Abstract
Chimeric antigen receptor (CAR) T cell therapy stands as a transformative advancement in immunotherapy, triumphing against hematological malignancies and, increasingly, autoimmune disorders. After a decade of relatively modest results for solid tumors, recent clinical trials and patient reports have also started to yield promising outcomes in glioblastoma and other challenging solid tumor entities. This Perspective seeks to explore the reasons behind these latest achievements and discusses how they can be sustained and expanded through different strategies involving CAR engineering and synthetic biology. Furthermore, we critically analyze how these breakthroughs can be leveraged to maintain momentum and broaden the therapeutic impact of CAR T cells across a variety of solid tumor landscapes.
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References
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).
Parikh, R. H. & Lonial, S. Chimeric antigen receptor T-cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA Cancer J. Clin. 73, 275–285 (2023).
Melenhorst, J. J. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503–509 (2022).
Muller, F. et al. CD19 CAR T-cell therapy in autoimmune disease — a case series with follow-up. N. Engl. J. Med. 390, 687–700 (2024).
Baker, D. J., Arany, Z., Baur, J. A., Epstein, J. A. & June, C. H. CAR T therapy beyond cancer: the evolution of a living drug. Nature 619, 707–715 (2023).
Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat. Med. 28, 2124–2132 (2022).
Mullard, A. FDA approves first tumour-infiltrating lymphocyte (TIL) therapy, bolstering hopes for cell therapies in solid cancers. Nat. Rev. Drug Discov. 23, 238 (2024).
Creelan, B. C. et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat. Med. 27, 1410–1418 (2021).
D’Angelo, S. P. et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet 403, 1460–1471 (2024).
Albelda, S. M. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat. Rev. Clin. Oncol. 21, 47–66 (2024).
Maalej, K. M. et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances. Mol. Cancer 22, 20 (2023).
Young, R. M., Engel, N. W., Uslu, U., Wellhausen, N. & June, C. H. Next-generation CAR T-cell therapies. Cancer Discov. 12, 1625–1633 (2022).
Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).
Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nat. Med. 30, 2224–2234 (2024).
Hegde, M. et al. Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial. Nat. Cancer 5, 880–894 (2024).
Choi, B. D. et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N. Engl. J. Med. 390, 1290–1298 (2024).
Bagley, S. J. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat. Med. 30, 1320–1329 (2024).
Brown, C. E. et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat. Med. 30, 1001–1012 (2024).
Del Bufalo, F. et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023).
Mackensen, A. et al. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. Nat. Med. 29, 2844–2853 (2023).
Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
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).
O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).
Bagley, S. J. et al. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. Nat. Cancer 5, 517–531 (2024).
Gargett, T. et al. Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers. J. Immunother. Cancer 12, e008659 (2024).
Liu, Z. et al. Safety and antitumor activity of GD2-specific 4SCAR-T cells in patients with glioblastoma. Mol. Cancer 22, 3 (2023).
Mahdi, J. et al. Tumor inflammation-associated neurotoxicity. Nat. Med. 29, 803–810 (2023).
Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).
Heczey, A. et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol. Ther. 25, 2214–2224 (2017).
De Sanctis, F. et al. Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer. Immunity 57, 1378–1393 (2024).
Huang, Z. et al. CAR T cells: engineered immune cells to treat brain cancers and beyond. Mol. Cancer 22, 22 (2023).
Spiegel, J. Y. et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat. Med. 27, 1419–1431 (2021).
Shi, M. et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nat. Commun. 15, 3371 (2024).
Labanieh, L. & Mackall, C. L. CAR immune cells: design principles, resistance and the next generation. Nature 614, 635–648 (2023).
Schneider, D. et al. Trispecific CD19–CD20–CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci. Transl. Med. 13, eabc6401 (2021).
Yin, Y. et al. Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors. Mol. Ther. 30, 2537–2553 (2022).
Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).
Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).
Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. 126, 3814–3826 (2016).
Zah, E., Lin, M. Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498–508 (2016).
Weber, E. W. et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 372, eac1786 (2021).
Mestermann, K. et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl. Med. 11, eaau5907 (2019).
Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).
Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).
Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438 (2018).
Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).
Courtney, A. N., Tian, G. & Metelitsa, L. S. Natural killer T cells and other innate-like T lymphocytes as emerging platforms for allogeneic cancer cell therapy. Blood 141, 869–876 (2023).
de Vries, N. L. et al. γδ T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 613, 743–750 (2023).
Heczey, A. et al. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Nat. Med. 29, 1379–1388 (2023).
Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R., Siegler, E. L. & Kenderian, S. S. CAR T cell therapy and the tumor microenvironment: current challenges and opportunities. Mol. Ther. Oncolytics 25, 69–77 (2022).
Uslu, U. et al. Chimeric antigen receptor T cells as adjuvant therapy for unresectable adenocarcinoma. Sci. Adv. 9, eade2526 (2023).
Ogunnaike, E. A. et al. Fibrin gel enhances the antitumor effects of chimeric antigen receptor T cells in glioblastoma. Sci. Adv. 7, eabg5841 (2021).
Foeng, J., Comerford, I. & McColl, S. R. Harnessing the chemokine system to home CAR-T cells into solid tumors. Cell Rep. Med. 3, 100543 (2022).
Jin, L. et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 10, 4016 (2019).
Peng, W. et al. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin. Cancer Res. 16, 5458–5468 (2010).
Craddock, J. A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010).
Moon, E. K. et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011).
Lesch, S. et al. T cells armed with C–X–C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat. Biomed. Eng. 5, 1246–1260 (2021).
Siddiqui, I., Erreni, M., van Brakel, M., Debets, R. & Allavena, P. Enhanced recruitment of genetically modified CX3CR1-positive human T cells into fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient. J. Immunother. Cancer 4, 21 (2016).
Li, H. et al. Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration. Nat. Commun. 13, 2154 (2022).
Watanabe, K. et al. Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma. Blood Adv. 7, 3416–3430 (2023).
Maciocia, P. M. et al. Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia. Blood 140, 25–37 (2022).
Adachi, K. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346–351 (2018).
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).
Lei, W. et al. Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma. Cell Discov. 10, 5 (2024).
Legler, D. F., Johnson-Leger, C., Wiedle, G., Bron, C. & Imhof, B. A. The α vβ 3 integrin as a tumor homing ligand for lymphocytes. Eur. J. Immunol. 34, 1608–1616 (2004).
Wallstabe, L. et al. CAR T cells targeting αvβ3 integrin are effective against advanced cancer in preclinical models. Adv. Cell Gene Ther. 1, e11 (2018).
Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).
Xiao, Z. et al. Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat. Commun. 14, 5110 (2023).
Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).
Zhao, R. et al. Human hyaluronidase PH20 potentiates the antitumor activities of mesothelin-specific CAR-T cells against gastric cancer. Front. Immunol. 12, 660488 (2021).
Gavil, N. V. et al. Chronic antigen in solid tumors drives a distinct program of T cell residence. Sci. Immunol. 8, eadd5976 (2023).
Jung, I.-Y. et al. Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors. Cell Rep. Med. 4, 101053 (2023).
Berg, T. J. & Pietras, A. Radiotherapy-induced remodeling of the tumor microenvironment by stromal cells. Semin. Cancer Biol. 86, 846–856 (2022).
DeSelm, C. et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol. Ther. 26, 2542–2552 (2018).
Murty, S. et al. Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model. Oncoimmunology 9, 1757360 (2020).
Amit, U. et al. Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 121, e2403002121 (2024).
Gumber, D. & Wang, L. D. Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion. EBioMedicine 77, 103941 (2022).
Hou, A. J., Chen, L. C. & Chen, Y. Y. Navigating CAR-T cells through the solid-tumour microenvironment. Nat. Rev. Drug Discov. 20, 531–550 (2021).
Hong, M., Clubb, J. D. & Chen, Y. Y. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell 38, 473–488 (2020).
Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).
Li, S. et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin. Cancer Res. 23, 6982–6992 (2017).
Good, C. R. et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 184, 6081–6100 (2021).
Agarwal, S. et al. Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells. Immunity 56, 2388–2407 (2023).
Hu, W. et al. CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol. Immunother. 68, 365–377 (2019).
Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).
Chiesa, R. et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N. Engl. J. Med. 389, 899–910 (2023).
Tang, L., Pan, S., Wei, X., Xu, X. & Wei, Q. Arming CAR-T cells with cytokines and more: innovations in the fourth-generation CAR-T development. Mol. Ther. 31, 3146–3162 (2023).
Chmielewski, M., Kopecky, C., Hombach, A. A. & Abken, H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 71, 5697–5706 (2011).
Pegram, H. J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).
Hoyos, V. et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170 (2010).
Chen, Y. et al. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin. Cancer Res. 25, 2915–2924 (2019).
Gargett, T. et al. GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma. J. Immunother. Cancer 10, e005187 (2022).
Hu, B. et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017).
Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130–2141 (2018).
Batra, S. A. et al. Glypican-3-specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma. Cancer Immunol. Res. 8, 309–320 (2020).
Wang, D., Shao, Y., Zhang, X., Lu, G. & Liu, B. IL-23 and PSMA-targeted duo-CAR T cells in prostate cancer eradication in a preclinical model. J. Transl. Med. 18, 23 (2020).
Li, X., Daniyan, A. F., Lopez, A. V., Purdon, T. J. & Brentjens, R. J. Cytokine IL-36γ improves CAR T-cell functionality and induces endogenous antitumor response. Leukemia 35, 506–521 (2021).
Lin, F. Y. et al. Phase I trial of GD2.CART cells augmented with constitutive interleukin-7 receptor for treatment of high-grade pediatric CNS tumors. J. Clin. Oncol. 42, 2769–2779 (2024).
Zhang, Q. et al. A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia. Sci. Transl. Med. 13, eabg6986 (2021).
Kalbasi, A. et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature 607, 360–365 (2022).
Zhu, X. et al. Hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors. Cancer Res. 84, 84–100 (2024).
Kosti, P. et al. Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors. Cell Rep. Med. 2, 100227 (2021).
Zhang, H. et al. Phase I trial of hypoxia-responsive CEA CAR-T cell therapy in patients with heavily pretreated solid tumor via intraperitoneal or intravenous transfusion. J. Clin. Oncol. 42, 1358–1363 (2024).
Tieu, V. et al. A versatile CRISPR–Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells. Cell 187, 1278–1295 (2024).
Hatae, R. et al. Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment. JCI Insight 9, e177141 (2024).
Uslu, U., Castelli, S. & June, C. H. CAR T cell combination therapies to treat cancer. Cancer Cell 42, 1319–1325 (2024).
Xu, N. et al. STING agonist promotes CAR T cell trafficking and persistence in breast cancer. J. Exp. Med. 218, e202000844 (2021).
Conde, E. et al. Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants. J. Immunother. Cancer 9, e003351 (2021).
Uslu, U. et al. The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion. Nat. Commun. 15, 3933 (2024).
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).
Smith, M. et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat. Med. 28, 713–723 (2022).
Stein-Thoeringer, C. K. et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat. Med. 29, 906–916 (2023).
Acknowledgements
We thank R.M. Young and members of the laboratory for helpful discussions. U.U. is supported by a Mildred-Scheel-Postdoctoral Fellowship from the German Cancer Aid. C.H.J. is supported by NIH grants (P01CA214278 and U54CA244711) and the Parker Institute for Cancer Immunotherapy.
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C.H.J. is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. C.H.J. is an inventor on patents and/or patent applications licensed to Kite Pharma, Capstan Therapeutics, Dispatch Therapeutics and BlueWhale Bio. C.H.J. is a member of the scientific advisory boards of AC Immune, Bluesphere Bio, BlueWhale Bio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Replay Bio, Verismo, ViTToria and WIRB-Copernicus. No competing interests were declared by U.U.
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Uslu, U., June, C.H. Beyond the blood: expanding CAR T cell therapy to solid tumors. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02446-2
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DOI: https://doi.org/10.1038/s41587-024-02446-2
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