatibility loci, first indicated in inbred mice, was then clearly demonstrated in humans in HCT, whereby they were associated with severe GvH. In this genetic situation, immune responses are directed against alloantigens encoded by histocompatibility (H) loci outside the MHC, the

called minor H loci. Minor histocompatibility antigens

so(mHags) are polymorphic self- derived peptides expressed on the cell surface in association with MHC class I and II molecules. The fact that they are recognized, as are viruses, by MHC- restricted T- cells with specificity for peptides brought to the cell surface during biosynthesis of MHC class I and II molecules makes their identification more difficult. Unlike invitro T- cell responses to MHC antigens, which can be measured readily by proliferation in mixed lymphocyte reactions without previous exposure to antigen, those against minor H antigens need prior invivo immunization.

Although many polymorphic proteins exist, not all give rise to peptides recognized as mHags. Furthermore, there are several factors that appear in practice to severely limit the number of mHags eliciting an invivo response in a particular donor/recipient combination. In fact, it is clear that there is a hierarchy of responsiveness. In a genetic situation where there are many mHag disparities, one or a few are immunodominant, with clones of CD8+ T-

cells responding to such an antigen expanding selectively, while T- cells against others appear transiently early in the response, or not at all. In most models, immunodominance results from competition for APC resources among responding CD8

T- cells, because it disappears when competing epitopes are presented on different APC or when APC are present in large excess. There is strong statistical and genetic evidence that this also occurs in human immune responses to multiple mHags, thus in principle making it possible to predict, measure and manipulate the immune response following allografting.

Graft- versus- leukemia

Clinical studies and experimental animal models have shown that the efficacy of allogeneic SCT in hematological malignancies is related not only to the intensive chemo- radiotherapy but also to an immunological anti- tumor effect exerted by the graft itself. This effect, referred to as GvL, has been initially recognized because patients who received T- cell- depleted HPC preparations with the intention of reducing GvHD had a higher incidence of leukemia recurrence after the transplant. Further lines of evidence support this concept. For example, the risk of relapse is higher if donor and recipient are identical twins and some reports have indicated that remission can be re- established by the withdrawal of posttransplant immunosuppressive treatment and/or by the recurrence of GvHD. Indeed, the development of acute or chronic GvHD has been reported to associate with protection from relapse in several retrospective studies. The proof of principle of the GvL effect came from the evidence that the infusion of lymphocytes from the original stem cell donor could restore complete remission in patients with chronic myeloid leukemia (CML) relapsed after allogeneic SCT. These data support the requirement of two main components for GvL to occur: the presence of T-

cells in the donor preparation and the existence of antigenic differences between donors and recipients.

The role of donor lymphocytes in induction of GvL

The paradigm of successful GvL induction using donor lymphocyte infusions (DLI) remains the therapeutic efficacy seen in the context of relapsed CML, where the response rate is >90%. The experience in other malignancies is not as good and, in some cases, rather disappointing. However, the introduction of reduced- intensity conditioning has extended the

本书版权归John Wiley & Sons Inc.所有

<<< < Предыдущая 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 4142 / 4542 43 44 45 > Следующая >>>

Соседние файлы в папке Библиотека им академика М.И. Перельмана

#
30.08.202644 Мб0Книга_103_библиотеки_им_акад_М_И_Перельмана.pdf
#
31.08.202625 Мб0Книга_1030_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1033_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1037_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1039_Библиотеки_им_академика_М_И_Перельмана.pdf
#
30.08.202642 Мб0Книга_104_библиотеки_им_акад_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1040_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1042_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1044_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202624 Мб0Книга_1045_Библиотеки_им_академика_М_И_Перельмана.pdf
#
31.08.202623 Мб0Книга_1047_Библиотеки_им_академика_М_И_Перельмана.pdf