Enhancing CAR-T Efficacy: The Role of Anti PD-1/PD-L1 Checkpoint Inhibitors in Modern Cancer Treatment

Abstract

The article "Enhancing CAR-T Efficacy: The Role of Anti PD-1/PD-L1 Checkpoint Inhibitors in Modern Cancer Treatment" provides an exhaustive study on CAR-T cell therapy and its role in cancer treatment, focusing on the problem of T-cell exhaustion and tumor immune evasion. Anti-PD-1/PD-L1 checkpoint inhibitors are said to help achieve enhanced CAR-T therapy by countering immune suppression within the tumor microenvironment. The introduction emphasizes the success level of CAR-T cells, especially in B-cell hematologic malignancies, while humbly candid in its limitation concerning solid tumors through mechanisms of immunosuppression. Of specific interest herein are the PD-1 and PD-L1 pathways as key immune checkpoints exploited by cancer to escape an immune response. To elaborate on this, it also explains how tumors upregulate PD-L1 to prevent T-cell functions through T-cell exhaustion, which entails depression in cytokine production and proliferation. The article explains the mechanisms of T-cell exhaustion: chronic antigen exposure, transcriptional reprogramming, metabolic dysfunction, and the suppressive nature of the tumor microenvironment. All these mechanisms combined lead to a loss of T-cell efficacy in counteracting tumor progression. The PD-1/PD-L1 axis preserves T-cell exhaustion and inhibits a strong immune response against the tumor. The paper puts forth the argument that the combination of CAR-T cell therapy with PD-1/PD-L1 checkpoint inhibitors leads to the reversal of immune suppression, improving T-cell function and persistence. A review of the preclinical and clinical trials, especially for solid tumor malignancies, puts forth advantages as well as challenges. Such challenges are experienced in terms of T-cell exhaustion, immunosuppressive tumor microenvironments, optimization of a dose, issues of toxicity, and inconsistent clinical outcomes.

Keywords

Cancer immunotherapy - PD-1/PD-L1 - T cell exhaustion - conventional chemotherapy

Author Contributions

Rishi Kant was responsible for writing the manuscript. Prashanjit Roy collected the data. Amandeep Kaur provided supervision. Ranjeet Kumar conducted the formal analysis.

Declaration of Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Publikationsverlauf

Eingereicht: 21. November 2024

Angenommen: 21. März 2025

Artikel online veröffentlicht:
30. Juni 2025

• References

• 1 Pitt JM, Vétizou M, Daillère R. et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and-extrinsic factors. Immunity 2016; 44 (06) 1255-1269
• 2 Schaft N. The landscape of CAR-T cell clinical trials against solid tumors—a comprehensive overview. Cancers (Basel) 2020; 12 (09) 2567
• 3 Ghosh C, Luong G, Sun Y. A snapshot of the PD-1/PD-L1 pathway. J Cancer 2021; 12 (09) 2735-2746
• 4 Cao L, Prithviraj P, Shrestha R. et al. Prognostic role of immune checkpoint regulators in cholangiocarcinoma: a pilot study. J Clin Med 2021; 10 (10) 2191
• 5 Hossain MA, Liu G, Dai B. et al. Reinvigorating exhausted CD8⁺ cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy. Med Res Rev 2021; 41 (01) 156-201
• 6 Ferlay J, Soerjomataram I, Dikshit R. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136 (05) E359-E386
• 7 Marin-Acevedo J, Dholaria B, Soyano A, Knutson K, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol 2018; 11 (01) 39 PubMed
• 8 Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A 1999; 96 (01) 185-190
• 9 Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009; 69 (15) 1694-1703
• 10 Wu M, Huang Q, Xie Y. et al. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J Hematol Oncol 2022; 15 (01) 24
• 11 Patel SA, Minn AJ. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 2018; 48 (03) 417-433
• 12 McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol 2019; 37 (01) 457-495
• 13 Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol 2022; 19 (12) 775-790
• 14 Fuertes Marraco SA, Neubert NJ, Verdeil G, Speiser DE. Inhibitory receptors beyond T cell exhaustion. Front Immunol 2015; 6: 310
• 15 Schmidl C, Delacher M, Huehn J, Feuerer M. Epigenetic mechanisms regulating T-cell responses. J Allergy Clin Immunol 2018; 142 (03) 728-743
• 16 Franco F, Jaccard A, Romero P, Yu Y-R, Ho P-C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020; 2 (10) 1001-1012
• 17 Dysthe M, Parihar R. Myeloid-derived suppressor cells in the tumor microenvironment. Tumor Microenvironment: Hematopoietic Cells–Part A. 2020; 117-140 PubMed
• 18 Goronzy JJ, Weyand CM. T-cell co-stimulatory pathways in autoimmunity. Arthritis Res Ther 2008; 10 (Suppl 1, Suppl 1) S3
• 19 Accogli T, Bruchard M, Végran F. Modulation of CD4 T cell response according to tumor cytokine microenvironment. Cancers (Basel) 2021; 13 (03) 373
• 20 Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol 2021; 14 (01) 10
• 21 Nagasaki J, Togashi Y. A variety of 'exhausted' T cells in the tumor microenvironment. Int Immunol 2022; 34 (11) 563-570
• 22 Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 2019; 36 (05) 471-482
• 23 Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3 (05) 541-547
• 24 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271 (5256) 1734-1736
• 25 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
• 26 Casey SC, Tong L, Li Y. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016; 352 (6282) 227-231
• 27 Gotwals P, Cameron S, Cipolletta D. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 2017; 17 (05) 286-301
• 28 Obeid M, Tesniere A, Ghiringhelli F. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13 (01) 54-61
• 29 Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 2020; 17 (12) 725-741
• 30 Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31 (01) 51-72
• 31 Mathew M, Enzler T, Shu CA, Rizvi NA. Combining chemotherapy with PD-1 blockade in NSCLC. Pharmacol Ther 2018; 186: 130-137
• 32 Tongu M, Harashima N, Monma H. et al. Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother 2013; 62 (02) 383-391
• 33 Wesolowski R, Duggan MC, Stiff A. et al. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol Immunother 2017; 66 (11) 1437-1447
• 34 Schiavoni G, Sistigu A, Valentini M. et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res 2011; 71 (03) 768-778
• 35 Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A. Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res 2009; 69 (17) 6987-6994
• 36 Schaer DA, Geeganage S, Amaladas N. et al. The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy. Clin Cancer Res 2019; 25 (23) 7175-7188
• 37 Langer CJ, Gadgeel SM, Borghaei H. et al; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17 (11) 1497-1508
• 38 Gandhi L, Rodríguez-Abreu D, Gadgeel S. et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 2018; 378 (22) 2078-2092
• 39 Paz-Ares L, Luft A, Vicente D. et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med 2018; 379 (21) 2040-2051
• 40 Cortes J, Cescon DW, Rugo HS. et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020; 396 (10265): 1817-1828
• 41 Sun J-M, Shen L, Shah MA. et al; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021; 398 (10302): 759-771
• 42 Janjigian Y, Kawazoe A, Weber P. et al. LBA-4: initial data from the phase 3 KEYNOTE-811 study of trastuzumab and chemotherapy with or without pembrolizumab for HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Ann Oncol 2021; 32: S227
• 43 Yang Y, Wang Z, Fang J. et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol 2020; 15 (10) 1636-1646
• 44 Zhou C, Chen G, Huang Y. et al; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med 2021; 9 (03) 305-314
• 45 Yang Y, Qu S, Li J. et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2021; 22 (08) 1162-1174
• 46 Lu S, Wang J, Yu Y. et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol 2021; 16 (09) 1512-1522
• 47 Socinski MA, Jotte RM, Cappuzzo F. et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018; 378 (24) 2288-2301
• 48 Schmid P, Rugo HS, Adams S. et al; IMpassion130 Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020; 21 (01) 44-59
• 49 Mansfield AS, Każarnowicz A, Karaseva N. et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol 2020; 31 (02) 310-317
• 50 Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11 (11) 3887-3895
• 51 Filippone A, Lanza M, Mannino D. et al. PD1/PD-L1 immune checkpoint as a potential target for preventing brain tumor progression. Cancer Immunol Immunother 2022; 71 (09) 2067-2075
• 52 Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8 (03) 239-245
• 53 Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. Structural biology of the immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure 2017; 25 (08) 1163-1174
• 54 Guzik K, Tomala M, Muszak D. et al. Development of the inhibitors that target the PD-1/PD-L1 interaction—a brief look at progress on small molecules, peptides and macrocycles. Molecules 2019; 24 (11) 2071
• 55 Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236 (01) 219-242
• 56 Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5 (12) 1365-1369
• 57 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26 (01) 677-704
• 58 Bardhan K, Anagnostou T, Boussiotis VA. The PD1: PD-L1/2 pathway from discovery to clinical implementation. Front Immunol 2016; 7: 550
• 59 Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker. Cancer Med 2020; 9 (21) 8086-8121
• 60 Bai J, Gao Z, Li X, Dong L, Han W, Nie J. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget 2017; 8 (66) 110693-110707
• 61 Lotfinejad P, Kazemi T, Mokhtarzadeh A. et al. PD-1/PD-L1 axis importance and tumor microenvironment immune cells. Life Sci 2020; 259: 118297
• 62 Cui J-W, Li Y, Yang Y. et al. Tumor immunotherapy resistance: Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape. Biomed Pharmacother 2024; 171: 116203
• 63 Lee HT, Lee JY, Lim H. et al. Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep 2017; 7 (01) 5532
• 64 Cortellini A. Studio sul ruolo della storia familiare di neoplasie come fattore predittivo surrogato per l'immunoterapia con inibitori dei checkpoint immunitari PD-1/PD-L1.. 2022
• 65 Xue Y, Gao S, Gou J. et al. Platinum-based chemotherapy in combination with PD-1/PD-L1 inhibitors: preclinical and clinical studies and mechanism of action. Expert Opin Drug Deliv 2021; 18 (02) 187-203
• 66 Connolly C, Bambhania K, Naidoo J. Immune-related adverse events: a case-based approach. Front Oncol 2019; 9: 530
• 67 Finger LR, Pu J, Wasserman R. et al. The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene 1997; 197 (1-2): 177-187
• 68 Agata Y, Kawasaki A, Nishimura H. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8 (05) 765-772
• 69 Terawaki S, Chikuma S, Shibayama S. et al. IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 2011; 186 (05) 2772-2779
• 70 Lázár-Molnár E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A 2008; 105 (30) 10483-10488
• 71 Yamazaki T, Akiba H, Iwai H. et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169 (10) 5538-5545
• 72 Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 2007; 37 (09) 2405-2410
• 73 Freeman GJ, Long AJ, Iwai Y. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192 (07) 1027-1034
• 74 Selenko-Gebauer N, Majdic O, Szekeres A. et al. B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol 2003; 170 (07) 3637-3644
• 75 Currie AJ, Prosser A, McDonnell A. et al. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol 2009; 183 (12) 7898-7908
• 76 Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 2009; 114 (08) 1545-1552
• 77 Hodi FS, O'Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (08) 711-723
• 78 Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012; 18 (24) 6580-6587
• 79 Hamid O, Robert C, Daud A. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369 (02) 134-144
• 80 Ansell SM, Lesokhin AM, Borrello I. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372 (04) 311-319
• 81 Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 1996; 88 (02) 100-108
• 82 Peng W, Chen JQ, Liu C. et al. Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov 2016; 6 (02) 202-216
• 83 Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523 (7559) 231-235
• 84 Gao J, Shi LZ, Zhao H. et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 2016; 167 (02) 397-404.e9
• 85 Liu C, Peng W, Xu C. et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 2013; 19 (02) 393-403
• 86 Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 2008; 105 (39) 15016-15021
• 87 Oida T, Zhang X, Goto M. et al. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-β-dependent mechanism. J Immunol 2003; 170 (05) 2516-2522
• 88 Yang L, Huang J, Ren X. et al. Abrogation of TGF β signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 2008; 13 (01) 23-35
• 89 Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 2014; 6 (03) 1670-1690
• 90 Lebrun J-J. The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012; 2012 (01) 381428
• 91 Thommen DS, Schreiner J, Müller P. et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res 2015; 3 (12) 1344-1355
• 92 Hugo W, Zaretsky JM, Sun L. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016; 165 (01) 35-44
• 93 Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene 2002; 21 (35) 5496-5503
• 94 Mirza NN, Antonia SJ, Fricke I. et al. Effective Combination of Cancer Vaccine With Chemotherapy in Patients With Extensive Stage Lung Cancer. J Immunother 2005; 28 (06) 612-613
• 95 Hsu MM, Balar AV. PD-1/PD-L1 combinations in advanced urothelial cancer: rationale and current clinical trials. Clin Genitourin Cancer 2019; 17 (03) e618-e626
• 96 Setlai BP, Hull R, Bida M. et al. Immunosuppressive signaling pathways as targeted cancer therapies. Biomedicines 2022; 10 (03) 682
• 97 Atkins MB, Plimack ER, Puzanov I. et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol 2018; 19 (03) 405-415
• 98 De Silva P, Aiello M, Gu-Trantien C, Migliori E, Willard-Gallo K, Solinas C. Targeting CTLA-4 in cancer: Is it the ideal companion for PD-1 blockade immunotherapy combinations?. Int J Cancer 2021; 149 (01) 31-41
• 99 Hao C, Tian J, Liu H, Li F, Niu H, Zhu B. Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017; 96 (26) e7325
• 100 Chen C, Liu Y, Cui B. Effect of radiotherapy on T cell and PD-1 / PD-L1 blocking therapy in tumor microenvironment. Hum Vaccin Immunother 2021; 17 (06) 1555-1567
• 101 Chen C-Y, Hutzen B, Wedekind MF, Cripe TP. Oncolytic virus and PD-1/PD-L1 blockade combination therapy. Oncolytic Virother 2018; 7: 65-77
• 102 Bommareddy PK, Patel A, Hossain S, Kaufman HL. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am J Clin Dermatol 2017; 18 (01) 1-15
• 103 Yoon DH, Osborn MJ, Tolar J, Kim CJ. Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): combination or built-in CAR-T. Int J Mol Sci 2018; 19 (02) 340
• 104 Chen Y, Liu C, Zhu S. et al. PD-1/PD-L1 immune checkpoint blockade-based combinational treatment: Immunotherapeutic amplification strategies against colorectal cancer. Int Immunopharmacol 2021; 96: 107607
• 105 Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother 2019; 15 (05) 1111-1122
• 106 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. Biomed Pharmacother 2020; 121: 109625
• 107 Xu J, Zhang Q, Tian K, Wang H, Yin H, Zheng J. Current status and future prospects of the strategy of combining CAR–T with PD–1 blockade for antitumor therapy (Review). Mol Med Rep 2018; 17 (02) 2083-2088
• 108 Li Z, Sun G, Sun G. et al. Various uses of PD1/PD-L1 inhibitor in oncology: opportunities and challenges. Front Oncol 2021; 11: 771335
• 109 Wang Z, Li N, Feng K. et al. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell Mol Immunol 2021; 18 (09) 2188-2198
• 110 Lv Y, Luo X, Xie Z. et al. Prospects and challenges of CAR-T cell therapy combined with ICIs. Front Oncol 2024; 14: 1368732