Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

In the paper

“These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment.”

In the paper

“Correspondingly, strengthening these positive elements might boost the cancer-immune cycle, drive the transformation from cold to hot tumors, and improve the response to α-PD-1/PD-L1 therapies [21].”

What the sources say

• Not checked yetcites [21] Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13:143–58. source

In the paper

“Apart from immunogenic cell death, chemotherapy could directly eliminate immune suppressor cells and enhance the functions of effector cells, especially administrated at the dose below maximum-tolerated dose [37].”

What the sources say

• Not checked yetcites [37] Mathew M, Enzler T, Shu CA, Rizvi NA. Combining chemotherapy with PD-1 blockade in NSCLC. Pharmacol Ther. 2018;186:130–7. source

In the paper

“Besides, some cytotoxic chemotherapeutic drugs such as anthracycline and oxaliplatin could induce immunogenic cell death and stimulate antitumor immune response [33, 34].”

What the sources say

• Not checked yetcites [33] Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61. source
• Not checked yetcites [34] Zhu H, Shan Y, Ge K, Lu J, Kong W, Jia C. Oxaliplatin induces immunogenic cell death in hepatocellular carcinoma cells and synergizes with immune checkpoint blockade therapy. Cell Oncol (Dordr). 2020;43:1203–14. source

In the paper

“The ATP-P2RX7 signaling recruits DCs into the tumor bed; the CRT-CD91 axis promotes DC to engulf cancer antigens; the HMGB1-TLR4 pathway facilitates the optimal cancer antigen presentation [36].”

What the sources say

• Not checked yetcites [36] Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72. source

In the paper

“Chemotherapy retards tumor growth mainly by arresting cell cycle, inhibiting DNA replication, disturbing cell metabolism, or suppressing microtubule assembly [32].”

What the sources say

• Not checked yetcites [32] Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17:286–301. source

In the paper

“For the non-responders, PD-1 signaling is not the speed-limiting rheostat of cancer-immunity cycle, and it is insufficient to revive antitumor immunity by blocking PD-1 or PD-L1 [14].”

What the sources say

• Not checked yetcites [14] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. source

In the paper

“Logically, removing these negative factors could enhance the therapeutic effect of α-PD-1/PD-L1 and relieve drug resistance.”

In the paper

“Therefore, the chemotherapy-mediated MDSC depletion remains further verification in cancer patients.”

In the paper

“Firstly, radiotherapy promoted T cell infiltration, increased the number of TILs, and expanded T-cell receptor (TCR) repertoire in the TME [72, 73].”

What the sources say

• Not checked yetcites [72] Lim JY, Gerber SA, Murphy SP, Lord EM. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother. 2014;63:259–71. source
• Not checked yetcites [73] Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7. source

In the paper

“Generally, pembrolizumab has a great advantage on chemoimmunotherapy, with a broad range of indications.”

In the paper

“Consequently, radiotherapy not only eliminates local lesions but also stimulates the systemic antitumor immune response (also known as abscopal effects) [71].”

What the sources say

• Not checked yetcites [71] Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol. 2018;11:104. source

In the paper

“Like some chemotherapeutic drugs, radiotherapy could induce immunogenic cell death and enhance antitumor immune response [70].”

What the sources say

• Not checked yetcites [70] Hwang WL, Pike LRG, Royce TJ, Mahal BA, Loeffler JS. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat Rev Clin Oncol. 2018;15:477–94. source

In the paper

“Thirdly, radiotherapy increased the MHC-I on tumor cells and relieved resistance to α-PD-1/PD-L1 (Fig. 1b) [75].”

What the sources say

• Not checked yetcites [75] Wang X, Schoenhals JE, Li A, Valdecanas DR, Ye H, Zang F, et al. Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy. Cancer Res. 2017;77:839–50. source

In the paper

“Secondly, radiotherapy upregulated the expression of PD-L1 on tumor cells, which can be utilized by additional α-PD-1/PD-L1 [74].”

What the sources say

• Not checked yetcites [74] Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95. source

In the paper

“Secondly, VEGF could inhibit the maturation of DC, induce the exhaustion of T cells, promote the proliferation of Tregs, and increase the ratio of MDSCs [90–93].”

What the sources say

• Not checked yetcites [90] Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52:1475–85. source
• Not checked yetcites [91] Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212:139–48. source
• Not checked yetcites [92] Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539–49. source
• Not checked yetcites [93] Bourhis M, Palle J, Galy-Fauroux I, Terme M. Direct and indirect modulation of T cells by VEGF-A counteracted by anti-Angiogenic treatment. Front Immunol. 2021;12:616837. source

In the paper

“Angiogenesis inhibitor blocks these proangiogenic pathways, promotes vessel normalization, improves tumor perfusion and oxygenation, restores the hypoxic TME, and enhances drug delivery [100, 101].”

What the sources say

• Not checked yetcites [100] Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017;20:409–26. source
• Not checked yetcites [101] Pan C, Liu H, Robins E, Song W, Liu D, Li Z, et al. Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. J Hematol Oncol. 2020;13:29. source

In the paper

“Thirdly, despite without direct influence on T cells, ANGPT2 recruits Tie-2-expressing monocytes, enhances the differentiation towards M2-like macrophages, and upregulates the expression of IL-10 [94–97].”

What the sources say

• Not checked yetcites [94] De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211–26. source
• Not checked yetcites [95] Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res. 2010;70:5270–80. source
• Not checked yetcites [96] Coffelt SB, Chen YY, Muthana M, Welford AF, Tal AO, Scholz A, et al. Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion. J Immunol. 2011;186:4183–90. source
• Not checked yetcites [97] Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res. 2019;25:5449–57. source

In the paper

“Ipilimumab (developed by Bristol-Myers Squibb) is the first approved α-CTLA-4 drug, initially used for advanced melanoma [127].”

What the sources say

• Not checked yetcites [127] Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64. source

In the paper

“Also, angiogenesis inhibitor reshapes the TME: promoting T cell infiltration and DC maturation, enhancing the differentiation towards M1-like macrophage, decreasing the ratio of Treg and MDSC, and alleviating hypoxia-induced PD-L1 (Fig. 1c) [93, 102–105].”

What the sources say

• Not checked yetcites [93] Bourhis M, Palle J, Galy-Fauroux I, Terme M. Direct and indirect modulation of T cells by VEGF-A counteracted by anti-Angiogenic treatment. Front Immunol. 2021;12:616837. source
• Not checked yetcites [102] Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6. source
• Not checked yetcites [103] Du Four S, Maenhout SK, Niclou SP, Thielemans K, Neyns B, Aerts JL. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res. 2016;6:2514–31.
• Not checked yetcites [104] Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, et al. Expression of vascular endothelial growth factor in ovarian Cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res. 2017;23:587–99. source
• Not checked yetcites [105] Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90. source

In the paper

“CTLA-4 is primarily expressed on activated T cells and Tregs, as a negative regulator for T cell activation [121].”

What the sources say

• Not checked yetcites [121] Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–8. source

In the paper

“Tremelimumab is a human IgG2 monoclonal antibody (developed by AstraZeneca) targeting CTLA-4, which has entered phase 3 clinical trials [139].”

What the sources say

• Not checked yetcites [139] Ribas A. Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol. 2010;37:450–4. source

In the paper

“EGFR is a member of ErbB family driving the initiation and development of multiple types of cancers [181].”

What the sources say

• Not checked yetcites [181] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37. source

In the paper

“The results of some clinical trials were unsatisfactory, and no additional benefit was brought by tremelimumab plus durvalumab, compared to durvalumab monotherapy or standard chemotherapy [140, 142, 144].”

What the sources say

• Not checked yetcites [140] Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22:51–65. source
• Not checked yetcites [142] Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21:1574–88. source
• Not checked yetcites [144] Ferris RL, Haddad R, Even C, Tahara M, Dvorkin M, Ciuleanu TE, et al. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol. 2020;31:942–50. source

In the paper

“The preliminary data showed that these combination strategies were well-tolerated, supporting further investigation in advanced solid tumors [177–180].”

What the sources say

• Not checked yetcites [177] Patel MR, Naing A III, HAB, Lin C-C, Curigliano G, Thistlethwaite F, et al. A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies. J Clin Oncol. 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.2624. source
• Not checked yetcites [178] Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, et al. A phase I study of APX005M and Cabiralizumab with or without Nivolumab in patients with melanoma, kidney Cancer, or non-small cell lung Cancer resistant to anti-PD-1/PD-L1. Clin Cancer Res. 2021;27:4757–67. source
• Not checked yetcites [179] Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, et al. Phase Ib study of Utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with Pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017;23:5349–57. source
• Not checked yetcites [180] Piha-Paul SA, Geva R, Tan TJ, Lim DW, Hierro C, Doi T, et al. First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas. J Immunother Cancer. 2021;9:e002863. source

In the paper

“In addition, in the phase 2 study NCT03563716, tiragolumab (α-TIGIT) plus atezolizumab showed an improvement in ORR (OR:2.57, 95%CI:1.07–6.14) and PFS (HR:0.57; 95%CI 0.37–0.90) in PD-L1 positive NSCLC, relative to placebo plus atezolizumab [167].”

What the sources say

• Not checked yetcites [167] Rodriguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.9503. source

In the paper

“Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models [157].”

What the sources say

• Not checked yetcites [157] Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–94. source

In the paper

“PD-1/PD-L1 blockade followed by osimertinib led to a higher incidence rate of irAE, while osimertinib followed by PD-1/PD-L1 blockade decreased the risk of irAE [194].”

What the sources say

• Not checked yetcites [194] Schoenfeld AJ, Arbour KC, Rizvi H, Iqbal AN, Gadgeel SM, Girshman J, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839–44. source

In the paper

“Overexpressed ALK fusion protein increased PD-L1 level, promoting the apoptosis of tumor-infiltrating T cells [201].”

What the sources say

• Not checked yetcites [201] Hong S, Chen N, Fang W, Zhan J, Liu Q, Kang S, et al. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology. 2016;5:e1094598. source

In the paper

“In the phase 1 trial CheckMate-012, nivolumab combined with erlotinib showed potent and durable antitumor activity in EGFR-mutated NSCLC patients, with tolerable adverse events (no grade 4/5 adverse event reported) (Table 6) [189].”

What the sources say

• Not checked yetcites [189] Gettinger S, Hellmann MD, Chow LQM, Borghaei H, Antonia S, Brahmer JR, et al. Nivolumab plus Erlotinib in patients with EGFR-mutant advanced NSCLC. J Thorac Oncol. 2018;13:1363–72. source

In the paper

“A retrospective analysis showed that the co-expression of PD-L1 and CD8 was rare in ALK-arranged tumors, which might contribute to the lower response rate to α-PD-1/PD-L1 [200].”

What the sources say

• Not checked yetcites [200] Liu SY, Dong ZY, Wu SP, Xie Z, Yan LX, Li YF, et al. Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. Lung Cancer. 2018;125:86–92. source

In the paper

“Upon the engagement with its ligands (such as epidermal growth factor, transforming growth factor-alpha, amphiregulin), EGFR would be homodimerized or heterodimerized [182].”

What the sources say

• Not checked yetcites [182] Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53. source

In the paper

“No pneumonitis and dose-limiting toxicity were reported in this study [190].”

What the sources say

• Not checked yetcites [190] Rudin C, Cervantes A, Dowlati A, Besse B, Ma B, Costa D, et al. P3.02c-046 safety, clinical activity and biomarker results from a phase Ib study of Erlotinib plus Atezolizumab in advanced NSCLC. J Thorac Oncol. 2017. https://doi.org/10.1016/j.jtho.2016.11.1841. source

In the paper

“ALK-TKI has dramatically prolonged the survival of ALK-arranged patients [198].”

What the sources say

• Not checked yetcites [198] Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, et al. First-line Lorlatinib or Crizotinib in advanced ALK-positive lung Cancer. N Engl J Med. 2020;383:2018–29. source

In the paper

“The constitutively activated ALK fusion gene promotes cancer development by initiating some oncogenic pathways including MAPK, PI3K-Akt, JAK-STAT, and PLCγ [197].”

What the sources say

• Not checked yetcites [197] Golding B, Luu A, Jones R, Viloria-Petit AM. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer. 2018;17:52. source

In the paper

“Besides, ALK inhibition induced immunogenic cell death in ALK-arranged cancer cells and conferred the protection of tumor rechallenge in the mouse model [202].”

What the sources say

• Not checked yetcites [202] Petrazzuolo A, Perez-Lanzon M, Martins I, Liu P, Kepp O, Minard-Colin V, et al. Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects. Cell Death Dis. 2021;12:713. source

In the paper

“In active state, RAS triggers several downstream pathways including MAPK and PI3K-AKT [209].”

What the sources say

• Not checked yetcites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source

In the paper

“EML4-ALK fusion is the most common ALK arrangement variant in NSCLC patients [196].”

What the sources say

• Not checked yetcites [196] Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res. 2015;21:2227–35. source

In the paper

“Conversely, some other combination strategies such as atezolizumab plus alectinib and avelumab plus lorlatinib had a manageable safety profile, indicating the hepatotoxicity might be ALK-TKI specific [205, 206].”

What the sources say

• Not checked yetcites [205] Kim D-W, Gadgeel SM, Gettinger SN, Riely GJ, Oxnard GR, Mekhail T, et al. Safety and clinical activity results from a phase Ib study of alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC). J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.9009. source
• Not checked yetcites [206] Shaw AT, Lee S-H, Ramalingam SS, Bauer TM, Boyer MJ, Costa EC, et al. Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN lung 101. J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.9008. source

In the paper

“Recent studies demonstrated that EGFR-TKI could promote T cell infiltration, decrease the ratios of tumor-infiltrating Treg and M2-like macrophage, and improve the responsiveness to α-PD-1/PD-L1 in EGFR-mutated models [17, 187].”

What the sources say

• Not checked yetcites [17] Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019;12:9527–38. source
• Not checked yetcites [187] Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci Immunol. 2020;5:eaav3937. source

In the paper

“ALK is a receptor tyrosine kinase belonging to insulin receptor superfamily [195].”

What the sources say

• Not checked yetcites [195] Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14:439–49. source

In the paper

“Mutated KRAS is a well-established driver gene of NSCLC, colorectal cancer, and pancreatic cancer [208].”

What the sources say

• Not checked yetcites [208] Hamarsheh S, Groß O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11:5439. source

In the paper

“In tumor cells, mutations in RAS disturb this switch between GTP-bound state and GDP-bound state. As a result, RAS is locked in GTP-bound state, leading to the hyperactive downstream pathways and tumor growth [209, 210].”

What the sources say

• Not checked yetcites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source
• Not checked yetcites [210] Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52. source

In the paper

“RAS is a small G protein, toggling between GTP-bound state (active) and GDP-bound state (inactive).”

What the sources say

• Not checked yetcites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source

In the paper

“Then, the cytoplasmic tyrosine kinases domain of EGFR is phosphorylated, triggering the activation of PI3K-AKT and MAPK pathways [182].”

What the sources say

• Not checked yetcites [182] Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53. source

In the paper

“CDK4/6 inhibitors promoted NF-κB activation, increased T cell chemoattractant and PD-L1 level, and prevented PD-L1 degradation in cancer cells [244].”

What the sources say

• Not checked yetcites [244] Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory effects of BRAF, MEK, and CDK4/6 inhibitors: implications for combining targeted therapy and immune checkpoint blockade for the treatment of melanoma. Front Immunol. 2021;12:661737. source

In the paper

“Besides synthetic lethal effect, PARP inhibitor (PARPi) modulates the TME and promotes the antitumor immune response [223].”

What the sources say

• Not checked yetcites [223] Stewart RA, Pilié PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations. Cancer Res. 2018;78:6717–25. source

In the paper

“In the phase 1 study NCT02660034, pamiparib plus tislelizumab was well-tolerated, and 20% of patients with advanced solid tumors achieved an objective response at a median follow-up of 8.3 months [226].”

What the sources say

• Not checked yetcites [226] Friedlander M, Meniawy T, Markman B, Mileshkin L, Harnett P, Millward M, et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 2019;20:1306–15. source

In the paper

“Besides, CDK4/6 inhibitors upregulated NFAT activity and elevated effector gene expression in T cells [244].”

What the sources say

• Not checked yetcites [244] Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory effects of BRAF, MEK, and CDK4/6 inhibitors: implications for combining targeted therapy and immune checkpoint blockade for the treatment of melanoma. Front Immunol. 2021;12:661737. source

In the paper

“Firstly, PARPi activates cGAS-STING pathway in cancer cells and increases T cell recruitment [224].”

What the sources say

• Not checked yetcites [224] Pantelidou C, Sonzogni O, De Oliveria TM, Mehta AK, Kothari A, Wang D, et al. PARP inhibitor efficacy depends on CD8(+) T-cell recruitment via Intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast Cancer. Cancer Discov. 2019;9:722–37. source

In the paper

“Mutant FGFR signaling might be related to the poor response to α-PD-1/PD-L1, and FGFR inhibitor synergized with α-PD-1/PD-L1 in FGFRmut models [234].”

What the sources say

• Not checked yetcites [234] Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res. 2019;7:1457–71. source

In the paper

“Moreover, in the phase 1/2 study KEYNOTE-162, niraparib plus pembrolizumab was tolerable, with a considerable antitumor efficacy in recurrent ovarian carcinoma (ORR: 18%; DCR: 65%) [228].”

What the sources say

• Not checked yetcites [228] Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, et al. Single-arm phases 1 and 2 trial of Niraparib in combination with Pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5:1141–9. source

In the paper

“c-MET signaling upregulated PD-L1 expression, and c-MET inhibitor impaired intrinsic and IFN-γ-induced PD-L1 expression [239–241].”

What the sources say

• Not checked yetcites [239] Saigi M, Alburquerque-Bejar JJ, Mc Leer-Florin A, Pereira C, Pros E, Romero OA, et al. MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung Cancer. Clin Cancer Res. 2018;24:4579–87. source
• Not checked yetcites [240] Balan M, Mier y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, et al. Novel roles of c-met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015;290:8110–20. source
• Not checked yetcites [241] Martin V, Chiriaco C, Modica C, Acquadro A, Cortese M, Galimi F, et al. Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours. Br J Cancer. 2019;120:527–36. source

In the paper

“The combination of erdafitinib (FGFR inhibitor) and α-PD-1 broadened the TCR repertoire and increased T cell fraction, contributing to the superior antitumor efficacy [234].”

What the sources say

• Not checked yetcites [234] Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res. 2019;7:1457–71. source

In the paper

“Recent studies have shown that RAS and its downstream pathways participated in cancer immune escape: negatively regulating MHC-I expression on cancer cells, increasing the cell-intrinsic PD-L1 level, elevating immune suppression-associated cytokine production [211, 212].”

What the sources say

• Not checked yetcites [211] Dennison L, Mohan AA, Yarchoan M. Tumor and systemic Immunomodulatory effects of MEK inhibition. Curr Oncol Rep. 2021;23:23. source
• Not checked yetcites [212] Nishida N. Role of oncogenic pathways on the Cancer immunosuppressive microenvironment and its clinical implications in hepatocellular carcinoma. Cancers (Basel). 2021;13:3666. source

In the paper

“Activated c-MET signaling triggers downstream MAPK, PI3K-AKT, RAC1, and FAK pathways [238].”

What the sources say

• Not checked yetcites [238] Fu J, Su X, Li Z, Deng L, Liu X, Feng X, et al. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene. 2021;40:4625–51. source

In the paper

“Cyclin-dependent kinase 4/6 (CDK4/6) is an essential component of cell cycle, which cooperates with cyclin D to promote cell cycle G1/S transition [243].”

What the sources say

• Not checked yetcites [243] Xu H, Yu S, Liu Q, Yuan X, Mani S, Pestell RG, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10:97. source

In the paper

“The interim results of phase 1/2 study NCT02393248 indicated pemigatinib (FGFR inhibitor) combined with pembrolizumab therapy was tolerable, with a potent antitumor effect in FGFRmut patients [236].”

What the sources say

• Not checked yetcites [236] Gutierrez M, Subbiah V, Nemunaitis JJ, Mettu NB, Papadopoulos KP, Barve MA, et al. Safety and efficacy of pemigatinib plus pembrolizumab combination therapy in patients (pts) with advanced malignancies: results from FIGHT-101, an open-label phase I/II study. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.3606. source

In the paper

“Then, STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I [257–259].”

What the sources say

• Not checked yetcites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source
• Not checked yetcites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source
• Not checked yetcites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

In the paper

“M7824 is a TGF-β × PD-L1 bifunctional protein, which had potent antitumor activity in murine tumor models (Fig. 2c) [278].”

What the sources say

• Not checked yetcites [278] Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018;10:eaan5488. source

In the paper

“On the one hand, STING agonist promotes immune cell infiltration and enhances the function of APC, NK, and T cells [272–274].”

What the sources say

• Not checked yetcites [272] Nakamura T, Sato T, Endo R, Sasaki S, Takahashi N, Sato Y, et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer. 2021;9:e002852. source
• Not checked yetcites [273] Yi M, Niu M, Zhang J, Li S, Zhu S, Yan Y, et al. Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers. J Hematol Oncol. 2021;14:146. source
• Not checked yetcites [274] Song Y, Liu Y, Teo HY, Hanafi ZB, Mei Y, Zhu Y, et al. Manganese enhances the antitumor function of CD8(+) T cells by inducing type I interferon production. Cell Mol Immunol. 2021;18:1571–4. source

In the paper

“SHP2 is an oncogenic protein belonging to protein tyrosine phosphatases family [250].”

What the sources say

• Not checked yetcites [250] Song Z, Wang M, Ge Y, Chen XP, Xu Z, Sun Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B. 2021;11:13–29. source

In the paper

“Stimulated by cGAMP, STING changes from monomer to dimer and translocates from ER to perinuclear microsome.”

What the sources say

• Not checked yetcites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source
• Not checked yetcites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source
• Not checked yetcites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

In the paper

“The results of phase 1 studies were encouraging, and patients receiving M7824 had a higher ORR, compared to previous data [303, 304].”

What the sources say

• Not checked yetcites [303] Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase I trial of M7824 (MSB0011359C), a Bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin Cancer Res. 2018;24:1287–95. source
• Not checked yetcites [304] Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, et al. Bintrafusp Alfa, a Bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J Thorac Oncol. 2020;15:1210–22. source

In the paper

“Bispecific/bifunctional antibody simultaneously blocks two molecules with one drug, having a strategic advantage over the combination therapy (Table 7) [277].”

What the sources say

• Not checked yetcites [277] Kontermann RE. Dual targeting strategies with bispecific antibodies. MAbs. 2012;4:182–97. source

In the paper

“The combination therapy of STING agonist and α-PD-1/PD-L1 simultaneously boosts innate immunity and adaptive immunity, effectively overcoming resistance to immunotherapy.”

In the paper

“cGAS-STING pathway is a cytosolic DNA sensing signaling.”

What the sources say

• Not checked yetcites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source
• Not checked yetcites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source
• Not checked yetcites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

In the paper

“Dimethyloxoxanthenyl acetic acid (DMXAA) is the first STING agonist which failed in the clinical trials [262].”

What the sources say

• Not checked yetcites [262] Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:2965–71. source

In the paper

“Besides, manganese is also identified as a natural STING agonist, playing an important role in antitumor immunity [270, 271].”

What the sources say

• Not checked yetcites [270] Lv M, Chen M, Zhang R, Zhang W, Wang C, Zhang Y, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30:966–79. source
• Not checked yetcites [271] Wang C, Guan Y, Lv M, Zhang R, Guo Z, Wei X, et al. Manganese increases the sensitivity of the cGAS-STING pathway for double-stranded DNA and is required for the host defense against DNA viruses. Immunity. 2018;48:675–87.e7. source

In the paper

“Further investigation has identified that DMXAA is a mouse-specific STING agonist, with a subtle influence on human STING pathway [263, 264].”

What the sources say

• Not checked yetcites [263] Shih AY, Damm-Ganamet KL, Mirzadegan T. Dynamic structural differences between human and mouse STING Lead to differing sensitivity to DMXAA. Biophys J. 2018;114:32–9. source
• Not checked yetcites [264] Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, et al. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol. 2013;190:5216–25. source

In the paper

“TGF-β is a well-studied immunoinhibitory cytokine: restraining immune cell infiltration, inducing Treg differentiation, and hampering the functions of T cell, APC, and NK [17].”

What the sources say

• Not checked yetcites [17] Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019;12:9527–38. source

In the paper

“Hyperactivated TGF-β signaling was associated with the poor response to α-PD-1/PD-L1, and blocking TGF-β significantly improved the efficacy of α-PD-1/PD-L1 [299–302].”

What the sources say

• Not checked yetcites [299] Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–43. source
• Not checked yetcites [300] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8. source
• Not checked yetcites [301] Chen X, Wang L, Li P, Song M, Qin G, Gao Q, et al. Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8(+) T cell response in esophageal squamous cell carcinoma. Int J Cancer. 2018;143:2561–74. source
• Not checked yetcites [302] Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14:55. source

In the paper

“The safety and efficacy of α-PD-1/PD-L1 combined with IL-2 pathway agonist (NKTR-214/BEMPEG) [321], PEGylated IL-10 (Pegilodecakin) [322], IL-12 plasmid (Tavo) [323], IL-15 agonist (ALT-803) [324], or PEGylated IFN-α [325] had been validated in cancer patients.”

What the sources say

• Not checked yetcites [321] Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. Bempegaldesleukin (NKTR-214) plus Nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10:1158–73. source
• Not checked yetcites [322] Naing A, Infante JR, Papadopoulos KP, Chan IH, Shen C, Ratti NP, et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8(+) T cell invigoration and polyclonal T cell expansion in Cancer patients. Cancer Cell. 2018;34:775–91.e3. source
• Not checked yetcites [323] Algazi AP, Twitty CG, Tsai KK, Le M, Pierce R, Browning E, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. Clin Cancer Res. 2020;26:2827–37. source

In the paper

“Besides, PD-1 × PD-L1 (LY3434172) and CD47 × PD-L1 (IBI322) bispecific antibodies had enhanced immunomodulatory properties and improved antitumor activity, relative to monospecific PD-1 and PD-L1 antibodies [297, 298].”

What the sources say

• Not checked yetcites [297] Kotanides H, Li Y, Malabunga M, Carpenito C, Eastman SW, Shen Y, et al. Bispecific targeting of PD-1 and PD-L1 enhances T-cell activation and antitumor immunity. Cancer Immunol Res. 2020;8:1300–10. source
• Not checked yetcites [298] Wang Y, Ni H, Zhou S, He K, Gao Y, Wu W, et al. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol Immunother. 2021;70:365–76. source

In the paper

“This antibody had an enhanced tumor specificity, reducing the risks of the indiscriminate reactivation of antitumor T cells and severe treatment-related adverse events [296].”

What the sources say

• Not checked yetcites [296] Koopmans I, Hendriks D, Samplonius DF, van Ginkel RJ, Heskamp S, Wierstra PJ, et al. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology. 2018;7:e1466016. source

In the paper

“Further investigation showed that YM101 promoted T cell infiltration, enhanced T cell function, impaired cancer-associated fibroblasts (CAF) activity, and induced macrophage polarization toward M2-like phenotype [279].”

What the sources say

• Not checked yetcites [279] Yi M, Zhang J, Li A, Niu M, Yan Y, Jiao Y, et al. The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1. J Hematol Oncol. 2021;14:27. source

In the paper

“c-MET×PD-1 bispecific antibodies simultaneously reversed c-Met-mediated cell proliferation and migration and enhanced T cell functions [292–295].”

What the sources say

• Not checked yetcites [292] Yuan Q, Liang Q, Sun Z, Yuan X, Hou W, Wang Y, et al. Development of bispecific anti-c-met/PD-1 diabodies for the treatment of solid tumors and the effect of c-met binding affinity on efficacy. Oncoimmunology. 2021;10:1914954. source
• Not checked yetcites [293] Hou W, Yuan Q, Yuan X, Wang Y, Mo W, Wang H, et al. A novel tetravalent bispecific antibody targeting programmed death 1 and tyrosine-protein kinase met for treatment of gastric cancer. Investig New Drugs. 2019;37:876–89. source
• Not checked yetcites [294] Wu Y, Yu M, Sun Z, Hou W, Wang Y, Yuan Q, et al. Generation and characterization of a Bispecific antibody targeting both PD-1 and c-MET. Protein Pept Lett. 2018;24:1105–12. source
• Not checked yetcites [295] Sun ZJ, Wu Y, Hou WH, Wang YX, Yuan QY, Wang HJ, et al. A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer. Oncotarget. 2017;8:29067–79. source

In the paper

“These bispecific antibodies augmented the functions of TILs and exerted a powerful antitumor efficacy [288–291].”

What the sources say

• Not checked yetcites [288] Geuijen C, Tacken P, Wang LC, Klooster R, van Loo PF, Zhou J, et al. A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat Commun. 2021;12:4445. source
• Not checked yetcites [289] Jeong S, Park E, Kim HD, Sung E, Kim H, Jeon J, et al. Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade. J Immunother Cancer. 2021;9:e002428. source
• Not checked yetcites [290] Zhai T, Wang C, Xu Y, Huang W, Yuan Z, Wang T, et al. Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer. J Immunother Cancer. 2021;9:e002131. source
• Not checked yetcites [291] Vitale LA, He LZ, Thomas LJ, Wasiuk A, O'Neill T, Widger J, et al. Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Cancer Immunol Immunother. 2020;69:2125–37. source

In the paper

“Moreover, avoiding ‘on-target/off-tumor’ binding to PD-L1 on nonmalignant cells, EGFR×PD-L1 bispecific antibody was developed for EGFR+ tumors [296].”

What the sources say

• Not checked yetcites [296] Koopmans I, Hendriks D, Samplonius DF, van Ginkel RJ, Heskamp S, Wierstra PJ, et al. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology. 2018;7:e1466016. source

In the paper

“Relative to widely used syngeneic murine models, humanized patient-derived models could provide a more precious efficacy evaluation.”

In the paper

“Although dozens of combination regimens exhibit potent antitumor activities in preclinical studies, some positive preclinical findings could not be validated in the clinic.”

In the paper

“However, the efficacy of CAR-T cell therapy is modest in most solid tumors, which is partly attributed to the immunosuppressive TME [340].”

What the sources say

• Not checked yetcites [340] Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J Hematol Oncol. 2020;13:54. source

In the paper

“Inappropriate combination treatments will expose patients to significantly higher toxicities.”

In the paper

“Considering the heterogeneity and evolution of tumors, liquid biopsy could dynamically monitor the immune landscape of the TME and provide a real-time biomarker for guiding precision immunotherapy [346].”

What the sources say

• Not checked yetcites [346] Zhang T, Agarwal A, Almquist RG, Runyambo D, Park S, Bronson E, et al. Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer. Biomark Res. 2021;9:14. source

In the paper

“Combining these therapies with α-PD-1/PD-L1 simultaneously boosts multiple processes in the cancer-immunity cycle, reshapes the TME, and substantially promotes the transformation from non-inflamed to inflamed tumors (Fig. 3).”

In the paper

“For patients with non-inflamed tumors, α-PD-1/PD-L1 monotherapy scarcely provides clinical benefits, and a personalized combination is needed to overcome drug resistance.”

In the paper

“CAR-T cell therapy provides numerous cancer-reactive T cells and overcomes MHC downregulation-mediated cancer immune evasion [339].”

What the sources say

• Not checked yetcites [339] Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10:78. source

In the paper

“The accumulated adenosine in the TME promotes cancer immune evasion, and A2AR blockade rescues immune cell function [335, 336].”

What the sources say

• Not checked yetcites [335] Borodovsky A, Barbon CM, Wang Y, Ye M, Prickett L, Chandra D, et al. Small molecule AZD4635 inhibitor of a(2A)R signaling rescues immune cell function including CD103(+) dendritic cells enhancing anti-tumor immunity. J Immunother Cancer. 2020;8:e000417. source
• Not checked yetcites [336] Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer. 2018;6:57. source

In the paper

“CAR-T cells are genetically engineered T cells, which could recognize and bind cancer antigen in an MHC-independent manner [339].”

What the sources say

• Not checked yetcites [339] Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10:78. source

In the paper

“Besides, with the development of next-generation α-PD-1/PD-L1 drugs such as bifunctional or bispecific antibodies, the indication of α-PD-1/PD-L1 therapies would be greatly extended, and more patients could benefit from the updated α-PD-1/PD-L1 treatments.”

In the paper

“This combination strategy protects CAR-T cells from immune exhaustion and optimizes CAR-T cell efficacy.”