EMERGING INSIGHTS INTO CAR-T THERAPY FOR SOLID MALIGNANCIES
Main Article Content
Keywords
Abstract
Background:
Chimeric antigen receptor (CAR) engineered T cells have achieved great success in combating certain hematologic malignancies; however, translating these breakthroughs to solid tumors remains a formidable challenge. This article explores key insights from recent clinical studies, elucidates the mechanisms by which solid tumors evade immune surveillance, and highlights innovative engineering strategies designed to overcome these barriers and enhance the therapeutic potential of CAR T cell treatments.
Summary:
Although early evidence suggested that CAR-T cells could effectively treat various diseases, their achievement in eradicating solid cancer has been limited. A major obstacle lies in the absence of unique tumor-specific markers, coupled with the inability of conventional CAR T therapies to overcome the complex challenges posed by solid tumor environments. Current research is actively exploring numerous plans to boost the potency and persistence of CAR T cells, though many remain in the preclinical stage. Looking ahead, innovative approaches such as engineering next generation CAR T cells, targeting structural barriers and immunosuppressive cells within the tumor microenvironment, and employing advanced methods to shield immune cells from hostile tumor conditions—hold significant promise. These cutting-edge strategies aim to report existing limitations and substantially advance the efficacy of CAR T cell treatments against solid cancer.
References
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39) Liu Y, Sun Y, Wang P, Li S, Dong Y, Zhou M, Shi B, Jiang H, Sun R, Li Z. FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18. 2-targeted CAR-T against pancreatic cancer. Journal of translational medicine. 2023 Apr 12;21(1):255.
40) Li F, Zhao S, Wei C, Hu Y, Xu T, Xin X, Zhu T, Shang L, Ke S, Zhou J, Xu X. Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors. Frontiers in immunology. 2022 Nov 21;13:958082.
41) Foeng J, Comerford I, McColl SR. Harnessing the chemokine system to home CAR-T cells into solid tumors. Cell Reports Medicine. 2022 Mar 15;3(3).
42) Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W, Wei XF, Han W, Wang H. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI insight. 2020 Feb 27;5(4):
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45) Willier S, Färber J, Ispyrlidou T, Stenger D, Nikolaides SL, Ernst PF, Peters AE, Wilhelm J, Stoll N, Breidenbach M, Becker-Dettling FA. CD28 CAR T Cells for the Treatment of T Cell Malignancies. Blood. 2023 Nov 2;142:3448.
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48) Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of blood and marrow transplantation. 2019 Apr 1;25(4):625-38.
49) Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, Schmierer M, Gabrusiewicz K, Anderson NR, Petty NE, Cummins KD. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature biotechnology. 2020 Aug 1;38(8):947-53.
50) Chen H, Yang Y, Deng Y, Wei F, Zhao Q, Liu Y, Liu Z, Yu B, Huang Z. Delivery of CD47 blocker SIRPα-Fc by CAR-T cells enhances antitumor efficacy. Journal for ImmunoTherapy of Cancer. 2022 Feb 2;10(2):e003737.
51) Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. Journal of hematology & oncology. 2020 May 18;13(1):54.
52) Bunse M, Pfeilschifter J, Bluhm J, Zschummel M, Joedicke JJ, Wirges A, Stark H, Kretschmer V, Chmielewski M, Uckert W, Abken H. CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells. Nature communications. 2021 Jan 11;12(1):240.
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2) Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2024 May;74(3):229-63.
3) Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. New England Journal of Medicine. 2016 Dec 29;375(26):2561-9.
4) Guzman G, Reed MR, Bielamowicz K, Koss B, Rodriguez A. CAR-T therapies in solid tumors: opportunities and challenges. Current oncology reports. 2023 May;25(5):479-89.
5) Baker DJ, Arany Z, Baur JA, Epstein JA, June CH. CAR T therapy beyond cancer: the evolution of a living drug. Nature. 2023 Jul 27;619(7971):707-15.
6) Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, Ye Z, Qian Q. Current Progress in CAR-T Cell Therapy for Solid Tumors. Int J Biol Sci. 2019 Sep 7;15(12):2548-2560. doi: 10.7150/ijbs.34213. PMID: 31754328; PMCID: PMC6854376.
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8) Hutchinson L. Adaptive resistance to CARs in glioma. Nature Reviews Clinical Oncology. 2017 Oct;14(10):586-.
9) Prapa M, Chiavelli C, Golinelli G, Grisendi G, Bestagno M, Di Tinco R, Dall’Ora M, Neri G, Candini O, Spano C, Petrachi T. GD2 CAR T cells against human glioblastoma. NPJ precision oncology. 2021 Oct 27;5(1):93.
10) Adusumilli PS, Zauderer MG, Rivière I, Solomon SB, Rusch VW, O'Cearbhaill RE, Zhu A, Cheema W, Chintala NK, Halton E, Pineda J. 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 discovery. 2021 Nov 1;11(11):2748-63.
11) Qi C, Liu C, Gong J, Liu D, Wang X, Zhang P, Qin Y, Ge S, Zhang M, Peng Z, Zhou J. Claudin18. 2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nature medicine. 2024 Aug;30(8):2224-34.
12) Gu X, Zhang Y, Zhou W, Wang F, Yan F, Gao H, Wang W. Infusion and delivery strategies to maximize the efficacy of CAR-T cell immunotherapy for cancers. Experimental Hematology & Oncology. 2024 Jul 26;13(1):70.
13) Albelda SM. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nature Reviews Clinical Oncology. 2024 Jan;21(1):47-66.
14) Donnadieu E, Dupré L, Pinho LG, Cotta-de-Almeida V. Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors. Journal of Leucocyte Biology. 2020 Oct;108(4):1067-79.
15) Papa S, Adami A, Metoudi M, Beatson R, George MS, Achkova D, Williams E, Arif S, Reid F, Elstad M, Beckley-Hoelscher N. Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study. Journal for Immunotherapy of Cancer. 2023 Jun 15;11(6):e007162.
16) Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature. 2023 Feb 23;614(7949):635-48.
17) Vitanza NA, Wilson AL, Huang W, Seidel K, Brown C, Gustafson JA, Yokoyama JK, Johnson AJ, Baxter BA, Koning RW, Reid AN. Intraventricular B7-H3 CAR T cells for diffuse intrinsic pontine glioma: preliminary first-in-human bioactivity and safety. Cancer discovery. 2023 Jan 9;13(1):114-31.
18) Chen R, Li J, Fujimoto J, Hong L, Hu X, Quek K, Tang M, Mitra A, Behrens C, Chow CW, Jiang P. Immunogenomic intertumor heterogeneity across primary and metastatic sites in a patient with lung adenocarcinoma. Journal of Experimental & Clinical Cancer Research. 2022 May 11;41(1):172.
19) Stanta G, Bonin S. Overview on clinical relevance of intra-tumor heterogeneity. Frontiers in medicine. 2018 Apr 6;5:85.
20) Hughes NR, Walls RS, Newland RC, Payne JE. Gland to gland heterogeneity in histologically normal mucosa of colon cancer patients demonstrated by monoclonal antibodies to tissue-specific antigens. Cancer research. 1986 Nov 1;46(11):5993-9.
21) Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, Shomali N, Chartrand MS, Pathak Y, Jarahian M, Izadi S. CAR T cells in solid tumors: challenges and opportunities. Stem cell research & therapy. 2021 Jan 25;12(1):81.
22) Liu B, Yan L, Zhou M. Target selection of CAR T cell therapy in accordance with the TME for solid tumors. Am J Cancer Res. 2019 Feb 1;9(2):228-241. PMID: 30906625; PMCID: PMC6405971.
23) Hompland T, Fjeldbo CS, Lyng H. Tumor hypoxia as a barrier in cancer therapy: why levels matter. Cancers. 2021 Jan 28;13(3):499.
24) Papalazarou V, Maddocks OD. Supply and demand: Cellular nutrient uptake and exchange in cancer. Molecular cell. 2021 Sep 16;81(18):3731-48.
25) D'Souza RR, Dimou P, Bughda R, Hawkins E, Babe CL, Klampatsa A. Overcoming tumor antigen heterogeneity in CAR-T cell therapy for malignant mesothelioma (MM). Journal of Cancer Metastasis and Treatment. 2022 Jul 28;8(5):N-A.
26) Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, Wu MF, Orange JS, Sumazin P, Man TK, Joseph SK, Hegde M, Ahmed N. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 2018 Mar 27;20(4):506-518. doi: 10.1093/neuonc/nox182. Erratum in: J Clin Invest. 2021 Jul 1;131(13):152477. doi: 10.1172/JCI152477. Erratum in: Neuro Oncol. 2023 Sep 5;25(9):1727-1728. doi: 10.1093/neuonc/noad091. PMID: 29016929; PMCID: PMC5909636.
27) Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K, Bielamowicz K, Chow KK, Brawley VS. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. The Journal of Clinical Investigation. 2021 Jul 1;131(13).
28) Campos NS, Souza BS, Silva GC, Porto VA, Chalbatani GM, Lagreca G, Janji B, Suarez ER. Carbonic anhydrase IX: a renewed target for cancer immunotherapy. Cancers. 2022 Mar 9;14(6):1392.
29) Mansilla-Soto J, Eyquem J, Haubner S, Hamieh M, Feucht J, Paillon N, Zucchetti AE, Li Z, Sjöstrand M, Lindenbergh PL, Saetersmoen M. HLA-independent T cell receptors for targeting tumors with low antigen density. Nature medicine. 2022 Feb;28(2):345-52.
30) Liu Y, Liu G, Wang J, Zheng ZY, Jia L, Rui W, Huang D, Zhou ZX, Zhou L, Wu X, Lin S. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Science translational medicine. 2021 Mar 24;13(586):eabb5191.
31) Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15(8):1145-54. doi: 10.1517/14712598.2015.1046430. Epub 2015 May 18. PMID: 25985798.
32) Hawkins ER, D'Souza RR, Klampatsa A. Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy. Biologics. 2021 Apr 14;15:95-105. doi: 10.2147/BTT.S291768. PMID: 33883875; PMCID: PMC8053711.
33) Svoboda J, Gerson JN, Landsburg DJ, Chong EA, Barta SK, Dwivedy Nasta S, Ruella M, Hexner EO, Marshall A, Leskowitz R, Four M. Interleukin-18 secreting autologous anti-CD19 CAR T-cells (huCART19-IL18) in patients with non-Hodgkin lymphomas relapsed or refractory to prior CAR T-cell therapy.
34) Lee EH, Murad JP, Christian L, Gibson J, Yamaguchi Y, Cullen C, Gumber D, Park AK, Young C, Monroy I, Yang J. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Nature communications. 2023 Aug 7;14(1):4737.
35) Koneru M, O'Cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med. 2015 Mar 28;13:102. doi: 10.1186/s12967-015-0460-x. PMID: 25890361; PMCID: PMC4438636.
36) Lange S, Sand LG, Bell M, Patil SL, Langfitt D, Gottschalk S. A chimeric GM-CSF/IL18 receptor to sustain CAR T-cell function. Cancer discovery. 2021 Jul 1;11(7):1661-71.
37) Herzyk DJ, Bugelski PJ, Hart TK, Wier PJ. Preclinical safety of recombinant human interleukin-18. Toxicol Pathol. 2003 Sep-Oct;31(5):554-61. doi: 10.1080/01926230390226681. PMID: 14692624.
38) Mhaidly R, Mechta-Grigoriou F. Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies. InSeminars in immunology 2020 Apr 1 (Vol. 48, p. 101417). Academic Press.
39) Liu Y, Sun Y, Wang P, Li S, Dong Y, Zhou M, Shi B, Jiang H, Sun R, Li Z. FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18. 2-targeted CAR-T against pancreatic cancer. Journal of translational medicine. 2023 Apr 12;21(1):255.
40) Li F, Zhao S, Wei C, Hu Y, Xu T, Xin X, Zhu T, Shang L, Ke S, Zhou J, Xu X. Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors. Frontiers in immunology. 2022 Nov 21;13:958082.
41) Foeng J, Comerford I, McColl SR. Harnessing the chemokine system to home CAR-T cells into solid tumors. Cell Reports Medicine. 2022 Mar 15;3(3).
42) Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W, Wei XF, Han W, Wang H. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI insight. 2020 Feb 27;5(4):
43) McGowan E, Lin Q, Ma G, Yin H, Chen S, Lin Y. PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges. Biomedicine & Pharmacotherapy. 2020 Jan 1;121:109625.
44) Seo H. Transforming TGF-β suppression into IL-15 stimulation: Advancing engineered CAR-T therapy for solid tumors. Molecular Therapy. 2025 Feb 5;33(2):440-2.
45) Willier S, Färber J, Ispyrlidou T, Stenger D, Nikolaides SL, Ernst PF, Peters AE, Wilhelm J, Stoll N, Breidenbach M, Becker-Dettling FA. CD28 CAR T Cells for the Treatment of T Cell Malignancies. Blood. 2023 Nov 2;142:3448.
46) Dagher OK, Posey Jr AD. Forks in the road for CAR T and CAR NK cell cancer therapies. Nature immunology. 2023 Dec;24(12):1994-2007.
47) Luo H, Wu X, Sun R, Su J, Wang Y, Dong Y, Shi B, Sun Y, Jiang H, Li Z. Target-dependent expression of IL12 by synNotch receptor-engineered NK92 cells increases the antitumor activities of CAR-T cells. Frontiers in Oncology. 2019 Dec 19;9:1448.
48) Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of blood and marrow transplantation. 2019 Apr 1;25(4):625-38.
49) Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, Schmierer M, Gabrusiewicz K, Anderson NR, Petty NE, Cummins KD. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature biotechnology. 2020 Aug 1;38(8):947-53.
50) Chen H, Yang Y, Deng Y, Wei F, Zhao Q, Liu Y, Liu Z, Yu B, Huang Z. Delivery of CD47 blocker SIRPα-Fc by CAR-T cells enhances antitumor efficacy. Journal for ImmunoTherapy of Cancer. 2022 Feb 2;10(2):e003737.
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52) Bunse M, Pfeilschifter J, Bluhm J, Zschummel M, Joedicke JJ, Wirges A, Stark H, Kretschmer V, Chmielewski M, Uckert W, Abken H. CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells. Nature communications. 2021 Jan 11;12(1):240.
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Aug 19, 2025
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JAMIL AHMAD, FARYAL GOHAR, SARAH JAFFRI, ALTAF HUSSAIN, AQSA JAFFRI, FAZAL GHAFAR, & SABA HUMAYUN. (2025). EMERGING INSIGHTS INTO CAR-T THERAPY FOR SOLID MALIGNANCIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 697-706. https://doi.org/10.53555/sqhne274
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Author Biographies
JAMIL AHMAD
Department of Laboratory, Oriana Hospital & Clinics, UAE
FARYAL GOHAR
Faculty of Life Sciences, University of central Punjab, Lahore, Pakistan
SARAH JAFFRI
Daemen University, United state of America
ALTAF HUSSAIN
Saidu Group of Teaching Hospitals, Saidu Sharif, Swat, Pakistan
AQSA JAFFRI
SUNY Niagara, United state of America
FAZAL GHAFAR
Department of Pathology, Bahria International Hospital Lahore, Pakistan
SABA HUMAYUN
Department of Pathology, CDA Hospital, Islamabad, Pakistan
How to Cite
JAMIL AHMAD, FARYAL GOHAR, SARAH JAFFRI, ALTAF HUSSAIN, AQSA JAFFRI, FAZAL GHAFAR, & SABA HUMAYUN. (2025). EMERGING INSIGHTS INTO CAR-T THERAPY FOR SOLID MALIGNANCIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 697-706. https://doi.org/10.53555/sqhne274