Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
12
02
2021
accepted:
27
06
2022
pubmed:
30
8
2022
medline:
28
9
2022
entrez:
29
8
2022
Statut:
ppublish
Résumé
Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.
Identifiants
pubmed: 36038629
doi: 10.1038/s41591-022-01916-x
pii: 10.1038/s41591-022-01916-x
pmc: PMC9499856
doi:
Substances chimiques
Antigens, CD19
0
Biological Products
0
Interleukin-15
0
Interleukin-7
0
Receptors, Chimeric Antigen
0
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1872-1882Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
Références
Jensen, M. C. & Riddell, S. R. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol. Rev. 257, 127–144 (2014).
pubmed: 24329794
pmcid: 3991306
doi: 10.1111/imr.12139
Yang, J. C. & Rosenberg, S. A. Adoptive T-cell therapy for cancer. Adv. Immunol. 130, 279–294 (2016).
pubmed: 26923004
pmcid: 6293459
doi: 10.1016/bs.ai.2015.12.006
Dunbar, C.E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).
June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).
pubmed: 29567707
doi: 10.1126/science.aar6711
Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, 31–42 (2019).
pubmed: 30518502
doi: 10.1016/S1470-2045(18)30864-7
Fu, K. et al. Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. J. Clin. Oncol. 26, 4587–4594 (2008).
pubmed: 18662967
doi: 10.1200/JCO.2007.15.9277
Carbone, A., Gloghini, A., Kwong, Y. L. & Younes, A. Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy. Ann. Hematol. 93, 1263–1277 (2014).
pubmed: 24870942
pmcid: 4082139
doi: 10.1007/s00277-014-2116-y
Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285–295 (2017).
pubmed: 28129122
pmcid: 5363293
doi: 10.1016/j.ymthe.2016.10.020
Galon, J., Fridman, W. H. & Pages, F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 67, 1883–1886 (2007).
pubmed: 17332313
doi: 10.1158/0008-5472.CAN-06-4806
Galon, J. et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J. Transl. Med. 14, 273 (2016).
pubmed: 27650038
pmcid: 5029056
doi: 10.1186/s12967-016-1029-z
Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).
pubmed: 29326431
pmcid: 6685071
doi: 10.1038/nrc.2017.117
Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765 (2018).
pubmed: 30318143
doi: 10.1016/j.cell.2018.09.018
Bedognetti, D. et al. Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop. J. Immunother. Cancer 7, 131 (2019).
pubmed: 31113486
pmcid: 6529999
doi: 10.1186/s40425-019-0602-4
Mascaux, C. et al. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature 571, 570–575 (2019).
pubmed: 31243362
doi: 10.1038/s41586-019-1330-0
Galon, J. & Bruni, D. Tumor immunology and tumor evolution: intertwined histories. Immunity 52, 55–81 (2020).
pubmed: 31940273
doi: 10.1016/j.immuni.2019.12.018
Bindea, G., Mlecnik, B., Angell, H. K. & Galon, J. The immune landscape of human tumors: implications for cancer immunotherapy. Oncoimmunology 3, e27456 (2014).
pubmed: 24800163
pmcid: 4006852
doi: 10.4161/onci.27456
Kirilovsky, A. et al. Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients. Int. Immunol. 28, 373–382 (2016).
pubmed: 27121213
pmcid: 4986234
doi: 10.1093/intimm/dxw021
Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).
pubmed: 29754777
doi: 10.1016/S0140-6736(18)30789-X
Van den Eynde, M. et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 34, 1012–1026 (2018).
pubmed: 30537506
doi: 10.1016/j.ccell.2018.11.003
Angell, H. K., Bruni, D., Barrett, J. C., Herbst, R. & Galon, J. The Immunoscore: colon cancer and beyond. Clin. Cancer Res. 26, 332–339 (2019).
Yomoda, T. et al. The Immunoscore is a superior prognostic tool in stages II and III colorectal cancer and is significantly correlated with programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating mononuclear cells. Ann. Surg. Oncol. 26, 415–424 (2019).
pubmed: 30569297
doi: 10.1245/s10434-018-07110-z
Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).
Sharma, P. et al. The next decade of immune checkpoint therapy. Cancer Discov. 11, 838–857 (2021).
pubmed: 33811120
doi: 10.1158/2159-8290.CD-20-1680
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
pubmed: 29226797
pmcid: 5882485
doi: 10.1056/NEJMoa1707447
Locke, F. L. et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N. Engl. J. Med. 386, 640–654 (2021).
Jain, M. D. et al. Tumor interferon signaling and suppressive myeloid cells associate with CAR T-cell failure in large B-cell lymphoma. Blood 137, 2621–2633 (2021).
Moschella, F. et al. Cyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients’ blood cells: implications for cancer chemoimmunotherapy. Clin. Cancer Res. 19, 4249–4261 (2013).
pubmed: 23759676
doi: 10.1158/1078-0432.CCR-12-3666
Stamenkovic, I. et al. The B cell antigen CD75 is a cell surface sialytransferase. J. Exp. Med. 172, 641–643 (1990).
pubmed: 2373995
doi: 10.1084/jem.172.2.641
Okuyama, K. et al. PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia. PLoS Genet. 15, e1008280 (2019).
pubmed: 31381561
pmcid: 6695195
doi: 10.1371/journal.pgen.1008280
Park, H. Y. et al. Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma. Oncotarget 7, 86433–86445 (2016).
pubmed: 27835906
pmcid: 5349924
doi: 10.18632/oncotarget.13239
Whitehurst, A. W. Cause and consequence of cancer/testis antigen activation in cancer. Annu. Rev. Pharmacol. Toxicol. 54, 251–272 (2014).
pubmed: 24160706
doi: 10.1146/annurev-pharmtox-011112-140326
Autio, M. et al. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. Haematologica 106, 718–729 (2021).
pubmed: 32079690
doi: 10.3324/haematol.2019.243626
Angell, H. & Galon, J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr. Opin. Immunol. 25, 261–267 (2013).
pubmed: 23579076
doi: 10.1016/j.coi.2013.03.004
Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 4898–4911 (2020).
pubmed: 33035333
pmcid: 7556133
doi: 10.1182/bloodadvances.2020002394
Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008).
pubmed: 19038878
pmcid: 9103713
doi: 10.1056/NEJMoa0802885
Liu, Y. & Barta, S. K. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am. J. Hematol. 94, 604–616 (2019).
pubmed: 30859597
doi: 10.1002/ajh.25460
Galon, J. et al. Characterization of anti-CD19 chimeric antigen receptor (CAR) T-cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19). J. Clin. Oncol. 35, 3025 (2017).
doi: 10.1200/JCO.2017.35.15_suppl.3025
Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3
pubmed: 24127572
pmcid: 3816454
doi: 10.1073/pnas.1316796110
Mizukami, Y. et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3
pubmed: 18224687
doi: 10.1002/ijc.23392
Kochenderfer, J. N. et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J. Clin. Oncol. 35, 1803–1813 (2017).
pubmed: 28291388
pmcid: 5455597
doi: 10.1200/JCO.2016.71.3024
Conlon, K. C., Miljkovic, M. D. & Waldmann, T. A. Cytokines in the treatment of cancer. J. Interferon Cytokine Res. 39, 6–21 (2019).
pubmed: 29889594
pmcid: 6350412
doi: 10.1089/jir.2018.0019
Cappell, K. M. et al. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J. Clin. Oncol. 38, 3805–3815 (2020).
pubmed: 33021872
pmcid: 7655016
doi: 10.1200/JCO.20.01467
Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).
pubmed: 26317471
pmcid: 4603556
doi: 10.1016/j.cell.2015.08.021
Campbell, C. & Rudensky, A. Roles of regulatory T cells in tissue pathophysiology and metabolism. Cell Metab. 31, 18–25 (2020).
pubmed: 31607562
doi: 10.1016/j.cmet.2019.09.010
Okeke, E. B. & Uzonna, J. E. The pivotal role of regulatory T cells in the regulation of innate immune cells. Front. Immunol. 10, 680 (2019).
pubmed: 31024539
pmcid: 6465517
doi: 10.3389/fimmu.2019.00680
Galon, J., Angell, H. K., Bedognetti, D. & Marincola, F. M. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39, 11–26 (2013).
pubmed: 23890060
doi: 10.1016/j.immuni.2013.07.008
Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).
pubmed: 30610226
doi: 10.1038/s41573-018-0007-y
Chen, P. H. et al. Activation of CAR and non-CAR T cells within the tumor microenvironment following CAR T cell therapy. JCI Insight 5, e134612 (2020).
Coutinho, R. et al. Revisiting the immune microenvironment of diffuse large B-cell lymphoma using a tissue microarray and immunohistochemistry: robust semi-automated analysis reveals CD3 and FoxP3 as potential predictors of response to R-CHOP. Haematologica 100, 363–369 (2015).
pubmed: 25425693
pmcid: 4349275
doi: 10.3324/haematol.2014.110189
Faramand, R. et al. Tumor microenvironment composition and severe cytokine release syndrome (CRS) influence toxicity in patients with large B-cell lymphoma treated with axicabtagene ciloleucel. Clin. Cancer Res. 26, 4823–4831 (2020).
pubmed: 32669372
pmcid: 7501265
doi: 10.1158/1078-0432.CCR-20-1434
Chou, C. K. & Turtle, C. J. Assessment and management of cytokine release syndrome and neurotoxicity following CD19 CAR-T cell therapy. Expert Opin. Biol. Ther. 20, 653–664 (2020).
pubmed: 32067497
pmcid: 7393694
doi: 10.1080/14712598.2020.1729735
Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).
pubmed: 28292435
pmcid: 5423788
doi: 10.1016/j.ccell.2017.02.008
Lanitis, E., Coukos, G. & Irving, M. All systems go: converging synthetic biology and combinatorial treatment for CAR-T cell therapy. Curr. Opin. Biotechnol. 65, 75–87 (2020).
pubmed: 32109718
doi: 10.1016/j.copbio.2020.01.009
Hudolin, T. et al. Immunohistochemical analysis of the expression of MAGE-A and NY-ESO-1 cancer/testis antigens in diffuse large B-cell testicular lymphoma. J. Transl. Med. 11, 123 (2013).
pubmed: 23680437
pmcid: 3663708
doi: 10.1186/1479-5876-11-123
Teater, M. et al. AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. Nat. Commun. 9, 222 (2018).
pubmed: 29335468
pmcid: 5768781
doi: 10.1038/s41467-017-02595-w
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8
pubmed: 31207603
pmcid: 6713202
doi: 10.1038/s41586-019-1325-x
Brudno, J. N. et al. Safety and feasibility of anti-CD19 CAR T-cells with fully human binding domains in patients with B-cell lymphoma. Nat. Med. 26, 270–280 (2020).
pubmed: 31959992
pmcid: 7781235
doi: 10.1038/s41591-019-0737-3
Singh, N. et al. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction. Cancer Discov. 10, 552–567 (2020).
pubmed: 32001516
pmcid: 7416790
doi: 10.1158/2159-8290.CD-19-0813
Upadhyay, R. et al. A critical role for Fas-mediated off-target tumor killing in T-cell immunotherapy. Cancer Discov. 11, 599–613 (2021).
pubmed: 33334730
doi: 10.1158/2159-8290.CD-20-0756
Plaks, V. et al. CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel. Blood 138, 1081–1085 (2021).
pubmed: 34041526
pmcid: 8462361
doi: 10.1182/blood.2021010930
Marliot, F. et al. Analytical validation of the Immunoscore and its associated prognostic value in patients with colon cancer. J. Immunother. Cancer 8, e000272 (2020).
Panda, A. et al. Immune activation and benefit from avelumab in EBV-positive gastric cancer. J. Natl Cancer Inst. 110, 316–320 (2018).
pubmed: 29155997
doi: 10.1093/jnci/djx213
Agocs, G. R. et al. LAG-3 expression predicts outcome in stage II colon cancer. J. Pers. Med. 11, 749 (2021).
Syed Khaja, A. S. et al. Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment. Oncotarget 8, 33159–33171 (2017).
pubmed: 28388539
doi: 10.18632/oncotarget.16565
Maestre, L. et al. High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations. PLoS ONE 15, e0229743 (2020).
pubmed: 32106280
pmcid: 7046285
doi: 10.1371/journal.pone.0229743
Liu, W. et al. Prognostic value of MTA1, SOX4 and EZH2 expression in esophageal squamous cell carcinoma. Exp. Ther. Med. 22, 722 (2021).
pubmed: 34007331
pmcid: 8120658
doi: 10.3892/etm.2021.10154
Yuan, J. et al. Combined high expression of CD47 and CD68 is a novel prognostic factor for breast cancer patients. Cancer Cell Int. 19, 238 (2019).
pubmed: 31528120
pmcid: 6737685
doi: 10.1186/s12935-019-0957-0
Xia, S. et al. SLC7A2 deficiency promotes hepatocellular carcinoma progression by enhancing recruitment of myeloid-derived suppressors cells. Cell Death Dis. 12, 570 (2021).
pubmed: 34108444
pmcid: 8190073
doi: 10.1038/s41419-021-03853-y
Marmey, B. et al. CD14 and CD169 expression in human lymph nodes and spleen: specific expansion of CD14
pubmed: 16360418
doi: 10.1016/j.humpath.2005.09.016
Hashimoto, A. et al. Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer. Clin. Cancer Res. 27, 5961–5978 (2021).
pubmed: 34407972
pmcid: 8756351
doi: 10.1158/1078-0432.CCR-21-0986
Scott, D. W. et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123, 1214–1217 (2014).
pubmed: 24398326
pmcid: 3931191
doi: 10.1182/blood-2013-11-536433
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
pubmed: 17008531
doi: 10.1126/science.1129139