Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 08 2023
07 08 2023
Historique:
received:
07
07
2022
accepted:
13
07
2023
medline:
9
8
2023
pubmed:
8
8
2023
entrez:
7
8
2023
Statut:
epublish
Résumé
Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.
Identifiants
pubmed: 37550294
doi: 10.1038/s41467-023-40115-1
pii: 10.1038/s41467-023-40115-1
pmc: PMC10406808
doi:
Substances chimiques
Interleukin-12
187348-17-0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4737Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. Springer Nature Limited.
Références
Frigault, M. J. & Maus, M. V. State of the art in CAR T cell therapy for CD19+ B cell malignancies. J. Clin. Invest. 130, 1586–1594 (2020).
pubmed: 32235098
pmcid: 7108913
June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).
pubmed: 29972754
pmcid: 7433347
Hong, M., Clubb, J. D. & Chen, Y. Y. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell 38, 473–488 (2020).
pubmed: 32735779
Priceman, S. J., Forman, S. J. & Brown, C. E. Smart CARs engineered for cancer immunotherapy. Curr. Opin. Oncol. 27, 466–474 (2015).
pubmed: 26352543
pmcid: 4659816
Schmidts, A. & Maus, M. V. Making CAR T cells a solid option for solid tumors. Front. Immunol. 9, 2593 (2018).
pubmed: 30467505
pmcid: 6235951
Sterner, R. C. & Sterner, R. M. CAR-T-cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021).
pubmed: 33824268
pmcid: 8024391
van der Stegen, S. J., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).
pubmed: 26129802
pmcid: 6410718
Larson, R. C. & Maus, M. V. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat. Rev. Cancer 21, 145–161 (2021).
pubmed: 33483715
pmcid: 8353572
Liu, X. et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 75, 3596–3607 (2015).
pubmed: 26330166
pmcid: 4560113
Heitzeneder, S. et al. GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Cancer Cell 40, 53–69.e59 (2022).
pubmed: 34971569
Jonnalagadda, M. et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol. Ther. 23, 757–768 (2015).
pubmed: 25366031
pmcid: 4395772
Lee, S. Y. et al. Preclinical optimization of a CD20-specific chimeric antigen receptor vector and culture conditions. J. Immunother. 41, 19–31 (2018).
pubmed: 29176334
pmcid: 5759780
Kunkele, A. et al. Functional tuning of CARs reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due to cell fas-fasl-dependent AICD. Cancer Immunol. Res. 3, 368–379 (2015).
pubmed: 25576337
Fujiwara, K. et al. Hinge and transmembrane domains of chimeric antigen receptor regulate receptor expression and signaling threshold. Cells 9, 1182 (2020).
Bridgeman, J. S. et al. The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J. Immunol. 184, 6938–6949 (2010).
pubmed: 20483753
Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).
pubmed: 26461090
pmcid: 5003056
Guedan, S. et al. Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability. J. Clin. Invest. 130, 3087–3097 (2020).
pubmed: 32069268
pmcid: 7260017
Salter, A. I. et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci. Signal. 11, eaat6753 (2018).
Yu, S., Yi, M., Qin, S. & Wu, K. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol. Cancer 18, 125 (2019).
pubmed: 31429760
pmcid: 6701025
Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).
pubmed: 28187291
pmcid: 5553442
Bell, M. & Gottschalk, S. Engineered cytokine signaling to improve CAR T cell effector function. Front. Immunol. 12, 684642 (2021).
pubmed: 34177932
pmcid: 8220823
Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).
pubmed: 28029927
pmcid: 5390684
Priceman, S. J. et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2(+) breast cancer metastasis to the brain. Clin. Cancer Res. 24, 95–105 (2018).
pubmed: 29061641
Wang, X. et al. The cerebroventricular environment modifies CAR T cells for potent activity against both central nervous system and systemic lymphoma. Cancer Immunol. Res. 9, 75–88 (2021).
pubmed: 33093217
Brown, C. E. et al. Optimization of IL13Ralpha2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol. Ther. 26, 31–44 (2018).
pubmed: 29103912
Vitanza, N. A. et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat. Med. 27, 1544–1552 (2021).
pubmed: 34253928
Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).
pubmed: 25378643
pmcid: 4373413
Adusumilli, P. S. et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 11, 2748–2763 (2021).
pubmed: 34266984
pmcid: 8563385
Tchou, J. et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol. Res. 5, 1152–1161 (2017).
pubmed: 29109077
pmcid: 5712264
Yeku, O. O., Purdon, T. J., Koneru, M., Spriggs, D. & Brentjens, R. J. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci. Rep. 7, 10541 (2017).
pubmed: 28874817
pmcid: 5585170
Murad, J. P. et al. Effective targeting of TAG72(+) peritoneal ovarian tumors via regional delivery of CAR-engineered T cells. Front. Immunol. 9, 2268 (2018).
pubmed: 30510550
pmcid: 6254427
Luo, H. et al. Coexpression of IL7 and CCL21 increases efficacy of CAR-T cells in solid tumors without requiring preconditioned lymphodepletion. Clin. Cancer Res. 26, 5494–5505 (2020).
pubmed: 32816947
Hege, K. M. et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J. Immunother. Cancer 5, 22 (2017).
pubmed: 28344808
pmcid: 5360066
Yoon, S. O. et al. Construction, affinity maturation, and biological characterization of an anti-tumor-associated glycoprotein-72 humanized antibody. J. Biol. Chem. 281, 6985–6992 (2006).
pubmed: 16407221
De Pascalis, R. et al. In vitro affinity maturation of a specificity-determining region-grafted humanized anticarcinoma antibody: isolation and characterization of minimally immunogenic high-affinity variants. Clin. Cancer Res. 9, 5521–5531 (2003).
pubmed: 14654532
Abate-Daga, D. & Davila, M. L. CAR models: next-generation CAR modifications for enhanced T-cell function. Mol. Ther. Oncolytics 3, 16014 (2016).
pubmed: 27231717
pmcid: 4871190
Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med 21, 581–590 (2015).
pubmed: 25939063
pmcid: 4458184
Priceman, S. J. et al. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. Oncoimmunology 7, e1380764 (2018).
pubmed: 29308300
Alizadeh, D. et al. IFNgamma is critical for CAR T cell-mediated myeloid activation and induction of endogenous immunity. Cancer Discov. 11, 2248–2265 (2021).
pubmed: 33837065
pmcid: 8561746
Jain, M. D. et al. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma. Blood 137, 2621–2633 (2021).
pubmed: 33512407
pmcid: 8120145
Textor, A. et al. Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNgamma. Cancer Res. 74, 6796–6805 (2014).
pubmed: 25297631
Larson, R. C. et al. CAR T cell killing requires the IFNgammaR pathway in solid but not liquid tumours. Nature 604, 563–570 (2022).
Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).
pubmed: 25695689
pmcid: 4433819
Sridhar, P. & Petrocca, F. Regional delivery of chimeric antigen receptor (CAR) T-cells for cancer therapy. Cancers (Basel) 9, 92 (2017).
Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 90, 2541–2548 (1997).
pubmed: 9326219
Nguyen, K. G. et al. Localized interleukin-12 for cancer immunotherapy. Front. Immunol. 11, 575597 (2020).
pubmed: 33178203
pmcid: 7593768
Murad, J. P. et al. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. Mol. Ther. 29, 2335–2349 (2021).
pubmed: 33647456
pmcid: 8261088
Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest 121, 4746–4757 (2011).
pubmed: 22056381
pmcid: 3226001
Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).
pubmed: 12563297
Zhang, L. et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol. Ther. 19, 751–759 (2011).
pubmed: 21285960
pmcid: 3070103
Koneru, M., Purdon, T. J., Spriggs, D., Koneru, S. & Brentjens, R. J. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).
pubmed: 25949921
pmcid: 4404840
Henry, C. J., Ornelles, D. A., Mitchell, L. M., Brzoza-Lewis, K. L. & Hiltbold, E. M. IL-12 produced by dendritic cells augments CD8+ T cell activation through the production of the chemokines CCL1 and CCL17. J. Immunol. 181, 8576–8584 (2008).
pubmed: 19050277
Guedan, S., Calderon, H., Posey, A. D. Jr. & Maus, M. V. Engineering and design of chimeric antigen receptors. Mol. Ther. Methods Clin. Dev. 12, 145–156 (2019).
pubmed: 30666307
Miller, I. C. et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nat. Biomed. Eng. 5, 1348–1359 (2021).
pubmed: 34385695
pmcid: 8791016
Huang, Z. et al. Engineering light-controllable CAR T cells for cancer immunotherapy. Sci. Adv. 6, eaay9209 (2020).
pubmed: 32128416
pmcid: 7030928
Prinzing, B. & Krenciute, G. Hypoxia-inducible CAR expression: an answer to the on-target/off-tumor dilemma? Cell Rep. Med. 2, 100244 (2021).
pubmed: 33948575
pmcid: 8080122
Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).
pubmed: 26830879
pmcid: 4752902
Srivastava, S. et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489–503.e488 (2019).
pubmed: 30889382
pmcid: 6450658
Giordano-Attianese, G. et al. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nat. Biotechnol. 38, 426–432 (2020).
pubmed: 32015549
Zhang, L. et al. Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models. J. Immunother. Cancer 8, e000210 (2020).
Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl Acad. Sci. USA 113, E7788–E7797 (2016).
pubmed: 27849617
pmcid: 5137758
Hu, J. et al. Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors. J. Immunother. Cancer 10, e003633 (2022).
Agarwal, Y. et al. Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity. Nat. Biomed. Eng. 6, 129–143 (2022).
pubmed: 35013574
pmcid: 9681025
Neman, J. et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc. Natl Acad. Sci. USA 111, 984–989 (2014).
pubmed: 24395782
pmcid: 3903266
Ogawa, T. et al. ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway. Oncotarget 8, 112550–112564 (2017).
pubmed: 29348846
pmcid: 5762531
Kern, P., Hussey, R. E., Spoerl, R., Reinherz, E. L. & Chang, H.-C. Expression, purification, and functional analysis of murine ectodomain fragments of CD8αα and CD8αβ dimers. J. Biol. Chem. 274, 27237–27243 (1999).
pubmed: 10480942
Classon, B. J. et al. The hinge region of the CD8 alpha chain: structure, antigenicity, and utility in expression of immunoglobulin superfamily domains. Int. Immunol. 4, 215–225 (1992).
pubmed: 1377946
Kochenderfer, J. N., Yu, Z., Frasheri, D., Restifo, N. P. & Rosenberg, S. A. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116, 3875–3886 (2010).
pubmed: 20631379
pmcid: 2981541
Park, A. K. et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci. Transl. Med. 12, eaaz1863 (2020).
Murad, J. P. et al. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. Mol. Ther. 29, 2335–2349 (2021).
Siddiqi, T. et al. CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma. Blood Adv. 5, 4059–4063 (2021).
pubmed: 34492703
pmcid: 8945630